Publications by authors named "Dirk Gevers"

92 Publications

Precise quantification of bacterial strains after fecal microbiota transplantation delineates long-term engraftment and explains outcomes.

Nat Microbiol 2021 10 27;6(10):1309-1318. Epub 2021 Sep 27.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Fecal microbiota transplantation (FMT) has been successfully applied to treat recurrent Clostridium difficile infection in humans, but a precise method to measure which bacterial strains stably engraft in recipients and evaluate their association with clinical outcomes is lacking. We assembled a collection of >1,000 different bacterial strains that were cultured from the fecal samples of 22 FMT donors and recipients. Using our strain collection combined with metagenomic sequencing data from the same samples, we developed a statistical approach named Strainer for the detection and tracking of bacterial strains from metagenomic sequencing data. We applied Strainer to evaluate a cohort of 13 FMT longitudinal clinical interventions and detected stable engraftment of 71% of donor microbiota strains in recipients up to 5 years post-FMT. We found that 80% of recipient gut bacterial strains pre-FMT were eliminated by FMT and that post-FMT the strains present persisted up to 5 years later, together with environmentally acquired strains. Quantification of donor bacterial strain engraftment in recipients independently explained (precision 100%, recall 95%) the clinical outcomes (relapse or success) after initial and repeat FMT. We report a compendium of bacterial species and strains that consistently engraft in recipients over time that could be used in defined live biotherapeutic products as an alternative to FMT. Our analytical framework and Strainer can be applied to systematically evaluate either FMT or defined live bacterial therapeutic studies by quantification of strain engraftment in recipients.
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http://dx.doi.org/10.1038/s41564-021-00966-0DOI Listing
October 2021

Defined microbiota transplant restores Th17/RORγt regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas.

Proc Natl Acad Sci U S A 2020 09 18;117(35):21536-21545. Epub 2020 Aug 18.

The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.
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http://dx.doi.org/10.1073/pnas.1922189117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474624PMC
September 2020

Transmission of human-associated microbiota along family and social networks.

Nat Microbiol 2019 06 25;4(6):964-971. Epub 2019 Mar 25.

Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

The human microbiome, described as an accessory organ because of the crucial functions it provides, is composed of species that are uniquely found in humans. Yet, surprisingly little is known about the impact of routine interpersonal contacts in shaping microbiome composition. In a relatively 'closed' cohort of 287 people from the Fiji Islands, where common barriers to bacterial transmission are absent, we examine putative bacterial transmission in individuals' gut and oral microbiomes using strain-level data from both core single-nucleotide polymorphisms and flexible genomic regions. We find a weak signal of transmission, defined by the inferred sharing of genotypes, across many organisms that, in aggregate, reveals strong transmission patterns, most notably within households and between spouses. We were unable to determine the directionality of transmission nor whether it was direct. We further find that women harbour strains more closely related to those harboured by their familial and social contacts than men, and that transmission patterns of oral-associated and gut-associated microbiota need not be the same. Using strain-level data alone, we are able to confidently predict a subset of spouses, highlighting the role of shared susceptibilities, behaviours or social interactions that distinguish specific links in the social network.
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http://dx.doi.org/10.1038/s41564-019-0409-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450247PMC
June 2019

Genetic Factors and the Intestinal Microbiome Guide Development of Microbe-Based Therapies for Inflammatory Bowel Diseases.

Gastroenterology 2019 06 14;156(8):2174-2189. Epub 2019 Mar 14.

Department of Pathology, University of California-San Diego, La Jolla, California; Chiba University and University of California-San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, California. Electronic address:

The intestinal microbiota is a dynamic community of bacteria, fungi, and viruses that mediates mucosal homeostasis and physiology. Imbalances in the microbiome and aberrant immune responses to gut bacteria can disrupt homeostasis and are associated with inflammatory bowel diseases (IBDs) in humans and colitis in mice. We review genetic variants associated with IBD and their effects on the intestinal microbiome, the immune response, and disease pathogenesis. The intestinal microbiome, which includes microbial antigens, adjuvants, and metabolic products, affects the development and function of the intestinal mucosa, influencing inflammatory responses in the gut. Therefore, strategies to manipulate the microbiome might be used in treatment of IBD. We review microbe-based therapies for IBD and the potential to engineer patients' intestinal microbiota. We discuss how studies of patients with IBD and mouse models have advanced our understanding of the interactions between genetic factors and the gut microbiome, and challenges to the development of microbe-based therapies for IBD.
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http://dx.doi.org/10.1053/j.gastro.2019.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568267PMC
June 2019

Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt Regulatory T Cells and Exacerbate Colitis in Mice.

