references.bib

@article{vegan2018,
title = {{vegan: Community Ecology Package}},
author = {Jari Oksanen and F. Guillaume Blanchet and Michael Friendly and Roeland Kindt and Pierre Legendre and Dan McGlinn and Peter R. Minchin and R. B. O'Hara and Gavin L. Simpson and Peter Solymos and M. Henry H. Stevens and Eduard Szoecs and Helene Wagner},
year = {2018},
note = {R package version 2.4-6},
url = {https://CRAN.R-project.org/package=vegan}
}
@article{Abraham2017,
abstract = {Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation. IAFGP thereby perturbs the tick gut microbiota, which influences the integrity of the peritrophic matrix and gut barrier-critical obstacles for Anaplasma colonization. Mechanistically, IAFGP binds the terminal d-alanine residue of the pentapeptide chain of bacterial peptidoglycan, resulting in altered permeability and the capacity of bacteria to form biofilms. These data elucidate the molecular mechanisms by which a human pathogen appropriates an arthropod antibacterial protein to alter the gut microbiota and more effectively colonize the vector.},
author = {Abraham, Nabil M. and Liu, Lei and Jutras, Brandon Lyon and Yadav, Akhilesh K. and Narasimhan, Sukanya and Gopalakrishnan, Vissagan and Ansari, Juliana M. and Jefferson, Kimberly K. and Cava, Felipe and Jacobs-Wagner, Christine and Fikrig, Erol},
doi = {10.1073/pnas.1613422114},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
pages = {201613422},
pmid = {28096373},
title = {{Pathogen-mediated manipulation of arthropod microbiota to promote infection}},
url = {http://www.pnas.org/lookup/doi/10.1073/pnas.1613422114},
year = {2017}
}
@article{Adlerberth2014,
abstract = {Clostridium difficile is a colonizer of the human gut, and toxin-producing strains may cause diarrhea if the infectious burden is heavy. Infants are more frequently colonized than adults, but they rarely develop C. difficile disease. It is not known whether strains of C. difficile differ in the capacity to colonize and persist in the human gut microbiota. Here, we strain typed isolates of C. difficile that had colonized 42 healthy infants followed from birth to ≥12 months of age by using PCR ribotyping of the 16S-23S rRNA intergenic spacer region. The isolates were also characterized regarding carriage of the toxin genes tcdA, tcdB, and cdtA/B and the capacity to produce toxin B in vitro. Most strains (71{\%}) were toxin producers, and 51{\%} belonged to the 001 or 014 ribotypes, which often cause disease in adults. These ribotypes were significantly more likely than others to persist for ≥6 months in the infant micobiota, and they were isolated from 13/15 children carrying such long-term-colonizing strains. Ribotype 001 strains were often acquired in the first week of life and attained higher population counts than other C. difficile ribotypes in newborn infants' feces. Several toxin-negative ribotypes were identified, two of which (GI and GIII) were long-term colonizers, each found in one infant. Our results suggest that the toxin-producing C. difficile ribotypes 001 and 014 have special fitness in the infantile gut microbiota. Toxin-producing strains colonizing young children for long time periods may represent a reservoir for strains causing disease in adults.},
author = {Adlerberth, Ingegerd and Huang, Haihui and Lindberg, Erika and {\AA}berg, Nils and Hesselmar, Bill and Saalman, Robert and Nord, Carl Erik and Wold, Agnes E. and Weintraubb, Andrej},
doi = {10.1128/JCM.01701-13},
isbn = {0095-1137},
issn = {00951137},
journal = {Journal of Clinical Microbiology},
number = {1},
pages = {173--179},
pmid = {24172156},
title = {{Toxin-Producing clostridium difficile strains as long-term gut colonizers in healthy infants}},
volume = {52},
year = {2014}
}
@article{Antharam2016,
abstract = {Clostridium difficile infection (CDI) is characterized by dysbiosis of the intestinal microbiota and a profound derangement in the fecal metabolome. However, the contribution of specific gut microbes to fecal metabolites in C. difficile-associated gut microbiome remains poorly understood. Using gas-chromatography mass spectrometry (GC-MS) and 16S rRNA deep sequencing, we analyzed the metabolome and microbiome of fecal samples obtained longitudinally from subjects with Clostridium difficile infection (n = 7) and healthy controls (n = 6). From 155 fecal metabolites, we identified two sterol metabolites at {\textgreater}95{\%} match to cholesterol and coprostanol that significantly discriminated C. difficile-associated gut microbiome from healthy microbiota. By correlating the levels of cholesterol and coprostanol in fecal extracts with 2,395 bacterial operational taxonomic units (OTUs) determined by 16S rRNA sequencing, we identified 63 OTUs associated with high levels of coprostanol and 2 OTUs correlated with low coprostanol levels. Using indicator species analysis (ISA), 31 of the 63 coprostanol-associated bacteria correlated with health, and two Veillonella species were associated with low coprostanol levels that correlated strongly with CDI. These 65 bacterial taxa could be clustered into 12 sub-communities, with each community containing a consortium of organisms that co-occurred with one another. Our studies identified 63 human gut microbes associated with cholesterol-reducing activities. Given the importance of gut bacteria in reducing and eliminating cholesterol from the GI tract, these results support the recent finding that gut microbiome may play an important role in host lipid metabolism.},
author = {Antharam, Vijay C. and McEwen, Daniel C. and Garrett, Timothy J. and Dossey, Aaron T. and Li, Eric C. and Kozlov, Andrew N. and Mesbah, Zhubene and Wang, Gary P.},
doi = {10.1371/journal.pone.0148824},
isbn = {10.1371/journal.pone.0148824},
issn = {19326203},
journal = {PLoS ONE},
number = {2},
pmid = {26871580},
title = {{An integrated metabolomic and microbiome analysis identified specific gut microbiota associated with fecal cholesterol and coprostanol in Clostridium difficile infection}},
volume = {11},
year = {2016}
}
@article{Antonopoulos2009,
abstract = {Shifts in microbial communities are implicated in the pathogenesis of a number of gastrointestinal diseases, but we have limited understanding of the mechanisms that lead to altered community structures. One difficulty with studying these mechanisms in human subjects is the inherent baseline variability of the microbiota in different individuals. In an effort to overcome this baseline variability, we employed a mouse model to control the host genotype, diet, and other possible influences on the microbiota. This allowed us to determine whether the indigenous microbiota in such mice had a stable baseline community structure and whether this community exhibited a consistent response following antibiotic administration. We employed a tag-sequencing strategy targeting the V6 hypervariable region of the bacterial small-subunit (16S) rRNA combined with massively parallel sequencing to determine the community structure of the gut microbiota. Inbred mice in a controlled environment harbored a reproducible baseline community that was significantly impacted by antibiotic administration. The ability of the gut microbial community to recover to baseline following the cessation of antibiotic administration differed according to the antibiotic regimen administered. Severe antibiotic pressure resulted in reproducible, long-lasting alterations in the gut microbial community, including a decrease in overall diversity. The finding of stereotypic responses of the indigenous microbiota to ecologic stress suggests that a better understanding of the factors that govern community structure could lead to strategies for the intentional manipulation of this ecosystem so as to preserve or restore a healthy microbiota.},
author = {Antonopoulos, Dionysios A. and Huse, Susan M. and Morrison, Hilary G. and Schmidt, Thomas M. and Sogin, Mitchell L. and Young, Vincent B.},
doi = {10.1128/IAI.01520-08},
isbn = {1098-5522 (Electronic)$\backslash$n0019-9567 (Linking)},
issn = {00199567},
journal = {Infection and Immunity},
number = {6},
pages = {2367--2375},
pmid = {19307217},
title = {{Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation}},
volume = {77},
year = {2009}
}
@article{Antunes2011,
abstract = {The importance of the mammalian intestinal microbiota to human health has been intensely studied over the past few years. It is now clear that the interactions between human hosts and their associated microbial communities need to be characterized in molecular detail if we are to truly understand human physiology. Additionally, the study of such host-microbe interactions is likely to provide us with new strategies to manipulate these complex systems to maintain or restore homeostasis in order to prevent or cure pathological states. Here, we describe the use of high-throughput metabolomics to shed light on the interactions between the intestinal microbiota and the host. We show that antibiotic treatment disrupts intestinal homeostasis and has a profound impact on the intestinal metabolome, affecting the levels of over 87{\%} of all metabolites detected. Many metabolic pathways that are critical for host physiology were affected, including bile acid, eicosanoid, and steroid hormone synthesis. Dissecting the molecular mechanisms involved in the impact of beneficial microbes on some of these pathways will be instrumental in understanding the interplay between the host and its complex resident microbiota and may aid in the design of new therapeutic strategies that target these interactions.},
author = {Antunes, L. Caetano M and Han, Jun and Ferreira, Rosana B R and Loli, Petra and Borchers, Christoph H. and Finlay, B. Brett},
doi = {10.1128/AAC.01664-10},
isbn = {0066-4804},
issn = {00664804},
journal = {Antimicrobial Agents and Chemotherapy},
number = {4},
pages = {1494--1503},
pmid = {21282433},
title = {{Effect of antibiotic treatment on the intestinal metabolome}},
volume = {55},
year = {2011}
}
@article{Bignardi1998,
abstract = {A systematic review of the literature to identify risk factors associated with Clostridium difficile infection was conducted. Two main outcomes were considered: C. difficile diarrhoea and C. difficile carriage. A qualitative assessment, based on a set of defined and consistently applied criteria, appeared to be the best approach for risk factors other than antibiotic use, as an approach based on meta-analysis would have utilized only the information provided by a minority of the studies. Risk factors for which there was evidence suggestive or consistent with an association with C. difficile diarrhoea were: increasing age (excluding infancy), severity of underlying diseases, non-surgical gastrointestinal procedures, presence of a nasogastric tube, anti-ulcer medications, stay on ITU, duration of hospital stay, duration of antibiotic course, administration of multiple antibiotics. For malignant haematological disorders there was evidence of an association only with C. difficile carriage, but there were no suitable studies to explore a possible association of this risk factor with symptomatic infection. Antibiotic use lent itself to quantitative assessment with meta-analysis using logistic regression. Exposure to an antibiotic was shown to be statistically significantly associated with both C. difficile diarrhoea and C. difficile carriage. The meta-analysis approach enabled the ranking of individual antibiotics in relation to the risk of C. difficile infection, though the 95{\%} confidence intervals were often wide and overlapping. Antibiotics associated with a lower risk of C. difficile diarrhoea should be considered, especially when attempting to control a C. difficile outbreak or when prescribing for a patient with other C. difficile risk factors. This systematic review of the literature enabled the identification of features it would be desirable to consider in future epidemiological studies.},
author = {Bignardi, G.E.},
doi = {10.1016/S0195-6701(98)90019-6},
isbn = {0195-6701},
issn = {01956701},
journal = {Journal of Hospital Infection},
number = {1},
pages = {1--15},
pmid = {9777516},
title = {{Risk factors for Clostridium difficile infection}},
volume = {40},
year = {1998}
}
@article{Bouillaut2015,
abstract = {Synthesis of the major toxin proteins of the diarrheal pathogen, Clostridium difficile, is dependent on the activity of TcdR, an initiation (sigma) factor of RNA polymerase. The synthesis of TcdR and the activation of toxin gene expression are responsive to multiple components in the bacterium's nutritional environment, such as the presence of certain sugars, amino acids, and fatty acids. This review summarizes current knowledge about the mechanisms responsible for repression of toxin synthesis when glucose or branched-chain amino acids or proline are in excess and the pathways that lead to synthesis of butyrate, an activator of toxin synthesis. The regulatory proteins implicated in these mechanisms also play key roles in modulating bacterial metabolic pathways, suggesting that C. difficile pathogenesis is intimately connected to the bacterium's metabolic state.},
archivePrefix = {arXiv},
arxivId = {15334406},
author = {Bouillaut, Laurent and Dubois, Thomas and Sonenshein, Abraham L. and Dupuy, Bruno},
doi = {10.1016/j.resmic.2014.10.002},
eprint = {15334406},
isbn = {10.1128/JB.00341-10},
issn = {17697123},
journal = {Research in Microbiology},
keywords = {Clostridium difficile,Metabolic regulation,Redox state,Stickland metabolism,Toxinogenesis},
number = {4},
pages = {375--383},
pmid = {20709897},
title = {{Integration of metabolism and virulence in Clostridium difficile}},
volume = {166},
year = {2015}
}
@article{Bouillaut2013,
abstract = {Clostridium difficile, a proteolytic Gram-positive anaerobe, has emerged as a significant nosocomial pathogen. Stickland fermentation reactions are thought to be important for growth of C. difficile and appear to influence toxin production. In Stickland reactions, pairs of amino acids donate and accept electrons, generating ATP and reducing power in the process. Reduction of the electron acceptors proline and glycine requires the d-proline reductase (PR) and the glycine reductase (GR) enzyme complexes, respectively. Addition of proline in the medium increases the level of PR protein but decreases the level of GR. We report the identification of PrdR, a protein that activates transcription of the PR-encoding genes in the presence of proline and negatively regulates the GR-encoding genes. The results suggest that PrdR is a central metabolism regulator that controls preferential utilization of proline and glycine to produce energy via the Stickland reactions.},
author = {Bouillaut, Laurent and Self, William T. and Sonenshein, Abraham L.},
doi = {10.1128/JB.01492-12},
isbn = {1098-5530 (Electronic)$\backslash$r0021-9193 (Linking)},
issn = {00219193},
journal = {Journal of Bacteriology},
number = {4},
pages = {844--854},
pmid = {23222730},
title = {{Proline-dependent regulation of Clostridium difficile stickland metabolism}},
volume = {195},
year = {2013}
}
@article{Breiman2001,
abstract = {Random forests are a combination of tree predictors such that each tree depends on the values of a random vector sampled independently and with the same distribution for all trees in the forest. The generalization error for forests converges a.s. to a limit as the number of trees in the forest becomes large. The generalization error of a forest of tree classifiers depends on the strength of the individual trees in the forest and the corre-lation between them. Using a random selection of features to split each node yields error rates that compare favorably to Adaboost (Y. Freund {\&} R. Schapire, Machine Learning: Proceedings of the Thirteenth Interna-tional conference, * * * , 148–156), but are more robust with respect to noise. Internal estimates monitor error, strength, and correlation and these are used to show the response to increasing the number of features used in the splitting. Internal estimates are also used to measure variable importance. These ideas are also applicable to regression.},
archivePrefix = {arXiv},
arxivId = {http://dx.doi.org/10.1023{\%}2FA{\%}3A1010933404324},
author = {Breiman, Leo},
doi = {10.1023/A:1010933404324},
eprint = {/dx.doi.org/10.1023{\%}2FA{\%}3A1010933404324},
isbn = {0885-6125},
issn = {08856125},
journal = {Machine Learning},
keywords = {Classification,Ensemble,Regression},
number = {1},
pages = {5--32},
pmid = {21816105},
primaryClass = {http:},
title = {{Random forests}},
volume = {45},
year = {2001}
}
@article{Britton2012,
abstract = {Clostridium difficile infection (CDI) has become one of the most prevalent and costly nosocomial infections. In spite of the importance of CDI, our knowledge of the pathogenesis of this infection is still rudimentary. Although previous use of antibiotics is generally considered to be the sine qua non of CDI, the mechanisms by which antibiotics render the host susceptible to C. difficile are not well defined. In this review, we will explore what is known about how the indigenous microbiota acts in concert with the host to prevent colonization and virulence of C. difficile and how antibiotic administration disturbs host-microbiota homeostasis, leading to CDI.},
archivePrefix = {arXiv},
arxivId = {NIHMS150003},
author = {Britton, Robert A and Young, Vincent B},
doi = {10.1016/j.tim.2012.04.001},
eprint = {NIHMS150003},
isbn = {1878-4380 (Electronic)$\backslash$r0966-842X (Linking)},
issn = {1878-4380},
journal = {Trends in microbiology},
keywords = {Anti-Bacterial Agents,Anti-Bacterial Agents: adverse effects,Anti-Bacterial Agents: therapeutic use,Clostridium Infections,Clostridium Infections: chemically induced,Clostridium Infections: microbiology,Clostridium difficile,Clostridium difficile: pathogenicity,Cross Infection,Cross Infection: chemically induced,Cross Infection: microbiology,Gastrointestinal Tract,Gastrointestinal Tract: microbiology,Humans,Metagenome,Metagenome: drug effects,Microbial Interactions},
number = {7},
pages = {313--9},
pmid = {22595318},
title = {{Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3408078{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {20},
year = {2012}
}
@article{Brown2013,
abstract = {c The rising incidence of Clostridium difficile infection (CDI) could be reduced by lowering exposure to high-risk antibiotics. The objective of this study was to determine the association between antibiotic class and the risk of CDI in the community setting. The EMBASE and PubMed databases were queried without restriction to time period or language. Comparative observational studies and randomized controlled trials (RCTs) considering the impact of exposure to antibiotics on CDI risk among nonhospi-talized populations were considered. We estimated pooled odds ratios (OR) for antibiotic classes using random-effect meta-analysis. Our search criteria identified 465 articles, of which 7 met inclusion criteria; all were observational studies. Five studies considered antibiotic risk relative to no antibiotic exposure: clindamycin (OR ‫؍‬ 16.80; 95{\%} confidence interval [95{\%} CI], 7.48 to 37.76), fluoroquinolones (OR ‫؍‬ 5.50; 95{\%} CI, 4.26 to 7.11), and cephalosporins, monobactams, and carbapenems (CMCs) (OR ‫؍‬ 5.68; 95{\%} CI, 2.12 to 15.23) had the largest effects, while macrolides (OR ‫؍‬ 2.65; 95{\%} CI, 1.92 to 3.64), sulfonamides and trimethoprim (OR ‫؍‬ 1.81; 95{\%} CI, 1.34 to 2.43), and penicillins (OR ‫؍‬ 2.71; 95{\%} CI, 1.75 to 4.21) had lower associations with CDI. We noted no effect of tetracyclines on CDI risk (OR ‫؍‬ 0.92; 95{\%} CI, 0.61 to 1.40). In the community setting, there is sub-stantial variation in the risk of CDI associated with different antimicrobial classes. Avoidance of high-risk antibiotics (such as clindamycin, CMCs, and fluoroquinolones) in favor of lower-risk antibiotics (such as penicillins, macrolides, and tetracyclines) may help reduce the incidence of CDI.},