Immunity 2019 01;50(1):212-224.e4

Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1 mice. The proportions of Th17 and RORγt Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1 colitis model. Thus, an impact on intestinal Th17 and RORγt Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.
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http://dx.doi.org/10.1016/j.immuni.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512335PMC
January 2019

The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.

Nature 2018 10 24;562(7728):589-594. Epub 2018 Oct 24.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors, including complex genetic elements, patient exposures and the gut microbiome. Viral infections and broader gut dysbioses have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts and a T1D mouse model, these data support the protective effects of short-chain fatty acids in early-onset human T1D.
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http://dx.doi.org/10.1038/s41586-018-0620-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296767PMC
October 2018

The classroom microbiome and asthma morbidity in children attending 3 inner-city schools.

J Allergy Clin Immunol 2018 06 5;141(6):2311-2313. Epub 2018 Mar 5.

Harvard Medical School, Boston, Mass; Broad Institute of MIT and Harvard University, Cambridge, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994187PMC
June 2018

Strain Tracking Reveals the Determinants of Bacterial Engraftment in the Human Gut Following Fecal Microbiota Transplantation.

Cell Host Microbe 2018 Feb;23(2):229-240.e5

Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA; Finch Therapeutics, Somerville, MA, USA; Department of Biological Engineering, MIT, Cambridge, MA, USA. Electronic address:

Fecal microbiota transplantation (FMT) from healthy donor to patient is a treatment for microbiome-associated diseases. Although the success of FMT requires donor bacteria to engraft in the patient's gut, the forces governing engraftment in humans are unknown. Here we use an ongoing clinical experiment, the treatment of recurrent Clostridium difficile infection, to uncover the rules of engraftment in humans. We built a statistical model that predicts which bacterial species will engraft in a given host, and developed Strain Finder, a method to infer strain genotypes and track them over time. We find that engraftment can be predicted largely from the abundance and phylogeny of bacteria in the donor and the pre-FMT patient. Furthermore, donor strains within a species engraft in an all-or-nothing manner and previously undetected strains frequently colonize patients receiving FMT. We validated these findings for metabolic syndrome, suggesting that the same principles of engraftment extend to other indications.
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http://dx.doi.org/10.1016/j.chom.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318347PMC
February 2018

Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer.

Sci Rep 2017 12 15;7(1):17686. Epub 2017 Dec 15.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

Oral squamous cell carcinomas are a major cause of morbidity and mortality, and tobacco usage, alcohol consumption, and poor oral hygiene are established risk factors. To date, no large-scale case-control studies have considered the effects of these risk factors on the composition of the oral microbiome, nor microbial community associations with oral cancer. We compared the composition, diversity, and function of the oral microbiomes of 121 oral cancer patients to 242 age- and gender-matched controls using a metagenomic multivariate analysis pipeline. Significant shifts in composition and function of the oral microbiome were observed with poor oral hygiene, tobacco smoking, and oral cancer. Specifically, we observed dramatically altered community composition and function after tooth loss, with smaller alterations in current tobacco smokers, increased production of antioxidants in individuals with periodontitis, and significantly decreased glutamate metabolism metal transport in oral cancer patients. Although the alterations in the oral microbiome of oral cancer patients were significant, they were of substantially lower effect size relative to microbiome shifts after tooth loss. Alterations following tooth loss, itself a major risk factor for oral cancer, are likely a result of severe ecological disruption due to habitat loss but may also contribute to the development of the disease.
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http://dx.doi.org/10.1038/s41598-017-17795-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732161PMC
December 2017

A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients.

Genome Med 2017 Nov 28;9(1):103. Epub 2017 Nov 28.

Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Background: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify strain-specific functional correlates with IBD outcomes.

Methods: We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and 12 controls (266 total samples). These were taxonomically profiled with MetaPhlAn2 and functionally profiled using HUMAnN2. Differentially abundant species were identified using MaAsLin and strain-specific pangenome haplotypes were analyzed using PanPhlAn.

Results: We found a significantly higher abundance in patients of facultative anaerobes that can tolerate the increased oxidative stress of the IBD gut. We also detected dramatic, yet transient, blooms of Ruminococcus gnavus in IBD patients, often co-occurring with increased disease activity. We identified two distinct clades of R. gnavus strains, one of which is enriched in IBD patients. To study functional differences between these two clades, we augmented the R. gnavus pangenome by sequencing nine isolates from IBD patients. We identified 199 IBD-specific, strain-specific genes involved in oxidative stress responses, adhesion, iron-acquisition, and mucus utilization, potentially conferring an adaptive advantage for this R. gnavus clade in the IBD gut.

Conclusions: This study adds further evidence to the hypothesis that increased oxidative stress may be a major factor shaping the dysbiosis of the microbiome observed in IBD and suggests that R. gnavus may be an important member of the altered gut community in IBD.
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http://dx.doi.org/10.1186/s13073-017-0490-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704459PMC
November 2017

Ectopic colonization of oral bacteria in the intestine drives T1 cell induction and inflammation.

Science 2017 10;358(6361):359-365

Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Intestinal colonization by bacteria of oral origin has been correlated with several negative health outcomes, including inflammatory bowel disease. However, a causal role of oral bacteria ectopically colonizing the intestine remains unclear. Using gnotobiotic techniques, we show that strains of spp. isolated from the salivary microbiota are strong inducers of T helper 1 (T1) cells when they colonize in the gut. These strains are resistant to multiple antibiotics, tend to colonize when the intestinal microbiota is dysbiotic, and elicit a severe gut inflammation in the context of a genetically susceptible host. Our findings suggest that the oral cavity may serve as a reservoir for potential intestinal pathobionts that can exacerbate intestinal disease.
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http://dx.doi.org/10.1126/science.aan4526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682622PMC
October 2017

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

Science 2017 09;357(6356):1156-1160

Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.
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http://dx.doi.org/10.1126/science.aah5043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727343PMC
September 2017

A Microbiome Foundation for the Study of Crohn's Disease.

Cell Host Microbe 2017 Mar;21(3):301-304

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Our 2014 study published in Cell Host & Microbe, "The Treatment-Naive Microbiome in New-Onset Crohn's Disease," was designed to improve our understanding of the microbiome's role in Crohn's disease by studying a unique, well-suited cohort and sample set. This commentary provides a hindsight perspective of this original study as well as future outlook.
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http://dx.doi.org/10.1016/j.chom.2017.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684696PMC
March 2017

Metagenomic Characterization of Microbial Communities Within the Deeper Layers of the Ileum in Crohn's Disease.

Cell Mol Gastroenterol Hepatol 2016 Sep 26;2(5):563-566.e5. Epub 2016 May 26.

Crohn's and Colitis Center, Massachusetts General Hospital, Boston, Massachusetts.

Background & Aims: Microbial dysbiosis and aberrant host-microbe interactions in the gut are believed to contribute to the development and progression of Crohn's disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine.

Methods: Paraffin blocks were obtained from 12 CD patients undergoing ileocecal resection, and healthy ileum samples (inflammatory bowel disease-free controls) were obtained from 12 patients undergoing surgery for right-sided colon cancer. Diseased and healthy-appearing ileum was identified using microscopy, and paraffin blocks were macrodissected using a core needle to specifically isolate DNA. Illumina Whole Genome Sequencing was used for microbial sequence identification and subsequent taxonomic classification using the tool.

Results: We observed significant differences between the microbiome of CD samples vs inflammatory bowel disease-free controls, including depletion of and . Notably, microbial composition at the phyla level did not differ markedly between healthy and diseased areas of CD patients. However, we observed enrichment of potentially pathogenic organisms at the species level.