author = {Brown, Kevin A. and Khanafer, Nagham and Daneman, Nick and Fisman, David N.},
doi = {10.1128/AAC.02176-12},
isbn = {0066-4804},
issn = {00664804},
journal = {Antimicrobial Agents and Chemotherapy},
number = {5},
pages = {2326--2332},
pmid = {23478961},
title = {{Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection}},
volume = {57},
year = {2013}
}
@article{Buchfink2015,
abstract = {The alignment of sequencing reads against a protein reference database is a major computational bottleneck in metagenomics and data-intensive evolutionary projects. Although recent tools offer improved performance over the gold standard BLASTX, they exhibit only a modest speedup or low sensitivity. We introduce DIAMOND, an open-source algorithm based on double indexing that is 20,000 times faster than BLASTX on short reads and has a similar degree of sensitivity.},
author = {Buchfink, Benjamin and Xie, Chao and Huson, Daniel H},
doi = {10.1038/nmeth.3176},
isbn = {1548-7091},
issn = {1548-7105},
journal = {Nature methods},
number = {1},
pages = {59--60},
pmid = {25402007},
title = {{Fast and sensitive protein alignment using DIAMOND.}},
url = {http://www.nature.com/doifinder/10.1038/nmeth.3176$\backslash$nhttp://dx.doi.org/10.1038/nmeth.3176$\backslash$nhttp://www.nature.com/doifinder/10.1038/nmeth.3176$\backslash$nhttp://www.ncbi.nlm.nih.gov/pubmed/25402007},
volume = {12},
year = {2015}
}
@article{Buffie2014,
abstract = {The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7$\alpha$-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.},
author = {Buffie, Charlie G. and Bucci, Vanni and Stein, Richard R. and McKenney, Peter T. and Ling, Lilan and Gobourne, Asia and No, Daniel and Liu, Hui and Kinnebrew, Melissa and Viale, Agnes and Littmann, Eric and van den Brink, Marcel R. M. and Jenq, Robert R. and Taur, Ying and Sander, Chris and Cross, Justin R. and Toussaint, Nora C. and Xavier, Joao B. and Pamer, Eric G.},
doi = {10.1038/nature13828},
isbn = {0028-0836},
issn = {0028-0836},
journal = {Nature},
number = {7533},
pages = {205--208},
pmid = {25337874},
title = {{Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile}},
url = {http://www.nature.com/doifinder/10.1038/nature13828},
volume = {517},
year = {2014}
}
@article{Buffie2012,
abstract = {Antibiotic-induced changes in the intestinal microbiota predispose mammalian hosts to infection with antibiotic-resistant pathogens. Clostridium difficile is a Gram-positive intestinal pathogen that causes colitis and diarrhea in patients following antibiotic treatment. Clindamycin predisposes patients to C. difficile colitis. Here, we have used Roche-454 16S rRNA gene pyrosequencing to longitudinally characterize the intestinal microbiota of mice following clindamycin treatment in the presence or absence of C. difficile infection. We show that a single dose of clindamycin markedly reduces the diversity of the intestinal microbiota for at least 28 days, with an enduring loss of ca. 90{\%} of normal microbial taxa from the cecum. Loss of microbial complexity results in dramatic sequential expansion and contraction of a subset of bacterial taxa that are minor contributors to the microbial consortium prior to antibiotic treatment. Inoculation of clindamycin-treated mice with C. difficile (VPI 10463) spores results in rapid development of diarrhea and colitis, with a 4- to 5-day period of profound weight loss and an associated 40 to 50{\%} mortality rate. Recovering mice resolve diarrhea and regain weight but remain highly infected with toxin-producing vegetative C. difficile bacteria and, in comparison to the acute stage of infection, have persistent, albeit ameliorated cecal and colonic inflammation. The microbiota of "recovered" mice remains highly restricted, and mice remain susceptible to C. difficile infection at least 10 days following clindamycin, suggesting that resolution of diarrhea and weight gain may result from the activation of mucosal immune defenses.},
author = {Buffie, Charlie G. and Jarchum, Irene and Equinda, Michele and Lipuma, Lauren and Gobourne, Asia and Viale, Agnes and Ubeda, Carles and Xavier, Joao and Pamer, Eric G.},
doi = {10.1128/IAI.05496-11},
isbn = {1098-5522 (Electronic)$\backslash$r0019-9567 (Linking)},
issn = {00199567},
journal = {Infection and Immunity},
number = {1},
pages = {62--73},
pmid = {22006564},
title = {{Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis}},
volume = {80},
year = {2012}
}
@article{Calle2011,
abstract = {OBJECTIVE Genomic profiling, the use of genetic variants at multiple loci simultaneously for the prediction of disease risk, requires the selection of a set of genetic variants that best predicts disease status. The goal of this work was to provide a new selection algorithm for genomic profiling. METHODS We propose a new algorithm for genomic profiling based on optimizing the area under the receiver operating characteristic curve (AUC) of the random forest (RF). The proposed strategy implements a backward elimination process based on the initial ranking of variables. RESULTS AND CONCLUSIONS We demonstrate the advantage of using the AUC instead of the classification error as a measure of predictive accuracy of RF. In particular, we show that the use of the classification error is especially inappropriate when dealing with unbalanced data sets. The new procedure for variable selection and prediction, namely AUC-RF, is illustrated with data from a bladder cancer study and also with simulated data. The algorithm is publicly available as an R package, named AUCRF, at http://cran.r-project.org/.},
author = {Calle, M. Luz and Urrea, Victor and Boulesteix, Anne Laure and Malats, Nuria},
doi = {10.1159/000330778},
isbn = {0001-5652},
issn = {00015652},
journal = {Human Heredity},
keywords = {AUC,Gene identification,Genomic profile,ROC curve,Random forest,Variable selection},
number = {2},
pages = {121--132},
pmid = {21996641},
title = {{AUC-RF: A new strategy for genomic profiling with random forest}},
volume = {72},
year = {2011}
}
@article{Cole2015,
abstract = {Clostridium difficile infection (CDI) is the most frequent cause of nosocomial diarrhea. It has become a significant dilemma in the treatment of patients, and causes increasing morbidity that, in extreme cases, may result in death. Persistent and recurrent disease hamper attempts at eradication of this infection. Escalating levels of treatment and novel therapeutics are being utilized and developed to treat CDI. Further trials are warranted to definitively determine what protocols can be used to treat persistent and recurrent disease.},
author = {Cole, Shola A and Stahl, Thomas J},
doi = {10.1055/s-0035-1547333},
issn = {1531-0043},
journal = {Clinics in colon and rectal surgery},
number = {2},
pages = {65--9},
pmid = {26034401},
title = {{Persistent and Recurrent Clostridium difficile Colitis.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/26034401},
volume = {28},
year = {2015}
}
@article{Dai2015,
abstract = {Reproduction is vital for producing offspring and preserving genetic resources. However, incidences of many reproductive disorders (e.g. miscarriage, intrauterine growth restriction, premature delivery and lower sperm quality) have either increased dramatically or remained at high rates over the last decades. Mounting evidence shows a strong correlation between enteral protein nutrition and reproduction. Besides serving as major nutrients in the diet, amino acids (AA) are signaling molecules in the regulation of diverse physiological processes, ranging from spermatogenesis to oocyte fertilization and to embryo implantation. Notably, the numbers of bacteria in the intestine exceed the numbers of host cells by 10 times. Microbes in the small-intestinal lumen actively metabolize large amounts of dietary AA and, therefore, affect the entry of AA into the portal circulation for whole-body utilization. Changes in the composition and abundance of AA-metabolizing bacteria in the gut during pregnancy, as well as their translocation to the uterus, may alter uterine function and epigenetic modifications of maternal physiology and metabolism, which are crucial for pregnancy recognition and fetal development. Thus, the presence of the maternal gut microbiota and AA metabolites in the intrauterine environments (e.g. endometrium and placenta) and breast milk is likely a unique signature for the programming of the whole-body microbiome and metabolism in both the fetus and infant. Dietary intervention with functional AA, probiotics and prebiotics to alter the abundance and activity of intestinal bacteria may ameliorate or prevent the development of metabolic syndrome, while improving reproductive performance in both males and females as well as their offspring.},
author = {Dai, Zhaolai and Wu, Zhenlong and Hang, Suqin and Zhu, Weiyun and Wu, Guoyao},
doi = {10.1093/molehr/gav003},
isbn = {1360-9947},
issn = {1460-2407},
journal = {Molecular human reproduction},
keywords = {amino acids,bacteria,intestine,metabolism,reproduction},
mendeley-groups = {Metatranscriptomics paper},
number = {5},
pages = {389--409},
pmid = {25609213},
title = {{Amino acid metabolism in intestinal bacteria and its potential implications for mammalian reproduction.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/25609213},
volume = {21},
year = {2015}
}
@article{Fekety1979,
abstract = {Fifteen isolates of Clostridium difficile  from hamsters and human patients were inhibited or killed by low concentrations of metronidazole, vancomycin, penicillin, and ampicillin; the isolates were often reesistant to tetracycline, cephalosporins, trimethoprim-sulfamethoxazole, clindamycin, erythromycin, and aminoglycosides. Antibiotics to which C. difficile was susceptible were able to prevent or postpone the colitis caused by clindamycin in hamsters. Colitis could be produced by treatment of hamsters with any one of these antibiotics. Production of colitis not only involved selection of resistant variants, but in some instances seemed to result from the acquisition of organisms after treatment, their persistence despite treatment, or from subinhibitory cecal concentrations of antibiotic (explainable by either pharmacologic factors or enzymatic inactivation). As in humans, no organisms other than C. difficile have been implicated conclusively as etiologic agents of colitis in hamsters. Our results suggest it may be wise to use isolation precautions for patients with colitis caused by C. difficile.},
author = {Fekety, Robert and Silva, Joseph and Toshniwal, Renu and Allo, Maria and Armstrong, John and Browne, Robert and Ebright, John and Rifkin, Gary},
doi = {10.1093/clinids/1.2.386},
isbn = {0162-0886 (Print)},
issn = {01620886},
journal = {Reviews of Infectious Diseases},
number = {2},
pages = {386--397},
pmid = {549190},
title = {{Antibiotic-associated colitis: Effects of antibiotics on clostridium difficile and the disease in hamsters}},
volume = {1},
year = {1979}
}
@article{Fonknechten2010,
abstract = {BACKGROUND: Clostridium sticklandii belongs to a cluster of non-pathogenic proteolytic clostridia which utilize amino acids as carbon and energy sources. Isolated by T.C. Stadtman in 1954, it has been generally regarded as a "gold mine" for novel biochemical reactions and is used as a model organism for studying metabolic aspects such as the Stickland reaction, coenzyme-B12- and selenium-dependent reactions of amino acids. With the goal of revisiting its carbon, nitrogen, and energy metabolism, and comparing studies with other clostridia, its genome has been sequenced and analyzed.$\backslash$n$\backslash$nRESULTS: C. sticklandii is one of the best biochemically studied proteolytic clostridial species. Useful additional information has been obtained from the sequencing and annotation of its genome, which is presented in this paper. Besides, experimental procedures reveal that C. sticklandii degrades amino acids in a preferential and sequential way. The organism prefers threonine, arginine, serine, cysteine, proline, and glycine, whereas glutamate, aspartate and alanine are excreted. Energy conservation is primarily obtained by substrate-level phosphorylation in fermentative pathways. The reactions catalyzed by different ferredoxin oxidoreductases and the exergonic NADH-dependent reduction of crotonyl-CoA point to a possible chemiosmotic energy conservation via the Rnf complex. C. sticklandii possesses both the F-type and V-type ATPases. The discovery of an as yet unrecognized selenoprotein in the D-proline reductase operon suggests a more detailed mechanism for NADH-dependent D-proline reduction. A rather unusual metabolic feature is the presence of genes for all the enzymes involved in two different CO2-fixation pathways: C. sticklandii harbours both the glycine synthase/glycine reductase and the Wood-Ljungdahl pathways. This unusual pathway combination has retrospectively been observed in only four other sequenced microorganisms.$\backslash$n$\backslash$nCONCLUSIONS: Analysis of the C. sticklandii genome and additional experimental procedures have improved our understanding of anaerobic amino acid degradation. Several specific metabolic features have been detected, some of which are very unusual for anaerobic fermenting bacteria. Comparative genomics has provided the opportunity to study the lifestyle of pathogenic and non-pathogenic clostridial species as well as to elucidate the difference in metabolic features between clostridia and other anaerobes.},
author = {Fonknechten, Nuria and Chaussonnerie, S{\'{e}}bastien and Tricot, Sabine and Lajus, Aur{\'{e}}lie and Andreesen, Jan R and Perchat, Nadia and Pelletier, Eric and Gouyvenoux, Michel and Barbe, Val{\'{e}}rie and Salanoubat, Marcel and {Le Paslier}, Denis and Weissenbach, Jean and Cohen, Georges N and Kreimeyer, Annett},
doi = {10.1186/1471-2164-11-555},
isbn = {1471216411},
issn = {1471-2164},
journal = {BMC genomics},
keywords = {Amino Acid Oxidoreductases,Amino Acid Oxidoreductases: metabolism,Amino Acid Sequence,Amino Acids,Amino Acids: metabolism,Bacterial,Bacterial Proteins,Bacterial Proteins: chemistry,Bacterial Proteins: genetics,Bacterial Proteins: metabolism,Bacterial: genetics,Base Sequence,Chromatography,Clostridium sticklandii,Clostridium sticklandii: enzymology,Clostridium sticklandii: genetics,Clostridium sticklandii: growth {\&} development,Clostridium sticklandii: metabolism,Conserved Sequence,Conserved Sequence: genetics,Energy Metabolism,Energy Metabolism: genetics,Genome,Liquid,Mass Spectrometry,Metabolic Networks and Pathways,Metabolic Networks and Pathways: genetics,Molecular Sequence Data,Multienzyme Complexes,Multienzyme Complexes: metabolism,Multigene Family,Multigene Family: genetics,Oxidative Stress,Oxidative Stress: genetics,Selenocysteine,Selenocysteine: metabolism,Sequence Alignment,Synteny,Synteny: genetics},
pages = {555},
pmid = {20937090},
title = {{Clostridium sticklandii, a specialist in amino acid degradation:revisiting its metabolism through its genome sequence.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3091704{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {11},
year = {2010}
}
@article{Franzosa2014,
abstract = {Although the composition of the human microbiome is now well-studied, the microbiota's {\textgreater}8 million genes and their regulation remain largely uncharacterized. This knowledge gap is in part because of the difficulty of acquiring large numbers of samples amenable to functional studies of the microbiota. We conducted what is, to our knowledge, one of the first human microbiome studies in a well-phenotyped prospective cohort incorporating taxonomic, metagenomic, and metatranscriptomic profiling at multiple body sites using self-collected samples. Stool and saliva were provided by eight healthy subjects, with the former preserved by three different methods (freezing, ethanol, and RNAlater) to validate self-collection. Within-subject microbial species, gene, and transcript abundances were highly concordant across sampling methods, with only a small fraction of transcripts ({\textless}5{\%}) displaying between-method variation. Next, we investigated relationships between the oral and gut microbial communities, identifying a subset of abundant oral microbes that routinely survive transit to the gut, but with minimal transcriptional activity there. Finally, systematic comparison of the gut metagenome and metatranscriptome revealed that a substantial fraction (41{\%}) of microbial transcripts were not differentially regulated relative to their genomic abundances. Of the remainder, consistently underexpressed pathways included sporulation and amino acid biosynthesis, whereas up-regulated pathways included ribosome biogenesis and methanogenesis. Across subjects, metatranscriptional profiles were significantly more individualized than DNA-level functional profiles, but less variable than microbial composition, indicative of subject-specific whole-community regulation. The results thus detail relationships between community genomic potential and gene expression in the gut, and establish the feasibility of metatranscriptomic investigations in subject-collected and shipped samples.},
author = {Franzosa, E. A. and Morgan, X. C. and Segata, N. and Waldron, L. and Reyes, J. and Earl, A. M. and Giannoukos, G. and Boylan, M. R. and Ciulla, D. and Gevers, D. and Izard, J. and Garrett, W. S. and Chan, A. T. and Huttenhower, C.},
doi = {10.1073/pnas.1319284111},
isbn = {1091-6490 (Electronic)$\backslash$n0027-8424 (Linking)},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
number = {22},
pages = {E2329--E2338},
pmid = {24843156},
title = {{Relating the metatranscriptome and metagenome of the human gut}},
url = {http://www.pnas.org/cgi/doi/10.1073/pnas.1319284111},
volume = {111},
year = {2014}
}
@article{Freter1955,
author = {Freter, Rolf},
journal = {The Journal of Infectious Diseases},
number = {1},
pages = {57--65},
title = {{The Fatal Enteric Cholera Infection in the Guinea Pig, Achieved by Inhibition of Normal Enteric Flora.}},
url = {www.jstor.org/stable/30092353},
volume = {97},
year = {1955}
}
@article{Ganesh2013,
abstract = {Excessive mucin degradation by intestinal bacteria may contribute to inflammatory bowel diseases because access of luminal antigens to the intestinal immune system is facilitated. This study investigated how the presence of a mucin degrading commensal bacterium affects the severity of an intestinal Salmonella enterica Typhimurium-induced gut inflammation. Using a gnotobiotic C3H mouse model with a background microbiota of eight bacterial species (SIHUMI) the impact of the mucin-degrading commensal bacterium Akkermansia muciniphila (SIHUMI-A) on inflammatory and infectious symptoms caused by S. Typhimurium was investigated. Presence of A. muciniphila in S. Typhimurium-infected SIHUMI mice caused significantly increased histopathology scores and elevated mRNA levels of IFN-$\gamma$, IP-10, TNF-$\alpha$, IL-12, IL-17 and IL-6 in cecal and colonic tissue. The increase in pro-inflammatory cytokines was accompanied by 10-fold higher S. Typhimurium cell numbers in mesenteric lymph nodes of SIHUMI mice associated with A. muciniphila and S. Typhimurium (SIHUMI-AS) compared to SIHUMI mice with S. Typhimurium only (SIHUMI-S). The number of mucin filled goblet cells was 2- to 3-fold lower in cecal tissue of SIHUMI-AS mice compared to SIHUMI-S, SIHUMI-A or SIHUMI mice. Reduced goblet cell numbers significantly correlated with increased IFN-$\gamma$ mRNA levels (r(2) = -0.86, ***P{\textless}0.001) in all infected mice. In addition, loss of cecal mucin sulphation was observed in SIHUMI mice containing both A. muciniphila and S. Typhimurium compared to other mouse groups. Concomitant presence of A. muciniphila and S. Typhimurium resulted in a drastic change in microbiota composition of SIHUMI mice: the proportion of B. thetaiotaomicron in SIHUMI-AS mice was 0.02{\%} of total bacteria compared to 78{\%}-88{\%} in the other mouse groups and the proportion of S. Typhimurium was 94{\%} in SIHUMI-AS mice but only 2.2{\%} in the SIHUMI-S mice. These results indicate that A. muciniphila exacerbates S. Typhimurium-induced intestinal inflammation by its ability to disturb host mucus homeostasis.},