Conclusions: Our study showed dysbiosis within deeper layers of the ileum of CD patients, specifically enrichment of enterotoxigenic and an environmental species not described previously. Future studies with larger cohort sizes are warranted to confirm these findings. Studies would benefit from effective microbial DNA extraction methods from paraffin sections and host nucleic acid depletion approaches to increase microbial read coverage.
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http://dx.doi.org/10.1016/j.jcmgh.2016.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042890PMC
September 2016

Urban Transit System Microbial Communities Differ by Surface Type and Interaction with Humans and the Environment.

mSystems 2016 May-Jun;1(3). Epub 2016 Jun 28.

Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Broad Institute, Cambridge, Massachusetts, USA.

Public transit systems are ideal for studying the urban microbiome and interindividual community transfer. In this study, we used 16S amplicon and shotgun metagenomic sequencing to profile microbial communities on multiple transit surfaces across train lines and stations in the Boston metropolitan transit system. The greatest determinant of microbial community structure was the transit surface type. In contrast, little variation was observed between geographically distinct train lines and stations serving different demographics. All surfaces were dominated by human skin and oral commensals such as , , , and . The detected taxa not associated with humans included generalists from alphaproteobacteria, which were especially abundant on outdoor touchscreens. Shotgun metagenomics further identified viral and eukaryotic microbes, including phage and . Functional profiling showed that pathways such as propionate production and porphyrin synthesis were enriched on train holding surfaces (holds), while electron transport chain components for aerobic respiration were enriched on touchscreens and seats. Lastly, the transit environment was not found to be a reservoir of antimicrobial resistance and virulence genes. Our results suggest that microbial communities on transit surfaces are maintained from a metapopulation of human skin commensals and environmental generalists, with enrichments corresponding to local interactions with the human body and environmental exposures. Mass transit environments, specifically, urban subways, are distinct microbial environments with high occupant densities, diversities, and turnovers, and they are thus especially relevant to public health. Despite this, only three culture-independent subway studies have been performed, all since 2013 and all with widely differing designs and conclusions. In this study, we profiled the Boston subway system, which provides 238 million trips per year overseen by the Massachusetts Bay Transportation Authority (MBTA). This yielded the first high-precision microbial survey of a variety of surfaces, ridership environments, and microbiological functions (including tests for potential pathogenicity) in a mass transit environment. Characterizing microbial profiles for multiple transit systems will become increasingly important for biosurveillance of antibiotic resistance genes or pathogens, which can be early indicators for outbreak or sanitation events. Understanding how human contact, materials, and the environment affect microbial profiles may eventually allow us to rationally design public spaces to sustain our health in the presence of microbial reservoirs. : An author video summary of this article is available.
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http://dx.doi.org/10.1128/mSystems.00018-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069760PMC
June 2016

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease.

Gut 2018 01 8;67(1):108-119. Epub 2016 Oct 8.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objective: Patients with IBD display substantial heterogeneity in clinical characteristics. We hypothesise that individual differences in the complex interaction of the host genome and the gut microbiota can explain the onset and the heterogeneous presentation of IBD. Therefore, we performed a case-control analysis of the gut microbiota, the host genome and the clinical phenotypes of IBD.

Design: Stool samples, peripheral blood and extensive phenotype data were collected from 313 patients with IBD and 582 truly healthy controls, selected from a population cohort. The gut microbiota composition was assessed by tag-sequencing the 16S rRNA gene. All participants were genotyped. We composed genetic risk scores from 11 functional genetic variants proven to be associated with IBD in genes that are directly involved in the bacterial handling in the gut: , , , and .

Results: Strikingly, we observed significant alterations of the gut microbiota of healthy individuals with a high genetic risk for IBD: the IBD genetic risk score was significantly associated with a decrease in the genus in healthy controls (false discovery rate 0.017). Moreover, disease location was a major determinant of the gut microbiota: the gut microbiota of patients with colonic Crohn's disease (CD) is different from that of patients with ileal CD, with a decrease in alpha diversity associated to ileal disease (p=3.28×10).

Conclusions: We show for the first time that genetic risk variants associated with IBD influence the gut microbiota in healthy individuals. are acetate-to-butyrate converters, and a decrease has already been observed in patients with IBD.
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http://dx.doi.org/10.1136/gutjnl-2016-312135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699972PMC
January 2018

Increased Intestinal Microbial Diversity Following Fecal Microbiota Transplant for Active Crohn's Disease.

Inflamm Bowel Dis 2016 09;22(9):2182-90

*Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Inflammatory Bowel Disease Center, Harvard Medical School, Boston, Massachusetts; †Broad Institute of MIT and Harvard, Cambridge, Massachusetts; ‡Department of Computer Science, Aalto University School of Science, Espoo, Finland; §Division of Gastroenterology, Crohn's and Colitis Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts; ‖Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and ¶Janssen Human Microbiome Institute, Janssen R&D, Cambridge, Massachusetts.

Background: The microbiota in the lumen of patients with Crohn's disease (CD) is characterized by reduced diversity, particularly Firmicutes and Bacteroidetes. It is unknown whether the introduction of the intestinal microbiota from healthy individuals could correct this dysbiosis and reverse mucosal inflammation. We investigated the response to fecal microbial transplantation (FMT) from healthy individuals to subjects with active CD.

Methods: We performed a prospective open-label study (uncontrolled) of FMT from healthy donors to subjects with active CD. A single FMT was performed by colonoscopy. Recipients' microbial diversity, mucosal T-cell phenotypes, and clinical and inflammatory parameters were measured over 12 weeks, and safety over 26 weeks.

Results: Nineteen subjects were treated with FMT and completed the study follow-up. Fifty-eight percent (11/19) demonstrated a clinical response (Harvey-Bradshaw Index decrease >3) following FMT. Fifteen subjects had sufficient pre/postfecal samples for analysis. A significant increase in microbial diversity occurred after FMT (P = 0.02). This was greater in clinical responders than nonresponders. Patients who experienced a clinical response demonstrated a significant shift in fecal microbial composition toward their donor's profile as assessed by the Bray-Curtis index at 4 weeks (P = 0.003). An increase in regulatory T cells (CD4CD25CD127lo) was also noted in recipients' lamina propria following FMT. No serious adverse events were noted over the 26-week study period.

Conclusions: In this open-label study, FMT led to an expansion in microbial bacterial diversity in patients with active CD. FMT was overall safe, although the clinical response was variable. Determining donor microbial factors that influence clinical response is needed before randomized clinical trials of FMT in CD.
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http://dx.doi.org/10.1097/MIB.0000000000000893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995064PMC
September 2016

Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability.

Sci Transl Med 2016 06;8(343):343ra81

Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA 02142, USA. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA 02139, USA.

The gut microbial community is dynamic during the first 3 years of life, before stabilizing to an adult-like state. However, little is known about the impact of environmental factors on the developing human gut microbiome. We report a longitudinal study of the gut microbiome based on DNA sequence analysis of monthly stool samples and clinical information from 39 children, about half of whom received multiple courses of antibiotics during the first 3 years of life. Whereas the gut microbiome of most children born by vaginal delivery was dominated by Bacteroides species, the four children born by cesarean section and about 20% of vaginally born children lacked Bacteroides in the first 6 to 18 months of life. Longitudinal sampling, coupled with whole-genome shotgun sequencing, allowed detection of strain-level variation as well as the abundance of antibiotic resistance genes. The microbiota of antibiotic-treated children was less diverse in terms of both bacterial species and strains, with some species often dominated by single strains. In addition, we observed short-term composition changes between consecutive samples from children treated with antibiotics. Antibiotic resistance genes carried on microbial chromosomes showed a peak in abundance after antibiotic treatment followed by a sharp decline, whereas some genes carried on mobile elements persisted longer after antibiotic therapy ended. Our results highlight the value of high-density longitudinal sampling studies with high-resolution strain profiling for studying the establishment and response to perturbation of the infant gut microbiome.
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http://dx.doi.org/10.1126/scitranslmed.aad0917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032909PMC
June 2016

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

Cell 2016 May 28;165(4):842-53. Epub 2016 Apr 28.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.
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http://dx.doi.org/10.1016/j.cell.2016.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950857PMC
May 2016

Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.