author = {Ganesh, Bhanu Priya and Klopfleisch, Robert and Loh, Gunnar and Blaut, Michael},
doi = {10.1371/journal.pone.0074963},
isbn = {10.1371/journal.pone.0074963},
issn = {19326203},
journal = {PLoS ONE},
number = {9},
pmid = {24040367},
title = {{Commensal Akkermansia muciniphila Exacerbates Gut Inflammation in Salmonella Typhimurium-Infected Gnotobiotic Mice}},
volume = {8},
year = {2013}
}
@article{Giorgino2009,
abstract = {Dynamic time warping is a popular technique for comparing time series, providing both a distance measure that is insensitive to local compression and stretches and the warping which optimally deforms one of the two input series onto the other. A variety of algorithms and constraints have been discussed in the literature. The dtw package provides an unification of them; it allows R users to compute time series alignments mixing freely a variety of continuity constraints, restriction windows, endpoints, local distance definitions, and so on. The package also provides functions for visualizing alignments and constraints using several classic diagram types.},
author = {Giorgino, Toni},
doi = {10.18637/jss.v031.i07},
isbn = {1548-7660},
issn = {1548-7660},
journal = {Journal of Statistical Software},
keywords = {alignment,dynamic programming,dynamic time warping,timeseries},
number = {7},
pages = {1--24},
pmid = {28535748},
title = {{Computing and Visualizing Dynamic Time Warping Alignments in R : The dtw Package}},
url = {http://www.jstatsoft.org/v31/i07{\%}5Cnhttp://www.jstatsoft.org/v31/i07/},
volume = {31},
year = {2009}
}
@article{Goyer2004,
abstract = {Sarcosine oxidase (SOX) is known as a peroxisomal enzyme in mammals and as a sarcosine-inducible enzyme in soil bacteria. Its presence in plants was unsuspected until the Arabidopsis genome was found to encode a protein (AtSOX) with approximately 33{\%} sequence identity to mammalian and bacterial SOXs. When overexpressed in Escherichia coli, AtSOX enhanced growth on sarcosine as sole nitrogen source, showing that it has SOX activity in vivo, and the recombinant protein catalyzed the oxidation of sarcosine to glycine, formaldehyde, and H(2) O(2) in vitro. AtSOX also attacked other N-methyl amino acids and, like mammalian SOXs, catalyzed the oxidation of l-pipecolate to Delta(1)-piperideine-6-carboxylate. Like bacterial monomeric SOXs, AtSOX was active as a monomer, contained FAD covalently bound to a cysteine residue near the C terminus, and was not stimulated by tetrahydrofolate. Although AtSOX lacks a typical peroxisome-targeting signal, in vitro assays established that it is imported into peroxisomes. Quantitation of mRNA showed that AtSOX is expressed at a low level throughout the plant and is not sarcosine-inducible. Consistent with a low level of AtSOX expression, Arabidopsis plantlets slowly metabolized supplied [(14)C]sarcosine to glycine and serine. Gas chromatography-mass spectrometry analysis revealed low levels of pipecolate but almost no sarcosine in wild type Arabidopsis and showed that pipecolate but not sarcosine accumulated 6-fold when AtSOX expression was suppressed by RNA interference. Moreover, the pipecolate catabolite alpha-aminoadipate decreased 30-fold in RNA interference plants. These data indicate that pipecolate is the endogenous substrate for SOX in plants and that plants can utilize exogenous sarcosine opportunistically, sarcosine being a common soil metabolite.},
author = {Goyer, Aymeric and Johnson, Tanya L. and Olsen, Laura J. and Collakova, Eva and Shachar-Hill, Yair and Rhodes, David and Hanson, Andrew D.},
doi = {10.1074/jbc.M400071200},
isbn = {1694716953},
issn = {00219258},
journal = {Journal of Biological Chemistry},
number = {17},
pages = {16947--16953},
pmid = {14766747},
title = {{Characterization and Metabolic Function of a Peroxisomal Sarcosine and Pipecolate Oxidase from Arabidopsis}},
volume = {279},
year = {2004}
}
@article{Gripp2011,
abstract = {Background$\backslash$nCampylobacter jejuni and Campylobacter coli are human intestinal pathogens of global importance. Zoonotic transmission from livestock animals or animal-derived food is the likely cause for most of these infections. However, little is known about their general and host-specific mechanisms of colonization, or virulence and pathogenicity factors. In certain hosts, Campylobacter species colonize persistently and do not cause disease, while they cause acute intestinal disease in humans.$\backslash$n$\backslash$nResults$\backslash$nHere, we investigate putative host-specificity using phenotypic characterization and genome-wide analysis of genetically closely related C. jejuni strains from different sources. A collection of 473 fresh Campylobacter isolates from Germany was assembled between 2006 and 2010 and characterized using MLST. A subset of closely related C. jejuni strains of the highly prevalent sequence type ST-21 was selected from different hosts and isolation sources. PCR typing of strain-variable genes provided evidence that some genes differed between these strains. Furthermore, phenotypic variation of these strains was tested using the following criteria: metabolic variation, protein expression patterns, and eukaryotic cell interaction. The results demonstrated remarkable phenotypic diversity within the ST-21 group, which however did not correlate with isolation source. Whole genome sequencing was performed for five ST-21 strains from chicken, human, bovine, and food sources, in order to gain insight into ST-21 genome diversity. The comparisons showed extensive genomic diversity, primarily due to recombination and gain of phage-related genes. By contrast, no genomic features associated with isolation source or host were identified.$\backslash$n$\backslash$nConclusions$\backslash$nThe genome information and phenotypic data obtained in vitro and in a chicken infection model provided little evidence of fixed adaptation to a specific host. Instead, the dominant C. jejuni ST-21 appeared to be characterized by phenotypic flexibility and high genetic microdiversity, revealing properties of a generalist. High genetic flexibility might allow generalist variants of C. jejuni to reversibly express diverse fitness factors in changing environments.},
author = {Gripp, Eugenia and Hlahla, Daniela and Didelot, Xavier and Kops, Friederike and Maurischat, Sven and Tedin, Karsten and Alter, Thomas and Ellerbroek, L{\"{u}}ppo and Schreiber, Kerstin and Schomburg, Dietmar and Janssen, Traute and Bartholom{\"{a}}us, Patrick and Hofreuter, Dirk and Woltemate, Sabrina and Uhr, Markus and Brenneke, Birgit and Gr{\"{u}}ning, Petra and Gerlach, Gerald and Wieler, Lothar and Suerbaum, Sebastian and Josenhans, Christine},
doi = {10.1186/1471-2164-12-584},
isbn = {1471-2164 (Electronic)$\backslash$r1471-2164 (Linking)},
issn = {1471-2164},
journal = {BMC Genomics},
number = {1},
pages = {584},
pmid = {22122991},
title = {{Closely related Campylobacter jejuni strains from different sources reveal a generalist rather than a specialist lifestyle}},
url = {http://www.biomedcentral.com/1471-2164/12/584},
volume = {12},
year = {2011}
}
@misc{Huang2009,
abstract = {Clostridium difficile is the leading cause of hospital-acquired diarrhoea and the number of outbreaks has risen markedly since 2003. The emergence and spread of resistance in C. difficile is complicating treatment and prevention. Most isolates are still susceptible to vancomycin and metronidazole (MTZ), however transient and heteroresistance to MTZ have been reported. The prevalence of resistance to other antimicrobial agents is highly variable in different populations and in different countries, ranging from 0{\%} to 100{\%}. Isolates of common polymerase chain reaction (PCR) ribotypes are more resistant than uncommon ribotypes. Most of the resistance mechanisms that have been identified in C. difficile are similar to those in other Gram-positive bacteria, including mutation, selection and acquisition of the genetic information that encodes resistance. Better antibiotic stewardship and infection control are needed to prevent further spread of resistance in C. difficile. {\textcopyright} 2009 Elsevier B.V. and the International Society of Chemotherapy.},
author = {Huang, Haihui and Weintraub, Andrej and Fang, Hong and Nord, Carl Erik},
booktitle = {International Journal of Antimicrobial Agents},
doi = {10.1016/j.ijantimicag.2009.09.012},
isbn = {1872-7913 (Electronic)$\backslash$r0924-8579 (Linking)},
issn = {09248579},
keywords = {Antimicrobial susceptibility,Clostridium difficile,Resistance mechanisms},
number = {6},
pages = {516--522},
pmid = {19828299},
title = {{Antimicrobial resistance in Clostridium difficile}},
volume = {34},
year = {2009}
}
@article{Ilari2000,
abstract = {Ferritin is characterized by a highly conserved architecture that comprises 24 subunits assembled into a spherical cage with 432 symmetry. The only known exception is the dodecameric ferritin from Listeria innocua. The structure of Listeria ferritin has been determined to a resolution of 2.35 A by molecular replacement, using as a search model the structure of Dps from Escherichia coli. The Listeria 12-mer is endowed with 23 symmetry and displays the functionally relevant structural features of the ferritin 24-mer, namely the negatively charged channels along the three-fold symmetry axes that serve for iron entry into the cavity and a negatively charged internal cavity for iron deposition. The electron density map shows 12 iron ions on the inner surface of the hollow core, at the interface between monomers related by two-fold axes. Analysis of the nature and stereochemistry of the iron-binding ligands reveals strong similarities with known ferroxidase sites. The L. innocua ferritin site, however, is the first described so far that has ligands belonging to two different subunits and is not contained within a four-helix bundle.},
archivePrefix = {arXiv},
arxivId = {arXiv:cond-mat/0402594v3},
author = {Ilari, Andrea and Stefanini, Simonetta and Chiancone, Emilia and Tsernoglou, Demetrius},
doi = {10.1038/71236},
eprint = {0402594v3},
isbn = {1072-8368 (Print)$\backslash$r1072-8368 (Linking)},
issn = {10728368},
journal = {Nature Structural Biology},
number = {1},
pages = {38--43},
pmid = {10625425},
primaryClass = {arXiv:cond-mat},
title = {{The dodecameric ferritin from Listeria innocua contains a novel intersubunit iron-binding site}},
volume = {7},
year = {2000}
}
@article {Jenior2017,
author = {Jenior, Matthew L. and Leslie, Jhansi L. and Young, Vincent B. and Schloss, Patrick D.},
editor = {Turnbaugh, Peter J.},
title = {Clostridium difficile Colonizes Alternative Nutrient Niches during Infection across Distinct Murine Gut Microbiomes},
volume = {2},
number = {4},
year = {2017},
doi = {10.1128/mSystems.00063-17},
publisher = {American Society for Microbiology Journals},
URL = {http://msystems.asm.org/content/2/4/e00063-17},
eprint = {http://msystems.asm.org/content/2/4/e00063-17.full.pdf},
journal = {mSystems}
}
@article{Jorth2014,
abstract = {The human microbiome plays important roles in health, but when disrupted, these same indigenous microbes can cause disease. The composition of the microbiome changes during the transition from health to disease; however, these changes are often not conserved among patients. Since microbiome-associated diseases like periodontitis cause similar patient symptoms despite interpatient variability in microbial community composition, we hypothesized that human-associated microbial communities undergo conserved changes in metabolism during disease. Here, we used patient-matched healthy and diseased samples to compare gene expression of 160,000 genes in healthy and diseased periodontal communities. We show that health- and disease-associated communities exhibit defined differences in metabolism that are conserved between patients. In contrast, the metabolic gene expression of individual species was highly variable between patients. These results demonstrate that despite high interpatient variability in microbial composition, disease-associated communities display conserved metabolic profiles that are generally accomplished by a patient-specific cohort of microbes. IMPORTANCE The human microbiome project has shown that shifts in our microbiota are associated with many diseases, including obesity, Crohn's disease, diabetes, and periodontitis. While changes in microbial populations are apparent during these diseases, the species associated with each disease can vary from patient to patient. Taking into account this interpatient variability, we hypothesized that specific microbiota-associated diseases would be marked by conserved microbial community behaviors. Here, we use gene expression analyses of patient-matched healthy and diseased human periodontal plaque to show that microbial communities have highly conserved metabolic gene expression profiles, whereas individual species within the community do not. Furthermore, disease-associated communities exhibit conserved changes in metabolic and virulence gene expression.},
author = {Jorth, Peter and Turner, Keith H. and Gumus, Pinar and Nizam, Nejat and Buduneli, Nurcan and Whiteley, Marvin},
doi = {10.1128/mBio.01012-14},
isbn = {2150-7511 (Electronic)},
issn = {21507511},
journal = {mBio},
number = {2},
pmid = {24692635},
title = {{Metatranscriptomics of the human oral microbiome during health and disease}},
volume = {5},
year = {2014}
}
@article{Joshi2011,
abstract = {Most modern sequencing technologies produce reads that have deteriorating quality towards the 3'-end and some towards the 5'-end as well. Incorrectly called bases in both regions negatively impact assembles, mapping, and downstream bioinformatics analyses. Sickle is a tool that uses sliding windows along with quality and length thresholds to determine when quality is sufficiently low to trim the 3'-end of reads and also determines when the quality is sufficiently high enough to trim the 5'-end of reads. It will also discard reads based upon the length threshold. It takes the quality values and slides a window across them whose length is 0.1 times the length of the read. If this length is less than 1, then the window is set to be equal to the length of the read. Otherwise, the window slides along the quality values until the average quality in the window rises above the threshold, at which point the algorithm determines where within the window the rise occurs and cuts the read and quality there for the 5'-end cut. Then when the average quality in the window drops below the threshold, the algorithm determines where in the window the drop occurs and cuts both the read and quality strings there for the 3'-end cut. However, if the length of the remaining sequence is less than the minimum length threshold, then the read is discarded entirely (or replaced with an "N" record). 5'-end trimming can be disabled. Sickle supports three types of quality values: Illumina, Solexa, and Sanger. Note that the Solexa quality setting is an approximation (the actual conversion is a non-linear transformation). The end approximation is close. Illumina quality refers to qualities encoded with the CASAVA pipeline between versions 1.3 and 1.7. Illumina quality using CASAVA {\textgreater}= 1.8 is Sanger encoded. Note that Sickle will remove the 2nd fastq record header (on the "+" line) and replace it with simply a "+". This is the default format for CASAVA {\textgreater}= 1.8. Sickle also supports gzipped file inputs and optional gzipped outputs. By default, Sickle will produce regular (i.e. not gzipped) output, regardless of the input. Sickle also has an option to truncate reads with Ns at the first N position. There is also a sickle.xml file included in the package that can be used to add sickle to your local Galaxy server.},
author = {Joshi, N. and Fass, J.},
journal = {Available at https://github.com/najoshi/sickle.},
pages = {2011},
title = {{Sickle: A sliding-window, adaptive, quality-based trimming tool for FastQ files (Version 1.33) [Software]}},
year = {2011}
}
@article{Jousset2017,
abstract = {Rare species are increasingly recognized as crucial, yet vulnerable components of Earth's ecosystems. This is also true for microbial communities, which are typically composed of a high number of relatively rare species. Recent studies have demonstrated that rare species can have an over-proportional role in biogeochemical cycles and may be a hidden driver of microbiome function. In this review, we provide an ecological overview of the rare microbial biosphere, including causes of rarity and the impacts of rare species on ecosystem functioning. We discuss how rare species can have a preponderant role for local biodiversity and species turnover with rarity potentially bound to phylogenetically conserved features. Rare microbes may therefore be overlooked keystone species regulating the functioning of host-associated, terrestrial and aquatic environments.We conclude this review with recommendations to guide scientists interested in investigating this rapidly emerging research area.},
author = {Jousset, Alexandre and Bienhold, Christina and Chatzinotas, Antonis and Gallien, Laure and Gobet, Ang{\'{e}}lique and Kurm, Viola and K{\"{u}}sel, Kirsten and Rillig, Matthias C and Rivett, Damian W and Salles, Joana F and van der Heijden, Marcel G A and Youssef, Noha H and Zhang, Xiaowei and Wei, Zhong and Hol, W H Gera},
doi = {10.1038/ismej.2016.174},
isbn = {1751-7370},
issn = {1751-7362},
journal = {The ISME Journal},
pmid = {28072420},
title = {{Where less may be more: how the rare biosphere pulls ecosystems strings}},
url = {http://www.nature.com/doifinder/10.1038/ismej.2016.174},
year = {2017}
}
@article{Jump2014,
abstract = {BACKGROUND: The intestinal microbiota protect the host against enteric pathogens through a defense mechanism termed colonization resistance. Antibiotics excreted into the intestinal tract may disrupt colonization resistance and alter normal metabolic functions of the microbiota. We used a mouse model to test the hypothesis that alterations in levels of bacterial metabolites in fecal specimens could provide useful biomarkers indicating disrupted or intact colonization resistance after antibiotic treatment.$\backslash$n$\backslash$nMETHODS: To assess in vivo colonization resistance, mice were challenged with oral vancomycin-resistant Enterococcus or Clostridium difficile spores at varying time points after treatment with the lincosamide antibiotic clindamycin. For concurrent groups of antibiotic-treated mice, stool samples were analyzed using quantitative real-time polymerase chain reaction to assess changes in the microbiota and using non-targeted metabolic profiling. To assess whether the findings were applicable to another antibiotic class that suppresses intestinal anaerobes, similar experiments were conducted with piperacillin/tazobactam.$\backslash$n$\backslash$nRESULTS: Colonization resistance began to recover within 5 days and was intact by 12 days after clindamycin treatment, coinciding with the recovery bacteria from the families Lachnospiraceae and Ruminococcaceae, both part of the phylum Firmicutes. Clindamycin treatment caused marked changes in metabolites present in fecal specimens. Of 484 compounds analyzed, 146 (30{\%}) exhibited a significant increase or decrease in concentration during clindamycin treatment followed by recovery to baseline that coincided with restoration of in vivo colonization resistance. Identified as potential biomarkers of colonization resistance, these compounds included intermediates in carbohydrate or protein metabolism that increased (pentitols, gamma-glutamyl amino acids and inositol metabolites) or decreased (pentoses, dipeptides) with clindamycin treatment. Piperacillin/tazobactam treatment caused similar alterations in the intestinal microbiota and fecal metabolites.$\backslash$n$\backslash$nCONCLUSIONS: Recovery of colonization resistance after antibiotic treatment coincided with restoration of several fecal bacterial metabolites. These metabolites could provide useful biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment.},