Science 2016 Apr 28;352(6285):565-9. Epub 2016 Apr 28.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.

Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These factors collectively explain 18.7% of the variation seen in the interindividual distance of microbial composition. We could associate 110 factors to 125 species and observed that fecal chromogranin A (CgA), a protein secreted by enteroendocrine cells, was exclusively associated with 61 microbial species whose abundance collectively accounted for 53% of microbial composition. Low CgA concentrations were seen in individuals with a more diverse microbiome. These results are an important step toward a better understanding of environment-diet-microbe-host interactions.
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http://dx.doi.org/10.1126/science.aad3369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240844PMC
April 2016

The influence of a short-term gluten-free diet on the human gut microbiome.

Genome Med 2016 Apr 21;8(1):45. Epub 2016 Apr 21.

Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Background: A gluten-free diet (GFD) is the most commonly adopted special diet worldwide. It is an effective treatment for coeliac disease and is also often followed by individuals to alleviate gastrointestinal complaints. It is known there is an important link between diet and the gut microbiome, but it is largely unknown how a switch to a GFD affects the human gut microbiome.

Methods: We studied changes in the gut microbiomes of 21 healthy volunteers who followed a GFD for four weeks. We collected nine stool samples from each participant: one at baseline, four during the GFD period, and four when they returned to their habitual diet (HD), making a total of 189 samples. We determined microbiome profiles using 16S rRNA sequencing and then processed the samples for taxonomic and imputed functional composition. Additionally, in all 189 samples, six gut health-related biomarkers were measured.

Results: Inter-individual variation in the gut microbiota remained stable during this short-term GFD intervention. A number of taxon-specific differences were seen during the GFD: the most striking shift was seen for the family Veillonellaceae (class Clostridia), which was significantly reduced during the intervention (p = 2.81 × 10(-05)). Seven other taxa also showed significant changes; the majority of them are known to play a role in starch metabolism. We saw stronger differences in pathway activities: 21 predicted pathway activity scores showed significant association to the change in diet. We observed strong relations between the predicted activity of pathways and biomarker measurements.

Conclusions: A GFD changes the gut microbiome composition and alters the activity of microbial pathways.
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http://dx.doi.org/10.1186/s13073-016-0295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841035PMC
April 2016

Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes.

Genome Med 2016 Feb 17;8(1):17. Epub 2016 Feb 17.

The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.

Background: Obesity and type 2 diabetes (T2D) are linked both with host genetics and with environmental factors, including dysbioses of the gut microbiota. However, it is unclear whether these microbial changes precede disease onset. Twin cohorts present a unique genetically-controlled opportunity to study the relationships between lifestyle factors and the microbiome. In particular, we hypothesized that family-independent changes in microbial composition and metabolic function during the sub-clinical state of T2D could be either causal or early biomarkers of progression.

Methods: We collected fecal samples and clinical metadata from 20 monozygotic Korean twins at up to two time points, resulting in 36 stool shotgun metagenomes. While the participants were neither obese nor diabetic, they spanned the entire range of healthy to near-clinical values and thus enabled the study of microbial associations during sub-clinical disease while accounting for genetic background.

Results: We found changes both in composition and in function of the sub-clinical gut microbiome, including a decrease in Akkermansia muciniphila suggesting a role prior to the onset of disease, and functional changes reflecting a response to oxidative stress comparable to that previously observed in chronic T2D and inflammatory bowel diseases. Finally, our unique study design allowed us to examine the strain similarity between twins, and we found that twins demonstrate strain-level differences in composition despite species-level similarities.

Conclusions: These changes in the microbiome might be used for the early diagnosis of an inflamed gut and T2D prior to clinical onset of the disease and will help to advance toward microbial interventions.
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http://dx.doi.org/10.1186/s13073-016-0271-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756455PMC
February 2016

Host genetic variation impacts microbiome composition across human body sites.