author = {Jump, Robin L P and Polinkovsky, Alex and Hurless, Kelly and Sitzlar, Brett and Eckart, Kevin and Tomas, Myreen and Deshpande, Abhishek and Nerandzic, Michelle M. and Donskey, Curtis J.},
doi = {10.1371/journal.pone.0101267},
issn = {19326203},
journal = {PLoS ONE},
number = {7},
pmid = {24988418},
title = {{Metabolomics analysis identifies intestinal microbiota-derived biomarkers of colonization resistance in clindamycin-treated mice}},
volume = {9},
year = {2014}
}
@misc{Keeney2011,
abstract = {Residing within the intestine is a large community of commensal organisms collectively termed the microbiota. This community generates a complex nutrient environment by breaking down indigestible food products into metabolites that are used by both the host and the microbiota. Both the invading intestinal pathogen and the microbiota compete for these metabolites, which can shape both the composition of the flora, as well as susceptibility to infection. After infection is established, pathogen mediated inflammation alters the composition of the microbiota, which further shifts the makeup of metabolites in the gastrointestinal tract. A greater understanding of the interplay between the microbiota, the metabolites they generate, and susceptibility to enteric disease will enable the discovery of novel therapies against infectious disease. {\textcopyright} 2010 Elsevier Ltd.},
archivePrefix = {arXiv},
arxivId = {NIHMS150003},
author = {Keeney, Kristie M. and Finlay, B. Brett},
booktitle = {Current Opinion in Microbiology},
doi = {10.1016/j.mib.2010.12.012},
eprint = {NIHMS150003},
isbn = {1879-0364 (Electronic)$\backslash$r1369-5274 (Linking)},
issn = {13695274},
number = {1},
pages = {92--98},
pmid = {21215681},
title = {{Enteric pathogen exploitation of the microbiota-generated nutrient environment of the gut}},
volume = {14},
year = {2011}
}
@article{Kelly2008,
abstract = {Clostridium difficile toxin A is known to cause actin disaggregation through the enzymatic inactivation of intracellular Rho proteins. Based on the rapid and severe cell rounding of toxin A-exposed cells, we speculated that toxin A may be involved in post-translational modification of tubulin, leading to microtubule instability. In the current study, we observed that toxin A strongly reduced tubulin acetylation in human colonocytes and mouse intestine. Fractionation analysis demonstrated that toxin A-induced tubulin deacetylation yielded monomeric tubulin, indicating the presence of microtubule depolymerization. Inhibition of the glucosyltransferase activity against Rho proteins of toxin A by UDP 23 dialdehyde significantly abrogated toxin A-induced tubulin deacetylation. In colonocytes treated with trichostatin A (TSA), an inhibitor of the HDAC6 tubulin deacetylase, toxin A-induced tubulin deacetylation and loss of tight junction were completely blocked. Administration of TSA also attenuated proinflammatory cytokine production, mucosal damage and epithelial cell apoptosis in mouse intestine exposed to toxin A. These results suggest that toxin A causes microtubule depolymerization by activation of HDAC6-mediated tubulin deacetylation. Indeed, blockage of HDAC6 by TSA markedly attenuates tubulin deacetylation, proinflammatory cytokine production and mucosal damage in a toxin A-induced mouse enteritis model. Tubulin deacetylation is an important component of the intestinal inflammatory cascade following toxin A-mediated Rho inactivation in vitro and in vivo.},
author = {Kelly, Ciar{\'{a}}n P. and LaMont, J. Thomas},
doi = {10.1056/NEJMra0707500},
isbn = {1533-4406 (Electronic)$\backslash$n0028-4793 (Linking)},
issn = {1533-4406},
journal = {The New England journal of medicine},
number = {18},
pages = {1932--1940},
pmid = {18971494},
title = {{Clostridium difficile--more difficult than ever.}},
volume = {359},
year = {2008}
}
@article{Koenigsknecht2015,
abstract = {Clostridium difficile infection (CDI) following antibiotic therapy is a major public health threat. While antibiotic disruption of the indigenous microbiota underlies the majority of cases of CDI, the early dynamics of infection in the disturbed intestinal ecosystem are poorly characterized. This study defines the dynamics of infection with C. difficile strain VPI 10463 throughout the gastrointestinal (GI) tract using a murine model of infection. After inducing susceptibility to C. difficile colonization via antibiotic administration, we followed the dynamics of spore germination, colonization, sporulation, toxin activity, and disease progression throughout the GI tract. C. difficile spores were able to germinate within 6 h postchallenge, resulting in the establishment of vegetative bacteria in the distal GI tract. Spores and cytotoxin activity were detected by 24 h postchallenge, and histopathologic colitis developed by 30 h. Within 36 h, all infected mice succumbed to infection. We correlated the establishment of infection with changes in the microbiota and bile acid profile of the small and large intestines. Antibiotic administration resulted in significant changes to the microbiota in the small and large intestines, as well as a significant shift in the abundance of primary and secondary bile acids. Ex vivo analysis suggested the small intestine as the site of spore germination. This study provides an integrated understanding of the timing and location of the events surrounding C. difficile colonization and identifies potential targets for the development of new therapeutic strategies.},
author = {Koenigsknecht, Mark J. and Theriot, Casey M. and Bergin, Ingrid L. and Schumacher, Cassie A. and Schloss, Patrick D. and Young, Vincent B.},
doi = {10.1128/IAI.02768-14},
isbn = {0019-9567},
issn = {10985522},
journal = {Infection and Immunity},
number = {3},
pages = {934--941},
pmid = {25534943},
title = {{Dynamics and establishment of Clostridium difficile infection in the murine gastrointestinal tract}},
volume = {83},
year = {2015}
}
@article{Kozich2013,
abstract = {The Purpose of this protocol is to define the steps and costs in both material and man hours for the preparation and sequencing of 16S rRNA gene sequence libraries using the Illumina MiSeq in the laboratory of Dr. Patrick Schloss Ph.D., Department of Microbiology and Immunology.},
author = {Kozich, JJ and Westcott, SL and Baxter, NT and Highlander, SK and Schloss, PD},
journal = {University of Michigan Health System SOP},
pages = {1--16},
title = {{16S Sequencing with the Illumina MiSeq Personal Sequencer}},
volume = {3.1},
year = {2013}
}
@article{Langmead2010,
abstract = {This unit shows how to use the Bowtie package to align short sequencing reads, such as those output by second-generation sequencing instruments. It also includes protocols for building a genome index and calling consensus sequences from Bowtie alignments using SAMtools.},
author = {Langmead, Ben},
doi = {10.1002/0471250953.bi1107s32},
isbn = {0471250953},
issn = {19343396},
journal = {Current Protocols in Bioinformatics},
keywords = {Alignment,Comparative genomics,Genome indexing,Mapping,Read alignment,Read mapping,Short reads,Software package},
number = {SUPP.32},
pmid = {21154709},
title = {{Aligning short sequencing reads with Bowtie}},
year = {2010}
}
@article{Langmead2012,
abstract = {As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.},
archivePrefix = {arXiv},
arxivId = {{\#}14603},
author = {Langmead, Ben and Salzberg, Steven L},
doi = {10.1038/nmeth.1923},
eprint = {{\#}14603},
isbn = {1548-7105 (Electronic) 1548-7091 (Linking)},
issn = {1548-7105},
journal = {Nature methods},
number = {4},
pages = {357--9},
pmid = {22388286},
title = {{Fast gapped-read alignment with Bowtie 2.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22388286 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3322381},
volume = {9},
year = {2012}
}
@article{Lawley2012,
abstract = {Relapsing C. difficile disease in humans is linked to a pathological imbalance within the intestinal microbiota, termed dysbiosis, which remains poorly understood. We show that mice infected with epidemic C. difficile (genotype 027/BI) develop highly contagious, chronic intestinal disease and persistent dysbiosis characterized by a distinct, simplified microbiota containing opportunistic pathogens and altered metabolite production. Chronic C. difficile 027/BI infection was refractory to vancomycin treatment leading to relapsing disease. In contrast, treatment of C. difficile 027/BI infected mice with feces from healthy mice rapidly restored a diverse, healthy microbiota and resolved C. difficile disease and contagiousness. We used this model to identify a simple mixture of six phylogenetically diverse intestinal bacteria, including novel species, which can re-establish a health-associated microbiota and clear C. difficile 027/BI infection from mice. Thus, targeting a dysbiotic microbiota with a defined mixture of phylogenetically diverse bacteria can trigger major shifts in the microbial community structure that displaces C. difficile and, as a result, resolves disease and contagiousness. Further, we demonstrate a rational approach to harness the therapeutic potential of health-associated microbial communities to treat C. difficile disease and potentially other forms of intestinal dysbiosis.},
author = {Lawley, Trevor D. and Clare, Simon and Walker, Alan W. and Stares, Mark D. and Connor, Thomas R. and Raisen, Claire and Goulding, David and Rad, Roland and Schreiber, Fernanda and Brandt, Cordelia and Deakin, Laura J. and Pickard, Derek J. and Duncan, Sylvia H. and Flint, Harry J. and Clark, Taane G. and Parkhill, Julian and Dougan, Gordon},
doi = {10.1371/journal.ppat.1002995},
isbn = {1553-7374 (Electronic) 1553-7366 (Linking)},
issn = {15537366},
journal = {PLoS Pathogens},
number = {10},
pmid = {23133377},
title = {{Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice}},
volume = {8},
year = {2012}
}
@article{Lee2014,
abstract = {Gut microbiota is found in virtually any metazoan, from invertebrates to vertebrates. It has long been believed that gut microbiota, more specifically, the activity of the microbiome and its metabolic products, directly influence a variety of aspects in metazoan physiology. However, the exact molecular relationship among microbe-derived gut metabolites, host signaling pathways, and host physiology remains to be elucidated. Here we review recent discoveries regarding the molecular links between gut metabolites and host physiology in different invertebrate and vertebrate animal models. We describe the different roles of gut microbiome activity and their metabolites in regulating distinct host physiology and the molecular mechanisms by which gut metabolites cause physiological homeostasis via regulating specific host signaling pathways. Future studies in this direction using different animal models will provide the key concepts to understanding the evolutionarily conserved chemical dialogues between gut microbiota and metazoan cells and also human diseases associated with gut microbiota and metabolites.},
author = {Lee, Won-Jae and Hase, Koji},
doi = {10.1038/nchembio.1535},
isbn = {1552-4469 (Electronic)$\backslash$n1552-4450 (Linking)},
issn = {1552-4469},
journal = {Nature chemical biology},
keywords = {Animals,Cardiovascular Diseases,Cardiovascular Diseases: metabolism,Cardiovascular Diseases: microbiology,Host-Pathogen Interactions,Host-Pathogen Interactions: immunology,Host-Pathogen Interactions: physiology,Humans,Immune System,Immune System: physiology,Intestines,Intestines: microbiology,Invertebrates,Invertebrates: microbiology,Invertebrates: physiology,Longevity,Longevity: physiology,Microbiota,Microbiota: physiology,Obesity,Obesity: metabolism,Obesity: microbiology,Vertebrates,Vertebrates: microbiology,Vertebrates: physiology},
number = {6},
pages = {416--24},
pmid = {24838170},
title = {{Gut microbiota-generated metabolites in animal health and disease.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24838170},
volume = {10},
year = {2014}
}
@article{Leslie2015,
abstract = {Clostridium difficile is the leading cause of infectious nosocomial diarrhea. The pathogenesis of C. difficile infection (CDI) results from the interactions between the pathogen, intestinal epithelium, host immune system, and gastrointestinal microbiota. Previous studies of the host-pathogen interaction in CDI have utilized either simple cell monolayers or in vivo models. While much has been learned by utilizing these approaches, little is known about the direct interaction of the bacterium with a complex host epithelium. Here, we asked if human intestinal organoids (HIOs), which are derived from pluripotent stem cells and demonstrate small intestinal morphology and physiology, could be used to study the pathogenesis of the obligate anaerobe C. difficile. Vegetative C. difficile, microinjected into the lumen of HIOs, persisted in a viable state for up to 12 h. Upon colonization with C. difficile VPI 10463, the HIO epithelium is markedly disrupted, resulting in the loss of paracellular barrier function. Since similar effects were not observed when HIOs were colonized with the nontoxigenic C. difficile strain F200, we directly tested the role of toxin using TcdA and TcdB purified from VPI 10463. We show that the injection of TcdA replicates the disruption of the epithelial barrier function and structure observed in HIOs colonized with viable C. difficile.},
author = {Leslie, Jhansi L. and Huang, Sha and Opp, Judith S. and Nagy, Melinda S. and Kobayashi, Masayuki and Young, Vincent B. and Spence, Jason R.},
doi = {10.1128/IAI.02561-14},
isbn = {5242956003},
issn = {10985522},
journal = {Infection and Immunity},
number = {1},
pages = {138--145},
pmid = {25312952},
title = {{Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function}},
volume = {83},
year = {2015}
}
@article{Lessa2015,
abstract = {Background The magnitude and scope of Clostridium difficile infection in the United States continue to evolve. Methods In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents ≥1 year of age). Cases were classified as community-associated or health care–associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection. Results A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8{\%} were health care–associated, but only 24.2{\%} had onset during hospitalization. After adjustment for predictors of disease incidence, the e...},
author = {Lessa, Fernanda C. and Mu, Yi and Bamberg, Wendy M. and Beldavs, Zintars G. and Dumyati, Ghinwa K. and Dunn, John R. and Farley, Monica M. and Holzbauer, Stacy M. and Meek, James I. and Phipps, Erin C. and Wilson, Lucy E. and Winston, Lisa G. and Cohen, Jessica A. and Limbago, Brandi M. and Fridkin, Scott K. and Gerding, Dale N. and McDonald, L. Clifford},
doi = {10.1056/NEJMoa1408913},
isbn = {1533-4406},
issn = {0028-4793},
journal = {New England Journal of Medicine},
number = {9},
pages = {825--834},
pmid = {25714160},
title = {{Burden of Clostridium difficile Infection in the United States}},
url = {http://www.nejm.org/doi/abs/10.1056/NEJMoa1408913},
volume = {372},
year = {2015}
}
@article{Li2014,
abstract = {Summary: MEGAHIT is a NGS de novo assembler for assembling large and complex metagenomics data in a time- and cost-efficient manner. It finished assembling a soil metagenomics dataset with 252 Gbps in 44.1 and 99.6 h on a single computing node with and without a graphics processing unit, respectively. MEGAHIT assembles the data as a whole, i.e. no pre-processing like partitioning and normalization was needed. When compared with previous methods on assembling the soil data, MEGAHIT generated a three-time larger assembly, with longer contig N50 and average contig length; furthermore, 55.8{\%} of the reads were aligned to the assembly, giving a fourfold improvement. Availability and implementation: The source code of MEGAHIT is freely available at https://github.com/voutcn/megahit under GPLv3 license.},
archivePrefix = {arXiv},
arxivId = {1401.7457},
author = {Li, Dinghua and Liu, Chi Man and Luo, Ruibang and Sadakane, Kunihiko and Lam, Tak Wah},
doi = {10.1093/bioinformatics/btv033},
eprint = {1401.7457},
isbn = {1367-4803},
issn = {14602059},
journal = {Bioinformatics},
number = {10},
pages = {1674--1676},
pmid = {25609793},
title = {{MEGAHIT: An ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph}},
volume = {31},
year = {2014}
}
@article{Li2009,
abstract = {SUMMARY: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. AVAILABILITY: http://samtools.sourceforge.net.},
archivePrefix = {arXiv},
arxivId = {1006.1266v2},
author = {Li, Heng and Handsaker, Bob and Wysoker, Alec and Fennell, Tim and Ruan, Jue and Homer, Nils and Marth, Gabor and Abecasis, Goncalo and Durbin, Richard},
doi = {10.1093/bioinformatics/btp352},
eprint = {1006.1266v2},
isbn = {1367-4803$\backslash$r1460-2059},
issn = {13674803},
journal = {Bioinformatics},
number = {16},
pages = {2078--2079},
pmid = {19505943},
title = {{The Sequence Alignment/Map format and SAMtools}},
volume = {25},
year = {2009}
}
@article{Liaw2002,
abstract = {Recently there has been a lot of interest in “ensemble learning” — methods that generate many classifiers and aggregate their results. Two well-known methods are boosting (see, e.g., Shapire et al., 1998) and bagging Breiman (1996) of classification trees. In boosting, successive trees give extra weight to points incorrectly predicted by earlier predictors. In the end, a weighted vote is taken for prediction. In bagging, successive trees do not depend on earlier trees — each is independently constructed using a bootstrap sample of the data set. In the end, a simple majority vote is taken for prediction.},
archivePrefix = {arXiv},
arxivId = {1609-3631},
author = {Liaw, a and Wiener, M},
doi = {10.1177/154405910408300516},
eprint = {1609-3631},
isbn = {1609-3631},
issn = {16093631},
journal = {R news},
number = {December},
pages = {18--22},
pmid = {21196786},
title = {{Classification and Regression by randomForest}},
volume = {2},
year = {2002}
}
@article{Lichtman2016,
abstract = {Improved understanding of the interplay between host and microbes stands to illuminate new avenues for disease diagnosis, treatment, and prevention. Here, we provide a high-resolution view of the dynamics between host and gut microbiota during antibiotic-induced intestinal microbiota depletion, opportunistic Salmonella typhimurium and Clostridium difficile pathogenesis, and recovery from these perturbed states in a mouse model. Host-centric proteome and microbial community profiles provide a nuanced longitudinal view, revealing the interdependence between host and microbiota in evolving dysbioses. Time- and condition-specific molecular and microbial signatures are evident and clearly distinguished from pathogen-independent inflammatory fingerprints. Our data reveal that mice recovering from antibiotic treatment or C. difficile infection retain lingering signatures of inflammation, despite compositional normalization of the microbiota, and host responses could be rapidly and durably relieved through fecal transplant. These experiments demonstrate insights that emerge from the combination of these orthogonal, untargeted approaches to the gastrointestinal ecosystem.},
author = {Lichtman, Joshua S. and Ferreyra, Jessica A. and Ng, Katharine M. and Smits, Samuel A. and Sonnenburg, Justin L. and Elias, Joshua E.},
doi = {10.1016/j.celrep.2016.01.009},
isbn = {2211-1247 (Electronic)},
issn = {22111247},
journal = {Cell Reports},
number = {5},
pages = {1049--1061},
pmid = {26832403},
title = {{Host-Microbiota Interactions in the Pathogenesis of Antibiotic-Associated Diseases}},
volume = {14},
year = {2016}
}
@article{Lopez-Medina2011,
abstract = {Pseudomonas aeruginosa (PA) infections result in significant morbidity and mortality in hosts with compromised immune systems, such as patients with leukemia, severe burn wounds, or organ transplants. In patients at high-risk for developing PA bloodstream infections, the gastrointestinal (GI) tract is the main reservoir for colonization, but the mechanisms by which PA transitions from an asymptomatic colonizing microbe to an invasive, and often deadly, pathogen are unclear. Previously, we performed in vivo transcription profiling experiments by recovering PA mRNA from bacterial cells residing in the cecums of colonized mice in order to identify changes in bacterial gene expression during alterations to the host's immune status. As with any transcription profiling experiment, the rate-limiting step is in the isolation of sufficient amounts of high quality mRNA. Given the abundance of enzymes, debris, food residues, and particulate matter in the GI tract, the challenge of RNA isolation is daunting. Here, we present a method for reliable and reproducible isolation of bacterial RNA recovered from the murine GI tract. This method utilizes a well-established murine model of PA GI colonization and neutropenia-induced dissemination. Once GI colonization with PA is confirmed, mice are euthanized and cecal contents are recovered and flash frozen. RNA is then extracted using a combination of mechanical disruption, boiling, phenol/chloroform extractions, DNase treatment, and affinity chromatography. Quantity and purity are confirmed by spectrophotometry (Nanodrop Technologies) and bioanalyzer (Agilent Technologies) (Fig 1). This method of GI microbial RNA isolation can easily be adapted to other bacteria and fungi as well.},
author = {Lopez-Medina, Eduardo and Neubauer, Megan M and Pier, Gerald B and Koh, Andrew Y},
doi = {10.3791/3293},
issn = {1940-087X},
journal = {Journal of visualized experiments : JoVE},
keywords = {Animals,Cecum,Cecum: microbiology,Chromatography, Affinity,Chromatography, Affinity: methods,Female,Mice,Mice, Inbred C3H,Pseudomonas aeruginosa,Pseudomonas aeruginosa: chemistry,Pseudomonas aeruginosa: genetics,Pseudomonas aeruginosa: isolation {\&} purification,RNA, Bacterial,RNA, Bacterial: isolation {\&} purification},
number = {55},
pages = {6--9},
pmid = {21989513},
title = {{RNA isolation of Pseudomonas aeruginosa colonizing the murine gastrointestinal tract.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3230207{\&}tool=pmcentrez{\&}rendertype=abstract},
year = {2011}
}
@article{Mahowald2009,
abstract = {The adult human distal gut microbial community is typically dominated by 2 bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here, we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from Eubacterium rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the Firmicutes possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole-genome transcriptional profiling, high-resolution proteomic analysis, and biochemical assays of microbial-microbial and microbial-host interactions. B. thetaiotaomicron adapts to E. rectale by up-regulating expression of a variety of polysaccharide utilization loci encoding numerous glycoside hydrolases, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is used by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of its major bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability.},
archivePrefix = {arXiv},
arxivId = {arXiv:1408.1149},
author = {Mahowald, M. A. and Rey, F. E. and Seedorf, H. and Turnbaugh, P. J. and Fulton, R. S. and Wollam, A. and Shah, N. and Wang, C. and Magrini, V. and Wilson, R. K. and Cantarel, B. L. and Coutinho, P. M. and Henrissat, B. and Crock, L. W. and Russell, A. and Verberkmoes, N. C. and Hettich, R. L. and Gordon, J. I.},
doi = {10.1073/pnas.0901529106},
eprint = {arXiv:1408.1149},
isbn = {1091-6490 (Electronic)$\backslash$r0027-8424 (Linking)},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
number = {14},
pages = {5859--5864},
pmid = {19321416},
title = {{Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla}},
url = {http://www.pnas.org/cgi/doi/10.1073/pnas.0901529106},
volume = {106},
year = {2009}
}
@article{Marcobal2013,
abstract = {Defining the functional status of host-associated microbial ecosystems has proven challenging owing to the vast number of predicted genes within the microbiome and relatively poor understanding of community dynamics and community-host interaction. Metabolomic approaches, in which a large number of small molecule metabolites can be defined in a biological sample, offer a promising avenue to 'fingerprint' microbiota functional status. Here, we examined the effects of the human gut microbiota on the fecal and urinary metabolome of a humanized (HUM) mouse using an optimized ultra performance liquid chromatography-mass spectrometry-based method. Differences between HUM and conventional mouse urine and fecal metabolomic profiles support host-specific aspects of the microbiota's metabolomic contribution, consistent with distinct microbial compositions. Comparison of microbiota composition and metabolome of mice humanized with different human donors revealed that the vast majority of metabolomic features observed in donor samples are produced in the corresponding HUM mice, and individual-specific features suggest 'personalized' aspects of functionality can be reconstituted in mice. Feeding the mice a defined, custom diet resulted in modification of the metabolite signatures, illustrating that host diet provides an avenue for altering gut microbiota functionality, which in turn can be monitored via metabolomics. Using a defined model microbiota consisting of one or two species, we show that simplified communities can drive major changes in the host metabolomic profile. Our results demonstrate that metabolomics constitutes a powerful avenue for functional characterization of the intestinal microbiota and its interaction with the host.},
author = {Marcobal, A and Kashyap, P C and Nelson, T A and Aronov, P A and Donia, M S and Spormann, A and Fischbach, M A and Sonnenburg, J L},
doi = {10.1038/ismej.2013.89},
isbn = {1751-7370 (Electronic)$\backslash$r1751-7362 (Linking)},
issn = {1751-7370},
journal = {The ISME journal},
keywords = {Animals,Bacteria,Bacteria: genetics,Bacteria: metabolism,Bacterial Physiological Phenomena,Biodiversity,Diet,Feces,Feces: chemistry,Germ-Free Life,Humans,Intestines,Intestines: metabolism,Intestines: microbiology,Metabolome,Metabolomics,Mice,Mice, Inbred C57BL,Microbiota,Microbiota: genetics,Microbiota: physiology,RNA, Ribosomal, 16S,RNA, Ribosomal, 16S: genetics,Urine,Urine: chemistry},
number = {10},
pages = {1933--43},
pmid = {23739052},
title = {{A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3965317{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {7},
year = {2013}
}

@article{Matsumoto2012,
abstract = {Low-molecular-weight metabolites produced by intestinal microbiota play a direct role in health and disease. In this study, we analyzed the colonic luminal metabolome using capillary electrophoresis mass spectrometry with time-of-flight (CE-TOFMS) -a novel technique for analyzing and differentially displaying metabolic profiles- in order to clarify the metabolite profiles in the intestinal lumen. CE-TOFMS identified 179 metabolites from the colonic luminal metabolome and 48 metabolites were present in significantly higher concentrations and/or incidence in the germ-free (GF) mice than in the Ex-GF mice (p {\textless} 0.05), 77 metabolites were present in significantly lower concentrations and/or incidence in the GF mice than in the Ex-GF mice (p {\textless} 0.05), and 56 metabolites showed no differences in the concentration or incidence between GF and Ex-GF mice. These indicate that intestinal microbiota highly influenced the colonic luminal metabolome and a comprehensive understanding of intestinal luminal metabolome is critical for clarifying host-intestinal bacterial interactions.},
author = {Matsumoto, Mitsuharu and Kibe, Ryoko and Ooga, Takushi and Aiba, Yuji and Kurihara, Shin and Sawaki, Emiko and Koga, Yasuhiro and Benno, Yoshimi},
doi = {10.1038/srep00233},
isbn = {2045-2322 (Electronic)
2045-2322 (Linking)},
issn = {2045-2322},
journal = {Scientific reports},
keywords = {Animals,Bacteria,Bacteria: classification,Bacteria: genetics,Bacteria: metabolism,Electrophoresis, Capillary,Electrophoresis, Capillary: methods,Female,Host-Pathogen Interactions,Intestines,Intestines: metabolism,Intestines: microbiology,Male,Mass Spectrometry,Mass Spectrometry: methods,Metabolomics,Metabolomics: methods,Metagenome,Metagenome: physiology,Mice,Mice, Inbred BALB C,Specific Pathogen-Free Organisms},
pages = {233},
pmid = {22724057},
title = {{Impact of intestinal microbiota on intestinal luminal metabolome.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3380406{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {2},
year = {2012}
}
@article{McHardy2013,
abstract = {BACKGROUND: Consistent compositional shifts in the gut microbiota are observed in IBD and other chronic intestinal disorders and may contribute to pathogenesis. The identities of microbial biomolecular mechanisms and metabolic products responsible for disease phenotypes remain to be determined, as do the means by which such microbial functions may be therapeutically modified.$\backslash$n$\backslash$nRESULTS: The composition of the microbiota and metabolites in gut microbiome samples in 47 subjects were determined. Samples were obtained by endoscopic mucosal lavage from the cecum and sigmoid colon regions, and each sample was sequenced using the 16S rRNA gene V4 region (Illumina-HiSeq 2000 platform) and assessed by UPLC mass spectroscopy. Spearman correlations were used to identify widespread, statistically significant microbial-metabolite relationships. Metagenomes for identified microbial OTUs were imputed using PICRUSt, and KEGG metabolic pathway modules for imputed genes were assigned using HUMAnN. The resulting metabolic pathway abundances were mostly concordant with metabolite data. Analysis of the metabolome-driven distribution of OTU phylogeny and function revealed clusters of clades that were both metabolically and metagenomically similar.$\backslash$n$\backslash$nCONCLUSIONS: The results suggest that microbes are syntropic with mucosal metabolome composition and therefore may be the source of and/or dependent upon gut epithelial metabolites. The consistent relationship between inferred metagenomic function and assayed metabolites suggests that metagenomic composition is predictive to a reasonable degree of microbial community metabolite pools. The finding that certain metabolites strongly correlate with microbial community structure raises the possibility of targeting metabolites for monitoring and/or therapeutically manipulating microbial community function in IBD and other chronic diseases.},
author = {McHardy, Ian H and Goudarzi, Maryam and Tong, Maomeng and Ruegger, Paul M and Schwager, Emma and Weger, John R and Graeber, Thomas G and Sonnenburg, Justin L and Horvath, Steve and Huttenhower, Curtis and McGovern, Dermot Pb and Fornace, Albert J and Borneman, James and Braun, Jonathan},
doi = {10.1186/2049-2618-1-17},
isbn = {2049-2618},
issn = {2049-2618},
journal = {Microbiome},
keywords = {Inter-omic analysis,Metabolome,Microbiome,inter-omic analysis,metabolome,microbiome},
number = {1},
pages = {17},
pmid = {24450808},
title = {{Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3971612{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {1},
year = {2013}
}
@article{Martin2011,
author = {Martin, Marcel},
doi = {10.14806/ej.17.1.200},
eprint = {ISSN 2226-6089},
issn = {2226-6089},
journal = {EMBnet},
number = {1},
pages = {10},
pmid = {1000006697},
title = {{Cutadapt removes adapter sequences from high-throughput sequencing reads}},
url = {http://journal.embnet.org/index.php/embnetjournal/article/view/200},
volume = {17},
year = {2011}
}
@article{Mayneris-Perxachs2016,
abstract = {Background: Environmental enteropathy, which is linked to under-nutrition and chronic infections, affects the physical and mental growth of children in developing areas worldwide. Key to understanding how these factors combine to shape developmental outcomes is to first understand the effects of nutritional deficiencies on the mammalian system including the effect on the gut microbiota. Objective: We dissected the nutritional components of environmen-tal enteropathy by analyzing the specific metabolic and gut-microbiota changes that occur in weaned-mouse models of zinc or protein de-ficiency compared with well-nourished controls. Design: With the use of a 1 H nuclear magnetic resonance spectroscopy– based metabolic profiling approach with matching 16S microbiota analyses, the metabolic consequences and specific effects on the fecal microbiota of protein and zinc deficiency were probed indepen-dently in a murine model. Results: We showed considerable shifts within the intestinal microbiota 14–24 d postweaning in mice that were maintained on a normal diet (including increases in Proteobacteria and striking decreases in Bacterioidetes). Although the zinc-deficient microbiota were com-parable to the age-matched, well-nourished profile, the protein-restricted microbiota remained closer in composition to the weaned enterotype with retention of Bacteroidetes. Striking increases in Verrucomicrobia (predominantly Akkermansia muciniphila) were observed in both well-nourished and protein-deficient mice 14 d postweaning. We showed that protein malnutrition impaired growth and had major metabolic consequences (much more than with zinc deficiency) that included altered energy, polyamine, and purine and pyrimidine metabolism. Consistent with major changes in the gut microbiota, reductions in microbial proteolysis and increases in microbial dietary choline processing were observed. Conclusions: These findings are consistent with metabolic alter-ations that we previously observed in malnourished children. The results show that we can model the metabolic consequences of mal-nutrition in the mouse to help dissect relevant pathways involved in the effects of undernutrition and their contribution to environmental enteric dysfunction. Am J Clin Nutr doi: 10.3945/ajcn.116.131797.},
author = {Mayneris-Perxachs, Jordi and Bolick, David T. and Leng, Joy and Medlock, Greg L. and Kolling, Glynis L. and Papin, Jason A. and Swann, Jonathan R. and Guerrant, Richard L.},
doi = {10.3945/ajcn.116.131797},
isbn = {0002-9165},
issn = {19383207},
journal = {American Journal of Clinical Nutrition},
keywords = {Malnutrition,Metabolome metabolic phenotype,Metabolome metabonomics,Microbiome microbiota,Protein deficiency,Undernutrition,Zinc deficiency},
number = {5},
pages = {1253--1262},
pmid = {27733402},
title = {{Protein-and zinc-deficient diets modulate the murine microbiome and metabolic phenotype}},
volume = {104},
year = {2016}
}
@article{Nakamura1982,
abstract = {Biochemical proporties of C. difficile were reinvestigated for the practical identification of the organism in clinical laboratories. Bacterial growth in 2{\%} proteose peptone medium supplemented with 0.01{\%} L-cysteineHCL and 0.1{\%} agar supported sufficient growth to read the fermentation results just as well as did pre-reduced anaerobically sterilized medium. Incubation for 2 days was long enough for determining the ability to ferment fructose, glucose, mannitol, mannose, melezitose, and sorbitol. All of the 82 strains liquified 2{\%} but not 10{\%} gelatin. The significance of mannitol fermentation and gelatin liquefaction is stressed since C. difficile is the only species fermenting mannitol among gelatin-liquefying species of clostridia having subterminal spores.},
author = {Nakamura, Shinichi and Nakashio, Satoshi and Yamakawa, Kiyotaka and Tanabe, Naomi and Nishida, Shoki},
doi = {10.1111/j.1348-0421.1982.tb00159.x},
isbn = {0385-5600},
issn = {13480421},
journal = {Microbiology and Immunology},
number = {2},
pages = {107--111},
pmid = {6806571},
title = {{Carbohydrate Fermentation by Clostridium difficile}},
volume = {26},
year = {1982}
}
@article{Neumann-Schaal2015,
abstract = {BACKGROUND: Clostridium difficile is one of the major nosocomial threats causing severe gastrointestinal infections. Compared to the well documented clinical symptoms, little is known about the processes in the bacterial cell like the regulation and activity of metabolic pathways. In this study, we present time-resolved and global data of extracellular substrates and products. In a second part, we focus on the correlation of fermentation products and substrate uptake with toxin production.$\backslash$nRESULTS: Formation of different fermentation products during growth in a comparison between the two different media in a global approach was studied using non-targeted gas chromatography-mass spectrometry (GC-MS) based analysis. During cultivation in a casamino acids medium and minimal medium, the clinical isolate C. difficile 630$\Delta$erm showed major differences in amino acid utilization: In casamino acids medium, C. difficile preferred proline, leucine and cysteine as carbon and energy sources while glutamate and lysine were not or hardly used. In contrast, proline and leucine were consumed at a significantly later stage in minimal medium. Due to the more complex substrate mixture more fermentation products were detectable in the casamino acids medium, accompanied by major changes in the ratios between oxidative and reductive Stickland products. Different glucose consumption dynamics were observed in presence of either casamino acids or the minimal set of amino acids, accompanied by major changes in butanoate formation. This was associated with a variation in both the toxin yield and a change in the ratio of toxin A to toxin B.$\backslash$nCONCLUSIONS: Since in all media compositions, more than one substrate was available as a suitable carbon source, availability of different carbon sources and their metabolic fate appears to be the key factor for toxin formation.$\backslash$n},
author = {Neumann-Schaal, Meina and Hofmann, Julia Danielle and Will, Sabine Eva and Schomburg, Dietmar},
doi = {10.1186/s12866-015-0614-2},
issn = {1471-2180},
journal = {BMC Microbiology},
keywords = {Clostridium difficile,Metabolism,Stickland reactio,amino acids,clostridium difficile,fermentation products,metabolism,stickland reaction,toxin},
pages = {281},
pmid = {26680234},
title = {{Time-resolved amino acid uptake of Clostridium difficile 630$\Delta$erm and concomitant fermentation product and toxin formation}},
url = {http://dx.doi.org/10.1186/s12866-015-0614-2},
year = {2015}
}
@article{Ng2013,