Genome Biol 2015 Sep 15;16:191. Epub 2015 Sep 15.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

Background: The composition of bacteria in and on the human body varies widely across human individuals, and has been associated with multiple health conditions. While microbial communities are influenced by environmental factors, some degree of genetic influence of the host on the microbiome is also expected. This study is part of an expanding effort to comprehensively profile the interactions between human genetic variation and the composition of this microbial ecosystem on a genome- and microbiome-wide scale.

Results: Here, we jointly analyze the composition of the human microbiome and host genetic variation. By mining the shotgun metagenomic data from the Human Microbiome Project for host DNA reads, we gathered information on host genetic variation for 93 individuals for whom bacterial abundance data are also available. Using this dataset, we identify significant associations between host genetic variation and microbiome composition in 10 of the 15 body sites tested. These associations are driven by host genetic variation in immunity-related pathways, and are especially enriched in host genes that have been previously associated with microbiome-related complex diseases, such as inflammatory bowel disease and obesity-related disorders. Lastly, we show that host genomic regions associated with the microbiome have high levels of genetic differentiation among human populations, possibly indicating host genomic adaptation to environment-specific microbiomes.

Conclusions: Our results highlight the role of host genetic variation in shaping the composition of the human microbiome, and provide a starting point toward understanding the complex interaction between human genetics and the microbiome in the context of human evolution and disease.
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http://dx.doi.org/10.1186/s13059-015-0759-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570153PMC
September 2015

Detection of low-abundance bacterial strains in metagenomic datasets by eigengenome partitioning.

Nat Biotechnol 2015 Oct 14;33(10):1053-60. Epub 2015 Sep 14.

Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

Analyses of metagenomic datasets that are sequenced to a depth of billions or trillions of bases can uncover hundreds of microbial genomes, but naive assembly of these data is computationally intensive, requiring hundreds of gigabytes to terabytes of RAM. We present latent strain analysis (LSA), a scalable, de novo pre-assembly method that separates reads into biologically informed partitions and thereby enables assembly of individual genomes. LSA is implemented with a streaming calculation of unobserved variables that we call eigengenomes. Eigengenomes reflect covariance in the abundance of short, fixed-length sequences, or k-mers. As the abundance of each genome in a sample is reflected in the abundance of each k-mer in that genome, eigengenome analysis can be used to partition reads from different genomes. This partitioning can be done in fixed memory using tens of gigabytes of RAM, which makes assembly and downstream analyses of terabytes of data feasible on commodity hardware. Using LSA, we assemble partial and near-complete genomes of bacterial taxa present at relative abundances as low as 0.00001%. We also show that LSA is sensitive enough to separate reads from several strains of the same species.
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http://dx.doi.org/10.1038/nbt.3329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720164PMC
October 2015

The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids.

Circ Res 2015 Oct 10;117(9):817-24. Epub 2015 Sep 10.

From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.

Rationale: Evidence suggests that the gut microbiome is involved in the development of cardiovascular disease, with the host-microbe interaction regulating immune and metabolic pathways. However, there was no firm evidence for associations between microbiota and metabolic risk factors for cardiovascular disease from large-scale studies in humans. In particular, there was no strong evidence for association between cardiovascular disease and aberrant blood lipid levels.

Objectives: To identify intestinal bacteria taxa, whose proportions correlate with body mass index and lipid levels, and to determine whether lipid variance can be explained by microbiota relative to age, sex, and host genetics.

Methods And Results: We studied 893 subjects from the Life-Lines-DEEP population cohort. After correcting for age and sex, we identified 34 bacterial taxa associated with body mass index and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota explain 4.5% of the variance in body mass index, 6% in triglycerides, and 4% in high-density lipoproteins, independent of age, sex, and genetic risk factors. A novel risk model, including the gut microbiome explained ≤ 25.9% of high-density lipoprotein variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on low-density lipoproteins or total cholesterol.