abstract = {The human intestine, colonized by a dense community of resident microbes, is a frequent target of bacterial pathogens. Undisturbed, this intestinal microbiota provides protection from bacterial infections. Conversely, disruption of the microbiota with oral antibiotics often precedes the emergence of several enteric pathogens. How pathogens capitalize upon the failure of microbiota-afforded protection is largely unknown. Here we show that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium (S. typhimurium) and Clostridium difficile, use a common strategy of catabolizing microbiota-liberated mucosal carbohydrates during their expansion within the gut. S. typhimurium accesses fucose and sialic acid within the lumen of the gut in a microbiota-dependent manner, and genetic ablation of the respective catabolic pathways reduces its competitiveness in vivo. Similarly, C. difficile expansion is aided by microbiota-induced elevation of sialic acid levels in vivo. Colonization of gnotobiotic mice with a sialidase-deficient mutant of Bacteroides thetaiotaomicron, a model gut symbiont, reduces free sialic acid levels resulting in C. difficile downregulating its sialic acid catabolic pathway and exhibiting impaired expansion. These effects are reversed by exogenous dietary administration of free sialic acid. Furthermore, antibiotic treatment of conventional mice induces a spike in free sialic acid and mutants of both Salmonella and C. difficile that are unable to catabolize sialic acid exhibit impaired expansion. These data show that antibiotic-induced disruption of the resident microbiota and subsequent alteration in mucosal carbohydrate availability are exploited by these two distantly related enteric pathogens in a similar manner. This insight suggests new therapeutic approaches for preventing diseases caused by antibiotic-associated pathogens.},
author = {Ng, Katharine M and Ferreyra, Jessica a and Higginbottom, Steven K and Lynch, Jonathan B and Kashyap, Purna C and Gopinath, Smita and Naidu, Natasha and Choudhury, Biswa and Weimer, Bart C and Monack, Denise M and Sonnenburg, Justin L},
doi = {10.1038/nature12503},
isbn = {doi:10.1038/nature12503},
issn = {1476-4687},
journal = {Nature},
keywords = {Animals,Anti-Bacterial Agents,Anti-Bacterial Agents: pharmacology,Bacteroides,Bacteroides: physiology,Carbohydrate Metabolism,Carbohydrate Metabolism: drug effects,Clostridium difficile,Clostridium difficile: physiology,Enterocolitis, Pseudomembranous,Enterocolitis, Pseudomembranous: microbiology,Female,Fucose,Fucose: metabolism,Gene Expression Profiling,Gene Expression Regulation, Bacterial,Intestinal Mucosa,Intestinal Mucosa: metabolism,Intestinal Mucosa: microbiology,Male,Metagenome,Metagenome: drug effects,Metagenome: physiology,Mice,N-Acetylneuraminic Acid,N-Acetylneuraminic Acid: metabolism,Neuraminidase,Neuraminidase: genetics,Neuraminidase: metabolism,Salmonella Infections,Salmonella Infections: microbiology,Salmonella typhimurium,Salmonella typhimurium: physiology,Specific Pathogen-Free Organisms},
number = {7469},
pages = {96--9},
pmid = {23995682},
title = {{Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3825626{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {502},
year = {2013}
}
@misc{Ogata1999,
abstract = {KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic analysis of gene functions, linking genomic information with higher order functional information. The genomic information is stored in the GENES database, which is a collection of gene catalogs for all the completely sequenced genomes and some partial genomes with up-to-date annotation of gene functions. The higher order functional information is stored in the PATHWAY database, which contains graphical representations of cellular processes, such as metabolism, membrane transport, signal transduction and cell cycle. The PATHWAY database is supplemented by a set of ortholog group tables for the information about conserved subpathways (pathway motifs), which are often encoded by positionally coupled genes on the chromosome and which are especially useful in predicting gene functions. A third database in KEGG is LIGAND for the information about chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java graphics tools for browsing genome maps, comparing two genome maps and manipulating expression maps, as well as computational tools for sequence comparison, graph comparison and path computation. The KEGG databases are daily updated and made freely available (http://www. genome.ad.jp/kegg/).},
author = {Ogata, Hiroyuki and Goto, Susumu and Sato, Kazushige and Fujibuchi, Wataru and Bono, Hidemasa and Kanehisa, Minoru},
booktitle = {Nucleic Acids Research},
doi = {10.1093/nar/27.1.29},
isbn = {0305-1048 (Print)$\backslash$r0305-1048 (Linking)},
issn = {03051048},
number = {1},
pages = {29--34},
pmid = {10592173},
title = {{KEGG: Kyoto encyclopedia of genes and genomes}},
volume = {27},
year = {1999}
}
@article{Perez-Cobas2014,
abstract = {Antibiotic therapy is a causative agent of severe disturbances in microbial communities. In healthy individuals, the gut microbiota prevents infection by harmful microorganisms through direct inhibition (releasing antimicrobial compounds), competition, or stimulation of the host's immune defenses. However, widespread antibiotic use has resulted in short- and long-term shifts in the gut microbiota structure, leading to a loss in colonization resistance in some cases. Consequently, some patients develop Clostridium difficile infection (CDI) after taking an antibiotic (AB) and, at present, this opportunistic pathogen is one of the main causes of antibiotic-associated diarrhea in hospitalized patients. Here, we analyze the composition and functional differences in the gut microbiota of C. difficile infected (CDI) vs. non-infected patients, both patient groups having been treated with AB therapy. To do so we used 16S rRNA gene and metagenomic 454-based pyrosequencing approaches. Samples were taken before, during and after AB treatment and were checked for the presence of the pathogen. We performed different analyses and comparisons between infected (CD+) vs. non-infected (CD-) samples, allowing proposing putative candidate taxa and functions that might protect against C. difficile colonization. Most of these potentially protective taxa belonged to the Firmicutes phylum, mainly to the order Clostridiales, while some candidate protective functions were related to aromatic amino acid biosynthesis and stress response mechanisms. We also found that CDI patients showed, in general, lower diversity and richness than non-infected, as well as an overrepresentation of members of the families Bacteroidaceae, Enterococcaceae, Lactobacillaceae and Clostridium clusters XI and XIVa. Regarding metabolic functions, we detected higher abundance of genes involved in the transport and binding of carbohydrates, ions, and others compounds as a response to an antibiotic environment.},
author = {Perez-Cobas, Ana E. and Artacho, Alejandro and Ott, Stephan J. and Moya, Andr??s and Gosalbes, Mar??a J. and Latorre, Amparo},
doi = {10.3389/fmicb.2014.00335},
issn = {1664302X},
journal = {Frontiers in Microbiology},
keywords = {Bacterial composition,C. difficile infection,Colonization resistance,Gut microbiota,Metabolic functions},
number = {JULY},
pmid = {25309515},
title = {{Structural and functional changes in the gut microbiota associated to Clostridium difficile infection}},
volume = {5},
year = {2014}
}
@article{Petrof2013,
abstract = {BACKGROUND: Fecal bacteriotherapy ('stool transplant') can be effective in treating recurrent Clostridium difficile infection, but concerns of donor infection transmission and patient acceptance limit its use. Here we describe the use of a stool substitute preparation, made from purified intestinal bacterial cultures derived from a single healthy donor, to treat recurrent C. difficile infection that had failed repeated standard antibiotics. Thirty-three isolates were recovered from a healthy donor stool sample. Two patients who had failed at least three courses of metronidazole or vancomycin underwent colonoscopy and the mixture was infused throughout the right and mid colon. Pre-treatment and post-treatment stool samples were analyzed by 16 S rRNA gene sequencing using the Ion Torrent platform.$\backslash$n$\backslash$nRESULTS: Both patients were infected with the hyper virulent C. difficile strain, ribotype 078. Following stool substitute treatment, each patient reverted to their normal bowel pattern within 2 to 3 days and remained symptom-free at 6 months. The analysis demonstrated that rRNA sequences found in the stool substitute were rare in the pre-treatment stool samples but constituted over 25{\%} of the sequences up to 6 months after treatment.$\backslash$n$\backslash$nCONCLUSION: This proof-of-principle study demonstrates that a stool substitute mixture comprising a multi-species community of bacteria is capable of curing antibiotic-resistant C. difficile colitis. This benefit correlates with major changes in stool microbial profile and these changes reflect isolates from the synthetic mixture.$\backslash$n$\backslash$nTRIAL REGISTRATION: $\backslash$n$\backslash$nCLINICAL TRIAL REGISTRATION NUMBER: CinicalTrials.gov NCT01372943.},
author = {Petrof, Elaine O and Gloor, Gregory B and Vanner, Stephen J and Weese, Scott J and Carter, David and Daigneault, Michelle C and Brown, Eric M and Schroeter, Kathleen and Allen-Vercoe, Emma},
doi = {10.1186/2049-2618-1-3},
isbn = {2049-2618 (Electronic)$\backslash$n2049-2618 (Linking)},
issn = {2049-2618},
journal = {Microbiome},
number = {1},
pages = {3},
pmid = {24467987},
title = {{Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating' the gut}},
url = {http://microbiomejournal.biomedcentral.com/articles/10.1186/2049-2618-1-3},
volume = {1},
year = {2013}
}
@article{Reeves2012,
abstract = {The indigenous microbial community of the gastrointestinal (GI) tract determines susceptibility to Clostridium difficile colonization and disease. Previous studies have demonstrated that antibiotic-treated mice challenged with C. difficile either developed rapidly lethal C. difficile infection or were stably colonized with mild disease. The GI microbial community of animals with mild disease was dominated by members of the bacterial family Lachnospiraceae, while the gut community in moribund animals had a predominance of Escherichia coli. We investigated the roles of murine Lachnospiraceae and E. coli strains in colonization resistance against C. difficile in germfree mice. Murine Lachnospiraceae and E. coli isolates were cultured from wild-type mice. The ability of each of these isolates to interfere with C. difficile colonization was tested by precolonizing germfree mice with these bacteria 4 days prior to experimental C. difficile challenge. Mice precolonized with a murine Lachnospiraceae isolate, but not those colonized with E. coli, had significantly decreased C. difficile colonization, lower intestinal cytotoxin levels and exhibited less severe clinical signs and colonic histopathology. Infection of germfree mice or mice precolonized with E. coli with C. difficile strain VPI 10463 was uniformly fatal by 48 h, but only 20{\%} mortality was seen at 2 days in mice precolonized with the Lachnospiraceae isolate prior to challenge with VPI 10463. These findings confirm that a single component of the GI microbiota, a murine Lachnospiraceae isolate, could partially restore colonization resistance against C. difficile. Further study of the members within the Lachnospiraceae family could lead to a better understanding of mechanisms of colonization resistance against C. difficile and novel therapeutic approaches for the treatment and prevention of C. difficile infection.},
author = {Reeves, Angela E. and Koenigsknecht, Mark J. and Bergin, Ingrid L. and Young, Vincent B.},
doi = {10.1128/IAI.00647-12},
isbn = {1098-5522 (Electronic)$\backslash$r0019-9567 (Linking)},
issn = {00199567},
journal = {Infection and Immunity},
number = {11},
pages = {3786--3794},
pmid = {22890996},
title = {{Suppression of Clostridium difficile in the gastrointestinal tracts of germfree mice inoculated with a murine isolate from the family Lachnospiraceae}},
volume = {80},
year = {2012}
}
@article{Reeves2011,
abstract = {Clostridium difficile infection (CDI) arises in the setting of antibiotic administration where disruption of the normal indigenous gut microbiota leads to susceptibility to C. difficile colonization and colitis. Using a murine model of CDI, we demonstrate that changes in the community structure of the indigenous gut microbiota are associated with the loss of colonization resistance against C. difficile. Several antibiotic regimens were tested in combination for the ability to overcome colonization resistance, including a five antibiotic cocktail consisting of kanamycin, gentamicin, colistin, metronidazole, and vancomycin administered in drinking water for three days, a single intraperitoneal dose of clindamycin or 10 days of cefoperazone in drinking water. Following antibiotic treatment animals were challenged with 105 colony forming units of C. difficile strain VPI 10463 via oral gavage. Animals that received the antibiotic cocktail and clindamycin prior to C. difficile challenge followed one of two clinical courses, either becoming clinically ill and moribund within 2-4 days post challenge, or remaining clinically well. Animals that became clinically ill developed histologically severe colitis. These histopathologic findings were significantly less severe in animals that remained clinically well. Analysis of 16S rRNA gene sequences retrieved from gut tissue at necropsy demonstrated that Proteobacteria dominated the gut microbiota in clinically ill animals. In contrast, the gut microbial community of clinically well animals more closely resembled untreated animals, which were dominated by members of the Firmicutes. All animals that received cefoperazone treatment prior to C. difficile challenge were clinically ill and moribund by 2-5 days post challenge in a dose dependent manner. The gut communities in these animals were dominated by C.difficile suggesting that cefoperazone treatment resulted in a greater loss in colonization resistance. Thus, the severity of colitis that arises in this system reflects the interplay between the expansion of C. difficile in the gut community and the ecologic dynamics of the indigenous microbial community as it recovers from antibiotic perturbation. We demonstrate that altering the balance of these two opposing processes alters clinical outcome and thus may lead to novel preventative and therapeutic approaches for CDI.},
author = {Reeves, Angela E. and Theriot, Casey M. and Bergin, Ingrid L. and Huffnagle, Gary B. and Schloss, Patrick D. and Young, Vincent B.},
doi = {10.4161/gmic.2.3.16333},
isbn = {1949-0984 (Electronic)},
issn = {19490976},
journal = {Gut Microbes},
keywords = {Antibiotic-associated diarrhea,C. difficile infection,Clostridium difficile,Colonization resistance,Microbial ecology},
number = {3},
pages = {145--158},
pmid = {21804357},
title = {{The interplay between microbiome dynamics and pathogen dynamics in a murine model of Clostridium difficile infection}},
volume = {2},
year = {2011}
}
@article{Robinson2010,
abstract = {We recently demonstrated that antibiotic administration has a reproducible effect on the community structure of the indigenous gastrointestinal microbiota of mice. In this addendum we report on additional experimentation using the antibiotic vancomycin. In accord with our previous findings, vancomycin administration results in consistent alteration of the microbiota of the cecal contents and the cecal mucosa. These alterations are largely reversed by a three-week period of recovery without antibiotics. In contrast to our previous results using other antibiotics, the alterations in community structure associated with vancomycin occured without a significant decrease in the overall bacterial biomass. These results indicate that different antibiotics have specific effects on the gut microbiota. This points the way towards targeted, therapeutic alteration of the gut bacterial community as a whole.},
author = {Robinson, Courtney J. and Young, Vincent B.},
doi = {10.4161/gmic.1.4.12614},
isbn = {10.4161/gmic.1.4.12614},
issn = {1949-0976},
journal = {Gut Microbes},
number = {4},
pages = {279--284},
pmid = {20953272},
title = {{Antibiotic administration alters the community structure of the gastrointestinal microbiota}},
url = {http://www.tandfonline.com/doi/abs/10.4161/gmic.1.4.12614},
volume = {1},
year = {2010}
}
@article{Rohlke2012,
abstract = {Clostridium difficile infection rates are Climbing in frequency and severity, and the spectrum of susceptible patients is expanding beyond the traditional scope of hospitalized patients receiving antibiotics. Fecal microbiota transplantation is becoming increasingly accepted as an effective and safe intervention in patients with recurrent disease, likely due to the restoration of a disrupted microbiome. Cure rates of {\textgreater} 90{\%} are being consistently reported from multiple centers. Transplantation can be provided through a variety of methodologies, either to the lower proximal, lower distal, or upper gastrointestinal tract. This review summarizes reported results, factors in donor selection, appropriate patient criteria, and the various preparations and mechanisms of fecal microbiota transplant delivery available to clinicians and patients.},
author = {Rohlke, Faith and Stollman, Neil},
doi = {10.1177/1756283X12453637},
isbn = {1756-2848 (Electronic)$\backslash$r1756-283X (Linking)},
issn = {1756-2848},
journal = {Therapeutic advances in gastroenterology},
keywords = {clostridium difficile,fecal bacteriotherapy,fecal flora,fecal flora reconstitution,fecal microbiota transplantation,fecal transplant,recurrent clostridium difficile infection,stool},
number = {6},
pages = {403--420},
pmid = {23152734},
title = {{Fecal microbiota transplantation in relapsing Clostridium difficile infection.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3491681{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {5},
year = {2012}
}
@article{Rojo2015,
abstract = {Clostridium difficile-associated diarrhoea (CDAD) is caused by C. difficile toxins A and B and represents a serious emerging health problem. Yet, its progression and functional consequences are unclear. We hypothesised that C. difficile can drive major measurable metabolic changes in the gut microbiota and that a relationship with the production or absence of toxins may be established. We tested this hypothesis by performing metabolic profiling on the gut microbiota of patients with C. difficile that produced (n = 6) or did not produce (n = 4) toxins and on non-colonised control patients (n = 6), all of whom were experiencing diarrhoea. We report a statistically significant separation (P-value o0.05) among the three groups, regardless of patient characteristics, duration of the disease, antibiotic therapy and medical history. This classification is associated with differences in the production of distinct molecules with presumptive global importance in the gut environment, disease progression and inflammation. Moreover, although severe impaired metabolite production and biological deficits were associated with the carriage of C. difficile that did not produce toxins, only previously unrecognised selective features, namely, choline-and acetylputrescine-deficient gut environments, characterised the carriage of toxin-producing C. difficile. Additional results showed that the changes induced by C. difficile become marked at the highest level of the functional hierarchy, namely the metabolic activity exemplified by the gut microbial metabolome regardless of heterogeneities that commonly appear below the functional level (gut bacterial composition). We discuss possible explanations for this effect and suggest that the changes imposed by CDAD are much more defined and predictable than previously thought.},
author = {Rojo, David and Gosalbes, Mar{\'{i}}a J and Ferrari, Rafaela and P{\'{e}}rez-Cobas, Ana E and Hern{\'{a}}ndez, Ester and Oltra, Rosa and Buesa, Javier and Latorre, Amparo and Barbas, Coral and Ferrer, Manuel and Moya, Andr{\'{e}}s},
doi = {10.1038/ismej.2015.32},
isbn = {1751-7370},
issn = {1751-7362},
journal = {The ISME Journal},
number = {10},
pages = {2206--2220},
pmid = {25756679},
title = {{Clostridium difficile heterogeneously impacts intestinal community architecture but drives stable metabolome responses}},
url = {http://www.nature.com/doifinder/10.1038/ismej.2015.32},
volume = {9},
year = {2015}
}
@article{Russel2017,
author = {Russel, Jakob and Roder, Henriette and Madsen, Jonas and Burmell, Mette and Soresen, Soren},
journal = {PNAS},
mendeley-groups = {Metatranscriptomics paper},
title = {{Antagonism correlates with metabolic similarity in diverse bacteria}},
year = {2017}
}
@article{Rutkowski2003,
abstract = {BACKGROUND: N-methyl-2-pyridone-5-carboxamide (2PY) is one of the end products of nicotinamide-adenine dinucleotide (NAD) degradation. We recently found that serum 2PY concentrations in chronic renal failure (CRF) patients were enhanced to the values, which are potentially toxic. The aim of this study was to determine whether 2PY is an inhibitor of poly(ADP-ribose) polymerase, the nuclear enzyme that is highly involved in variety of physiologic events, including regulation of DNA replication and DNA repair.$\backslash$n$\backslash$nMETHODS: High-performance liquid chromatography (HPLC) was used to determine 2PY and other NAD catabolite concentrations in serum of: nondialyzed patients; patients chronically hemodialyzed; patients after kidney transplantation; and healthy individuals (control group). Moreover, the effect of nicotinamide and 2PY on poly(ADP-ribose) polymerase (PARP-1) in vitro was studied.$\backslash$n$\backslash$nRESULTS: The serum nicotinamide, 2PY, and 4PY (N-methyl-4-pyridone-3-carboxamide) concentrations are many times elevated in nondialyzed CRF patients when compared with controls. The direct correlations were found between serum 2PY (as well as 4PY and nicotinamide) concentrations and serum creatinine concentration, and negative correlations between serum concentrations of these compounds and creatinine clearance. The concentration of 2PY decreases considerably after hemodialysis (HD) session, but elevates back 48 hours later. It permanently declines after kidney transplantation. Nicotinamide and 2PY significantly inhibit PARP-1 activity in vitro.$\backslash$n$\backslash$nCONCLUSIONS: Increased serum 2PY concentration, along with a deterioration of kidney function and its toxic properties (significant inhibition of PARP-1 by 2PY), suggest that it could be a novel uremic toxin.},
author = {Rutkowski, Boleslaw and Slominska, Ewa and Szolkiewicz, Marek and Smolenski, Ryszard T. and Striley, Cindy and Rutkowski, Przemyslaw and Swierczynski, Julian},
doi = {10.1046/j.1523-1755.63.s84.36.x},
issn = {00852538},
journal = {Kidney International},
pages = {S19--S21},
pmid = {12694300},
title = {{N-methyl-2-pyridone-5-carboxamide: A novel uremic toxin?}},
url = {http://linkinghub.elsevier.com/retrieve/pii/S0085253815492075},
volume = {63},
year = {2003}
}
@article{Sambol2002,
abstract = {Studies suggest that asymptomatic colonization with Clostridium difficile (CD) decreases the risk of CD-associated disease (CDAD) in humans. A hamster model was used to test the efficacy of colonization with 3 nontoxigenic CD strains for preventing CDAD after exposure to toxigenic CD. Groups of 10 hamsters were given 106 nontoxigenic CD spores 2 days after receiving a single dose of clindamycin. Five days later, the hamsters were given 100 spores of 1 of 3 toxigenicCDstrains previously shown to cause mortality within 48 h. Each nontoxigenic strain prevented disease in 87{\%}–97{\%} of hamsters that were challenged with toxigenic strains. Failure to prevent CDAD was associated with failure of colonization with nontoxigenic CD. Colonization with nontoxigenicCDstrains is highly effective in preventingCDADin hamsters challenged with toxigenicCDstrains, which suggests that use of a probiotic strategy forCDAD prevention in humans receiving antibiotics might be beneficial},
author = {Sambol, Susan P and Merrigan, Michelle M and Tang, Janet K and Johnson, Stuart and Gerding, Dale N},
doi = {10.1086/345676},
isbn = {0022-1899 (Print)$\backslash$r0022-1899 (Linking)},
issn = {0022-1899},
journal = {The Journal of infectious diseases},
pages = {14--16},
pmid = {12447764},
title = {{Colonization for the Prevention of Clostridium difficile Disease in Hamsters}},
volume = {186},
year = {2002}
}
@article{Schubert2015,
abstract = {UNLABELLED: Perturbations to the gut microbiota can result in a loss of colonization resistance against gastrointestinal pathogens such as Clostridium difficile. Although C. difficile infection is commonly associated with antibiotic use, the precise alterations to the microbiota associated with this loss in function are unknown. We used a variety of antibiotic perturbations to generate a diverse array of gut microbiota structures, which were then challenged with C. difficile spores. Across these treatments we observed that C. difficile resistance was never attributable to a single organism, but rather it was the result of multiple microbiota members interacting in a context-dependent manner. Using relative abundance data, we built a machine learning regression model to predict the levels of C. difficile that were found 24 h after challenging the perturbed communities. This model was able to explain 77.2{\%} of the variation in the observed number of C. difficile per gram of feces. This model revealed important bacterial populations within the microbiota, which correlation analysis alone did not detect. Specifically, we observed that populations associated with the Porphyromonadaceae, Lachnospiraceae, Lactobacillus, and Alistipes were protective and populations associated with Escherichia and Streptococcus were associated with high levels of colonization. In addition, a population affiliated with the Akkermansia indicated a strong context dependency on other members of the microbiota. Together, these results indicate that individual bacterial populations do not drive colonization resistance to C. difficile. Rather, multiple diverse assemblages act in concert to mediate colonization resistance.$\backslash$n$\backslash$nIMPORTANCE: The gastrointestinal tract harbors a complex community of bacteria, known as the microbiota, which plays an integral role preventing its colonization by gut pathogens. This resistance has been shown to be crucial for protection against Clostridium difficile infections (CDI), which are the leading source of hospital-acquired infections in the United States. Antibiotics are a major risk factor for acquiring CDI due to their effect on the normal structure of the indigenous gut microbiota. We found that diverse antibiotic perturbations gave rise to altered communities that varied in their susceptibility to C. difficile colonization. We found that multiple coexisting populations, not one specific population of bacteria, conferred resistance. By understanding the relationships between C. difficile and members of the microbiota, it will be possible to better manage this important infection.},
author = {Schubert, Alyxandria M. and Sinani, Hamide and Schloss, Patrick D.},
doi = {10.1128/mBio.00974-15},
isbn = {2150-7511 (Electronic)},
issn = {21507511},
journal = {mBio},
number = {4},
pmid = {26173701},
title = {{Antibiotic-induced alterations of the murine gut microbiota and subsequent effects on colonization resistance against Clostridium difficile}},
volume = {6},
year = {2015}
}
@article{Segal2004,
abstract = {Breiman (2001a,b) has recently developed an ensemble classification and regression approach that displayed outstanding performance with regard prediction error on a suite of benchmark datasets. As the base constituents of the ensemble are tree-structured predictors, and since each of these is constructed using an injection of randomness, the method is called random forests. That the exceptional performance is attained with seemingly only a single tuning parameter, to which sensitivity is minimal, makes the methodology all the more remarkable. The individual trees comprising the forest are all grown to maximal depth. While this helps with regard bias, there is the familiar tradeoff with variance. However, these variability concerns were potentially obscured because of an interesting feature of those benchmarking datasets extracted from the UCI machine learning repository for testing: all these datasets are hard to overfit using tree-structured methods. This raises issues about the scope of the repository. With this as motivation, and coupled with experience from boosting methods, we revisit the formulation of random forests and investigate prediction performance on real-world and simulated datasets for which maximally sized trees do overfit. These explorations reveal that gains can be realized by additional tuning to regulate tree size via limiting the number of splits and/or the size of nodes for which splitting is allowed. Nonetheless, even in these settings, good performance for random forests can be attained by using larger (than default) primary tuning parameter values.},
author = {Segal, Mark R},
journal = {Biostatistics},
keywords = {prediction error,regression,uci repository},
number = {MAY 2003},
pages = {1--14},
title = {{Machine Learning Benchmarks and Random Forest Regression}},
url = {http://escholarship.org/uc/item/35x3v9t4.pdf},
year = {2004}
}
@article{Segata2011,
abstract = {This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes.},
author = {Segata, Nicola and Izard, Jacques and Waldron, Levi and Gevers, Dirk and Miropolsky, Larisa and Garrett, Wendy S and Huttenhower, Curtis},
doi = {10.1186/gb-2011-12-6-r60},
isbn = {1465-6914 (Electronic)$\backslash$n1465-6906 (Linking)},
issn = {1465-6906},
journal = {Genome Biology},
number = {6},
pages = {R60},
pmid = {21702898},
title = {{Metagenomic biomarker discovery and explanation}},
url = {http://genomebiology.biomedcentral.com/articles/10.1186/gb-2011-12-6-r60},
volume = {12},
year = {2011}
}
@article{Semba2017,
abstract = {Background Environmental enteric dysfunction (EED), a condition characterized by small intestine inflammation and abnormal gut permeability, is widespread in children in developing countries and a major cause of growth failure. The pathophysiology of EED remains poorly understood. Methods We measured serum metabolites using liquid chromatography-tandem mass spectrometry in 400 children, aged 12–59 months, from rural Malawi. Gut permeability was assessed by the dual-sugar absorption test. Findings 80.7{\%} of children had EED. Of 677 serum metabolites measured, 21 were negatively associated and 56 were positively associated with gut permeability, using a false discovery rate approach (q {\textless} 0.05, p {\textless} 0.0095). Increased gut permeability was associated with elevated acylcarnitines, deoxycarnitine, fatty acid $\beta$-oxidation intermediates, fatty acid $\omega$-oxidation products, odd-chain fatty acids, trimethylamine-N-oxide, cystathionine, and homocitrulline, and with lower citrulline, ornithine, polyphenol metabolites, hippurate, tryptophan, and indolelactate. Interpretation EED is a syndrome characterized by secondary carnitine deficiency, abnormal fatty acid oxidation, alterations in polyphenol and amino acid metabolites, and metabolic dysregulation of sulfur amino acids, tryptophan, and the urea cycle. Future studies are needed to corroborate the presence of secondary carnitine deficiency among children with EED and to understand how these metabolic derangements may negatively affect the growth and development of young children.},
author = {Semba, Richard D. and Trehan, Indi and Li, Ximin and Moaddel, Ruin and Ordiz, M. Isabel and Maleta, Kenneth M. and Kraemer, Klaus and Shardell, Michelle and Ferrucci, Luigi and Manary, Mark},
doi = {10.1016/j.ebiom.2017.01.026},
isbn = {0000000000},
issn = {23523964},
journal = {EBioMedicine},
keywords = {Acylcarnitines,Carnitine,Environmental enteric dysfunction,Fatty acid oxidation,Hippurate,Polyphenols,Tryptophan,Urea cycle},
pages = {57--66},
pmid = {28122695},
title = {{Environmental Enteric Dysfunction is Associated with Carnitine Deficiency and Altered Fatty Acid Oxidation}},
volume = {17},
year = {2017}
}
@article{Shade2014,
abstract = {Microbial communities typically contain many rare taxa that make up the majority of the observed membership, yet the contribution of this microbial "rare biosphere" to community dynamics is unclear. Using 16S rRNA amplicon sequencing of 3,237 samples from 42 time series of microbial communities from nine different ecosystems (air; marine; lake; stream; adult human skin, tongue, and gut; infant gut; and brewery wastewater treatment), we introduce a new method to detect typically rare microbial taxa that occasionally become very abundant (conditionally rare taxa [CRT]) and then quantify their contributions to temporal shifts in community structure. We discovered that CRT made up 1.5 to 28{\%} of the community membership, represented a broad diversity of bacterial and archaeal lineages, and explained large amounts of temporal community dissimilarity (i.e., up to 97{\%} of Bray-Curtis dissimilarity). Most of the CRT were detected at multiple time points, though we also identified "one-hit wonder" CRT that were observed at only one time point. Using a case study from a temperate lake, we gained additional insights into the ecology of CRT by comparing routine community time series to large disturbance events. Our results reveal that many rare taxa contribute a greater amount to microbial community dynamics than is apparent from their low proportional abundances. This observation was true across a wide range of ecosystems, indicating that these rare taxa are essential for understanding community changes over time. Importance: Microbial communities and their processes are the foundations of ecosystems. The ecological roles of rare microorganisms are largely unknown, but it is thought that they contribute to community stability by acting as a reservoir that can rapidly respond to environmental changes. We investigated the occurrence of typically rare taxa that very occasionally become more prominent in their communities ("conditionally rare"). We quantified conditionally rare taxa in time series from a wide variety of ecosystems and discovered that not only were conditionally rare taxa present in all of the examples, but they also contributed disproportionately to temporal changes in diversity when they were most abundant. This result indicates an important and general role for rare microbial taxa within their communities.},
author = {Shade, Ashley and Jones, Stuart E. and {Gregory Caporaso}, J. and Handelsman, Jo and Knight, Rob and Fierer, Noah and Gilbert, Jack A.},
doi = {10.1128/mBio.01371-14},
isbn = {2150-7511 (Electronic)},
issn = {21507511},
journal = {mBio},
number = {4},
pmid = {25028427},
title = {{Conditionally rare taxa disproportionately contribute to temporal changes in microbial diversity}},
volume = {5},
year = {2014}
}
@article{Sheik2014,
abstract = {Chemolithotrophy is a pervasive metabolic lifestyle for microorganisms in the dark ocean. The SAR324 group of Deltaproteobacteria is ubiquitous in the ocean and has been implicated in sulfur oxidation and carbon fixation, but also contains genomic signatures of C1 utilization and heterotrophy. Here, we reconstructed the metagenome and metatranscriptome of a population of SAR324 from a hydrothermal plume and surrounding waters in the deep Gulf of California to gain insight into the genetic capability and transcriptional dynamics of this enigmatic group. SAR324's metabolism is signified by genes that encode a novel particulate hydrocarbon monooxygenase (pHMO), degradation pathways for corresponding alcohols and short-chain fatty acids, dissimilatory sulfur oxidation, formate dehydrogenase (FDH) and a nitrite reductase (NirK). Transcripts of the pHMO, NirK, FDH and transporters for exogenous carbon and amino acid uptake were highly abundant in plume waters. Sulfur oxidation genes were also abundant in the plume metatranscriptome, indicating SAR324 may also utilize reduced sulfur species in hydrothermal fluids. These results suggest that aspects of SAR324's versatile metabolism (lithotrophy, heterotrophy and alkane oxidation) operate simultaneously, and may explain SAR324's ubiquity in the deep Gulf of California and in the global marine biosphere.},
author = {Sheik, Cody S. and Jain, Sunit and Dick, Gregory J.},
doi = {10.1111/1462-2920.12165},
file = {:C$\backslash$:/Users/Matt Jenior/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sheik, Jain, Dick - 2014 - Metabolic flexibility of enigmatic SAR324 revealed through metagenomics and metatranscriptomics.pdf:pdf},
isbn = {1734763469},
issn = {14622912},
journal = {Environmental Microbiology},
number = {1},
pages = {304--317},
pmid = {23809230},
title = {{Metabolic flexibility of enigmatic SAR324 revealed through metagenomics and metatranscriptomics}},
volume = {16},
year = {2014}
}
@article{Sorg2010,
abstract = {To cause disease, Clostridium difficile spores must germinate in the host gastrointestinal tract. Germination is initiated upon exposure to glycine and certain bile acids, e.g., taurocholate. Chenodeoxycholate, another bile acid, inhibits taurocholate-mediated germination. By applying Michaelis-Menten kinetic analysis to C. difficile spore germination, we found that chenodeoxycholate is a competitive inhibitor of taurocholate-mediated germination and appears to interact with the spores with greater apparent affinity than does taurocholate. We also report that several analogs of chenodeoxycholate are even more effective inhibitors. Some of these compounds resist 7$\alpha$-dehydroxylation by Clostridium scindens, a core member of the normal human colonic microbiota, suggesting that they are more stable than chenodeoxycholate in the colonic environment.},
author = {Sorg, Joseph A. and Sonenshein, Abraham L.},
doi = {10.1128/JB.00610-10},
isbn = {1098-5530 (Electronic)$\backslash$r0021-9193 (Linking)},
issn = {00219193},
journal = {Journal of Bacteriology},
number = {19},
pages = {4983--4990},
pmid = {20675492},
title = {{Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid}},
volume = {192},
year = {2010}
}
@article{Theriot2011,
abstract = {The toxin-producing bacterium C. difficile is the leading cause of antibiotic-associated colitis, with an estimated 500,000 cases C. difficile infection (CDI) each year in the US with a cost approaching 3 billion dollars. Despite the significance of CDI, the pathogenesis of this infection is still being defined. The recent development of tractable murine models of CDI will help define the determinants of C. difficile pathogenesis in vivo. To determine if cefoperazone-treated mice could be utilized to reveal differential pathogenicity of C. difficile strains, 5–8 week old C57BL/6 mice were pretreated with a 10 d course of cefoperazone administered in the drinking water. Following a 2-d recovery period without antibiotics, the animals were orally challenged with C. difficile strains chosen to represent the potential range of virulence of this organism from rapidly fatal to nonpathogenic. Animals were monitored for loss of weight and clinical signs of colitis. At the time of harvest, C. difficile strains were isolated from cecal contents and the severity of colitis was determined by histopathologic examination of the cecum and colon. Cefoperazone treated mice challenged with C. difficile strains VPI 10463 and BI1 exhibited signs of severe colitis while infection with 630 and F200 was subclinical. This increased clinical severity was correlated with more severe histopathology with significantly more edema, inflammation and epithelial damage encountered in the colons of animals infected with VPI 10463 and BI1. Disease severity also correlated with levels of C. difficile cytotoxic activity in intestinal tissues and elevated blood neutrophil counts. Cefoperazone treated mice represent a useful model of C. difficile infection that will help us better understand the pathogenesis and virulence of this re-emerging pathogen.},
author = {Theriot, Casey M. and Koumpouras, Charles C. and Carlson, Paul E. and Bergin, Ingrid I. and Aronoff, David M. and Young, Vincent B.},
doi = {10.4161/gmic.2.6.19142},
isbn = {1949-0984 (Electronic)},
issn = {19490984},
journal = {Gut microbes},
number = {6},
pages = {326--334},
pmid = {22198617},
title = {{Cefoperazone-treated mice as an experimental platform to assess differential virulence of Clostridium difficile strains.}},
volume = {2},
year = {2011}
}
@article{Theriot2014,
abstract = {Antibiotics can have significant and long-lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and ex vivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotics, including the primary bile acid taurocholate for germination, and carbon sources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate that antibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one that favours C. difficile germination and growth.},
author = {Theriot, Casey M and Koenigsknecht, Mark J and Carlson, Paul E and Hatton, Gabrielle E and Nelson, Adam M and Li, Bo and Huffnagle, Gary B and {Z Li}, Jun and Young, Vincent B},
doi = {10.1038/ncomms4114},
isbn = {2041-1723 (Electronic)$\backslash$r2041-1723 (Linking)},
issn = {2041-1723},
journal = {Nature communications},
pages = {3114},
pmid = {24445449},
title = {{Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3950275{\&}tool=pmcentrez{\&}rendertype=abstract},
volume = {5},
year = {2014}
}
@article{Fletcher2018,
abstract = {Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in the gut metabolome, specifically, with increases in levels of nutrients that C. difficile can utilize for growth in vitro. To define the nutrients that C. difficile requires for colonization and pathogenesis in vivo, we used a combination of mass spectrometry and RNA sequencing (RNA Seq) to model the gut metabolome and C. difficile transcriptome throughout an acute infection in a mouse model at the following time points: 0, 12, 24, and 30 h. We also performed multivariate-based integration of the omics data to define the signatures that were most important throughout colonization and infection. Here we show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time in the mouse cecum and that C. difficile gene expression is consistent with their utilization in vivo. This was also reinforced by the multivariate-based integration of the omics data where we were able to discriminate the metabolites and transcripts that support C. difficile physiology between the different time points throughout colonization and infection. This report illustrates how important the availability of amino acids and other nutrients is for the initial stages of C. difficile colonization and progression of disease. Future studies identifying the source of the nutrients and engineering bacteria capable of outcompeting C. difficile in the gut will be important for developing new targeted bacterial therapeutics.},
author = {Fletcher, Joshua R and Erwin, Samantha and Lanzas,  Cristina and Theriot, Casey M},
doi = {10.1128/mSphere.00089-18},
journal = {mSphere},
pmid = {29600278},
title = {{Shifts in the Gut Metabolome and Clostridium difficile Transcriptome throughout Colonization and Infection in a Mouse Model}},
volume = {3(2)},
year = {2018}
}
@article{Thomas2003,
abstract = {A systematic review of studies that investigated the association of antibiotics with hospital-acquired Clostridium difficile-associated diarrhoea (CDAD) was undertaken to summarize the strength of the evidence for this relationship. The results from the studies identified were considered after critically reviewing the design and conduct of each study. Although the majority of studies found an association with various antibiotics, antibiotic classes or components of antibiotic administration, most were limited in their ability to establish a causal relationship by the use of incorrect control groups, the presence of bias, inadequate control of confounding and small sample sizes. The limitations identified in this review prevented the pooling of results in a meta-analysis. Two studies of reasonable quality suggested an association between clindamycin, cephalosporins, penicillins and CDAD. Well-designed studies grounded in epidemiological principles are needed to identify true risk factors for CDAD and to provide reliable estimates of the strength of association.},
author = {Thomas, Claudia and Stevenson, Mark and Riley, Thomas V.},
booktitle = {Journal of Antimicrobial Chemotherapy},
doi = {10.1093/jac/dkg254},
isbn = {0305-7453},
issn = {03057453},
keywords = {Clostridium Difficile,Systematic review},
number = {6},
pages = {1339--1350},
pmid = {12746372},
title = {{Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: A systematic review}},
volume = {51},
year = {2003}
}
@article{VanEijk2015,
abstract = {BACKGROUND Clostridium difficile strain 630$\Delta$erm is a spontaneous erythromycin sensitive derivative of the reference strain 630 obtained by serial passaging in antibiotic-free media. It is widely used as a defined and tractable C. difficile strain. Though largely similar to the ancestral strain, it demonstrates phenotypic differences that might be the result of underlying genetic changes. Here, we performed a de novo assembly based on single-molecule real-time sequencing and an analysis of major methylation patterns. RESULTS In addition to single nucleotide polymorphisms and various indels, we found that the mobile element CTn5 is present in the gene encoding the methyltransferase rumA rather than adhesin CD1844 where it is located in the reference strain. CONCLUSIONS Together, the genetic features identified in this study may help to explain at least part of the phenotypic differences. The annotated genome sequence of this lab strain, including the first analysis of major methylation patterns, will be a valuable resource for genetic research on C. difficile.},
author = {van Eijk, Erika and Anvar, Seyed and Browne, Hilary P and Leung, Wai and Frank, Jeroen and Schmitz, Arnoud M and Roberts, Adam P and Smits, Wiep},
doi = {10.1186/s12864-015-1252-7},
isbn = {1471-2164},
issn = {1471-2164},
journal = {BMC Genomics},
number = {1},
pages = {31},
pmid = {25636331},
title = {{Complete genome sequence of the Clostridium difficile laboratory strain 630$\Delta$erm reveals differences from strain 630, including translocation of the mobile element CTn5}},
url = {http://www.biomedcentral.com/1471-2164/16/31},
volume = {16},
year = {2015}
}
@misc{Vollaard1994,
abstract = {In 1987 we reviewed the literature on the concept of colonization resistance (CR) (12). In this concept, the indige- nous anaerobic flora limits the concentration of potentially pathogenic (mostly aerobic) flora in the digestive tract. This implies that the risk of superinfections by aerobic flora would be eliminated by selecting those antimicrobial agents which spare the anaerobic flora. The concept of CR was based on experiments in animals and uncontrolled observations in pa- tients. It was not validated conclusively. Since publication of our previous review (12), we have improved the design for studying the influence of antimicrobial agents on CR, especially by using human volunteers and analyzing the data in each volunteer separately with single- patient statistics (57, 63). This methodology was applied in the study of several antimicrobial agents (57-61, 63, 64). The resulting data provide a better understanding of the impact of antimicrobial agents on the microbial flora of the bowel. At present, it seems to be the case that some former conclusions were made prematurely, especially those pertaining to the availability of antimicrobial agents that do not impair CR (12, 47). This review will be restricted to a discussion of CR of the bowel.},
author = {Vollaard, E. J. and Clasener, H. A L},
booktitle = {Antimicrobial Agents and Chemotherapy},
doi = {10.1128/AAC.38.3.409},
isbn = {00664804 (ISSN)},
issn = {00664804},
number = {3},
pages = {409--414},
pmid = {8203832},
title = {{Colonization resistance}},
volume = {38},
year = {1994}
}
@article{Willing2011,
abstract = {Antibiotics have been used effectively as a means to treat bacterial infections in humans and animals for over half a century. However, through their use, lasting alterations are being made to a mutualistic relationship that has taken millennia to evolve: the relationship between the host and its microbiota. Host-microbiota interactions are dynamic; therefore, changes in the microbiota as a consequence of antibiotic treatment can result in the dysregulation of host immune homeostasis and an increased susceptibility to disease. A better understanding of both the changes in the microbiota as a result of antibiotic treatment and the consequential changes in host immune homeostasis is imperative, so that these effects can be mitigated.},
author = {Willing, B P and Russell, S L and Finlay, B B},
doi = {nrmicro2536 [pii]\r10.1038/nrmicro2536},
isbn = {1740-1534 (Electronic)$\backslash$r1740-1526 (Linking)},
issn = {1740-1534},
journal = {Nat Rev Microbiol},
keywords = {*Immunity, Mucosal,Animals,Anti-Bacterial Agents/*pharmacology/therapeutic us,Bacteria/*drug effects/metabolism,Bacterial Infections/*drug therapy/microbiology,Biomass,Disease Susceptibility,Enterocolitis, Pseudomembranous/etiology,Fatty Acids, Volatile/metabolism,Gastrointestinal Tract/*drug effects/immunology/mi,Homeostasis/drug effects,Host-Pathogen Interactions/*drug effects,Humans,Metagenome/*drug effects,Microbial Interactions/*drug effects ARMS-I,antiviral,ferret model},
number = {4},
pages = {233--243},
pmid = {21358670},
title = {{Shifting the balance: antibiotic effects on host-microbiota mutualism}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21358670},
volume = {9},
year = {2011}
}
@article{Wilson1982,
abstract = {Isolation of Clostridium difficile from fecal specimens has been facilitated by the development of a selective and differential medium, cefoxitin-cycloserinefructose agar (CCFA). We substituted 0.1{\%} sodium taurocholate for the 2.5{\%} egg yolk in CCFA and compared the growth of 15 isolates of C. difficile on the resulting medium with growth on conventional CCFA. The taurocholate-containing medium (TCCFA) quantitatively recovered vegetative forms of C. difficile in the same numbers as CCFA medium. Recovery of spores was a mean 1.7 log(10) higher on TCCFA than on CCFA. Thirty-six of 60 patient stool specimens growing C. difficile gave a heavier growth on TCCFA than on CCFA, and 9 failed to yield C. difficile on CCFA. TCCFA detected spores of 75 colony-forming units per ml from artificially inoculated fecal specimens when conventional stool culturing techniques were used. Fluorescence of colonies of C. difficile was more intense on TCCFA than on CCFA. TCCFA was simpler to prepare and, overall, was more sensitive than CCFA.},
author = {Wilson, K. H. and Kennedy, M. J. and Fekety, F. R.},
isbn = {0095-1137 (Print)$\backslash$r0095-1137 (Linking)},
issn = {00951137},
journal = {Journal of Clinical Microbiology},
number = {3},
pages = {443--446},
pmid = {7076817},
title = {{Use of sodium taurocholate to enhance spore recovery on a medium selective for Clostridium difficile}},
volume = {15},
year = {1982}
}
@article{Wilson1988,
abstract = {The cecal flora of mice is able to eliminate Clostridium difficile from the mouse cecum even when C. difficile is the first organism established. We used a continuous-flow (CF) culture model of the cecal flora to investigate the possibility that competition for nutrients is one mechanism for this antagonism. The medium for the CF cultures consisted of homogenates of fecal pellets from germfree mice. Carbohydrate analysis showed that mouse flora depleted 74 to 99.8{\%} of the various carbohydrates from this environment-simulating medium. When inoculated into filtrates made from CF cultures of mouse flora, C. difficile multiplied slower than the dilution rate of the CF cultures unless glucose, N-acetylglucosamine, or N-acetylneuraminic acid was added. C. difficile did not synthesize hydrolytic enzymes able to cleave these monosaccharides from oligosaccharide side chains. As found previously, veal infusion broth did not support the growth of a microflora that could be transferred to gnotobiotic mice and fully suppress C. difficile. When mucin or monosaccharides found in mucin were added to veal infusion broth, the flora functioned normally in this regard. These data suggest that as yet unidentified organisms compete more efficiently than C. difficile for monomeric glucose, N-acetylglucosamine, and sialic acids found in colonic contents.},
author = {Wilson, K. H. and Perini, F.},
isbn = {0019-9567 (Print)$\backslash$r0019-9567 (Linking)},
issn = {00199567},
journal = {Infection and Immunity},
number = {10},
pages = {2610--2614},
pmid = {3417352},
title = {{Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora}},
volume = {56},
year = {1988}
}
@article{Winter2010,
abstract = {Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to use tetrathionate as an electron acceptor produce a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen.},
author = {Winter, Sebastian E. and Thiennimitr, Parameth and Winter, Maria G. and Butler, Brian P. and Huseby, Douglas L. and Crawford, Robert W. and Russell, Joseph M. and Bevins, Charles L. and Adams, L. Garry and Tsolis, Ren{\'{e}}e M. and Roth, John R. and B{\"{a}}umler, Andreas J.},
doi = {10.1038/nature09415},
isbn = {1476-4687 (Electronic)$\backslash$n0028-0836 (Linking)},
issn = {0028-0836},
journal = {Nature},
number = {7314},
pages = {426--429},
pmid = {20864996},
title = {{Gut inflammation provides a respiratory electron acceptor for Salmonella}},
url = {http://www.nature.com/doifinder/10.1038/nature09415},
volume = {467},
year = {2010}
}
@article{Zaura2015,
abstract = {UNLABELLED Due to the spread of resistance, antibiotic exposure receives increasing attention. Ecological consequences for the different niches of individual microbiomes are, however, largely ignored. Here, we report the effects of widely used antibiotics (clindamycin, ciprofloxacin, amoxicillin, and minocycline) with different modes of action on the ecology of both the gut and the oral microbiomes in 66 healthy adults from the United Kingdom and Sweden in a two-center randomized placebo-controlled clinical trial. Feces and saliva were collected at baseline, immediately after exposure, and 1, 2, 4, and 12 months after administration of antibiotics or placebo. Sequences of 16S rRNA gene amplicons from all samples and metagenomic shotgun sequences from selected baseline and post-antibiotic-treatment sample pairs were analyzed. Additionally, metagenomic predictions based on 16S rRNA gene amplicon data were performed using PICRUSt. The salivary microbiome was found to be significantly more robust, whereas the antibiotics negatively affected the fecal microbiome: in particular, health-associated butyrate-producing species became strongly underrepresented. Additionally, exposure to different antibiotics enriched genes associated with antibiotic resistance. In conclusion, healthy individuals, exposed to a single antibiotic treatment, undergo considerable microbial shifts and enrichment in antibiotic resistance in their feces, while their salivary microbiome composition remains unexpectedly stable. The health-related consequences for the gut microbiome should increase the awareness of the individual risks involved with antibiotic use, especially in a (diseased) population with an already dysregulated microbiome. On the other hand, understanding the mechanisms behind the resilience of the oral microbiome toward ecological collapse might prove useful in combating microbial dysbiosis elsewhere in the body. IMPORTANCE Many health care professionals use antibiotic prophylaxis strategies to prevent infection after surgery. This practice is under debate since it enhances the spread of antibiotic resistance. Another important reason to avoid nonessential use of antibiotics, the impact on our microbiome, has hardly received attention. In this study, we assessed the impact of antibiotics on the human microbial ecology at two niches. We followed the oral and gut microbiomes in 66 individuals from before, immediately after, and up to 12 months after exposure to different antibiotic classes. The salivary microbiome recovered quickly and was surprisingly robust toward antibiotic-induced disturbance. The fecal microbiome was severely affected by most antibiotics: for months, health-associated butyrate-producing species became strongly underrepresented. Additionally, there was an enrichment of genes associated with antibiotic resistance. Clearly, even a single antibiotic treatment in healthy individuals contributes to the risk of resistance development and leads to long-lasting detrimental shifts in the gut microbiome.},
author = {Zaura, Egija and Brandt, Bernd W. and de Mattos, M. Joost Teixeira and Buijs, Mark J. and Caspers, Martien P M and Rashid, Mamun Ur and Weintraub, Andrej and Nord, Carl Erik and Savell, Ann and Hu, Yanmin and Coates, Antony R. and Hubank, Mike and Spratt, David A. and Wilson, Michael and Keijser, Bart J F and Crielaard, Wim},
doi = {10.1128/mBio.01693-15},
isbn = {2150-7511 (Electronic)},
issn = {21507511},
journal = {mBio},
number = {6},
pmid = {26556275},
title = {{Same Exposure but two radically different responses to antibiotics: Resilience of the salivary microbiome versus long-term microbial shifts in feces}},
volume = {6},
year = {2015}
}
@article{Zelezniak2015,
abstract = {SignificanceAlthough metabolic interactions have long been implicated in the assembly of microbial communities, their general prevalence has remained largely unknown. In this study, we systematically survey, by using a metabolic modeling approach, the extent of resource competition and metabolic cross-feeding in over 800 microbial communities from diverse habitats. We show that interspecies metabolic exchanges are widespread in natural communities, and that such exchanges can provide group advantage under nutrient-poor conditions. Our results highlight metabolic dependencies as a major driver of species co-occurrence. The presented methodology and mechanistic insights have broad implications for understanding compositional variation in natural communities as well as for facilitating the design of synthetic microbial communities. Microbial communities populate most environments on earth and play a critical role in ecology and human health. Their composition is thought to be largely shaped by interspecies competition for the available resources, but cooperative interactions, such as metabolite exchanges, have also been implicated in community assembly. The prevalence of metabolic interactions in microbial communities, however, has remained largely unknown. Here, we systematically survey, by using a genome-scale metabolic modeling approach, the extent of resource competition and metabolic exchanges in over 800 communities. We find that, despite marked resource competition at the level of whole assemblies, microbial communities harbor metabolically interdependent groups that recur across diverse habitats. By enumerating flux-balanced metabolic exchanges in these co-occurring subcommunities we also predict the likely exchanged metabolites, such as amino acids and sugars, that can promote group survival under nutritionally challenging conditions. Our results highlight metabolic dependencies as a major driver of species co-occurrence and hint at cooperative groups as recurring modules of microbial community architecture.},
archivePrefix = {arXiv},
arxivId = {1408.1149},
author = {Zelezniak, Aleksej and Andrejev, Sergej and Ponomarova, Olga and Mende, Daniel R. and Bork, Peer and Patil, Kiran Raosaheb},
doi = {10.1073/pnas.1421834112},
eprint = {1408.1149},
isbn = {1215421109},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
number = {20},
pages = {6449--6454},
pmid = {25941371},
title = {{Metabolic dependencies drive species co-occurrence in diverse microbial communities}},
url = {http://www.pnas.org/lookup/doi/10.1073/pnas.1421834112},
volume = {112},
year = {2015}
}