Conclusions: Our studies suggest that the gut microbiome may play an important role in the variation in body mass index and blood lipid levels, independent of age, sex, and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body mass, triglycerides, and high-density lipoproteins.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.306807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596485PMC
October 2015

ConStrains identifies microbial strains in metagenomic datasets.

Nat Biotechnol 2015 Oct 7;33(10):1045-52. Epub 2015 Sep 7.

Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.

An important fraction of microbial diversity is harbored in strain individuality, so identification of conspecific bacterial strains is imperative for improved understanding of microbial community functions. Limitations in bioinformatics and sequencing technologies have to date precluded strain identification owing to difficulties in phasing short reads to faithfully recover the original strain-level genotypes, which have highly similar sequences. We present ConStrains, an open-source algorithm that identifies conspecific strains from metagenomic sequence data and reconstructs the phylogeny of these strains in microbial communities. The algorithm uses single-nucleotide polymorphism (SNP) patterns in a set of universal genes to infer within-species structures that represent strains. Applying ConStrains to simulated and host-derived datasets provides insights into microbial community dynamics.
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http://dx.doi.org/10.1038/nbt.3319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676274PMC
October 2015

Identifying personal microbiomes using metagenomic codes.

Proc Natl Acad Sci U S A 2015 Jun 11;112(22):E2930-8. Epub 2015 May 11.

Biostatistics Department, Harvard School of Public Health, Boston, MA 02115; Microbial Systems and Communities, Genome Sequencing and Analysis Program, The Broad Institute, Cambridge, MA 02142;

Community composition within the human microbiome varies across individuals, but it remains unknown if this variation is sufficient to uniquely identify individuals within large populations or stable enough to identify them over time. We investigated this by developing a hitting set-based coding algorithm and applying it to the Human Microbiome Project population. Our approach defined body site-specific metagenomic codes: sets of microbial taxa or genes prioritized to uniquely and stably identify individuals. Codes capturing strain variation in clade-specific marker genes were able to distinguish among 100s of individuals at an initial sampling time point. In comparisons with follow-up samples collected 30-300 d later, ∼30% of individuals could still be uniquely pinpointed using metagenomic codes from a typical body site; coincidental (false positive) matches were rare. Codes based on the gut microbiome were exceptionally stable and pinpointed >80% of individuals. The failure of a code to match its owner at a later time point was largely explained by the loss of specific microbial strains (at current limits of detection) and was only weakly associated with the length of the sampling interval. In addition to highlighting patterns of temporal variation in the ecology of the human microbiome, this work demonstrates the feasibility of microbiome-based identifiability-a result with important ethical implications for microbiome study design. The datasets and code used in this work are available for download from huttenhower.sph.harvard.edu/idability.
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http://dx.doi.org/10.1073/pnas.1423854112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460507PMC
June 2015

Dirk Gevers.

Nat Rev Drug Discov 2015 May 24;14(5):305. Epub 2015 Apr 24.

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http://dx.doi.org/10.1038/nrd4614DOI Listing
May 2015

Associations between host gene expression, the mucosal microbiome, and clinical outcome in the pelvic pouch of patients with inflammatory bowel disease.

Genome Biol 2015 Apr 8;16:67. Epub 2015 Apr 8.

Department of Biostatistics, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA, 02115, USA.

Background: Pouchitis is common after ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC). Similar to inflammatory bowel disease (IBD), both host genetics and the microbiota are implicated in its pathogenesis. We use the IPAA model of IBD to associate mucosal host gene expression with mucosal microbiomes and clinical outcomes. We analyze host transcriptomic data and 16S rRNA gene sequencing data from paired biopsies from IPAA patients with UC and familial adenomatous polyposis. To achieve power for a genome-wide microbiome-transcriptome association study, we use principal component analysis for transcript and clade reduction, and identify significant co-variation between clades and transcripts.

Results: Host transcripts co-vary primarily with biopsy location and inflammation, while microbes co-vary primarily with antibiotic use. Transcript-microbe associations are surprisingly modest, but the most strongly microbially-associated host transcript pattern is enriched for complement cascade genes and for the interleukin-12 pathway. Activation of these host processes is inversely correlated with Sutterella, Akkermansia, Bifidobacteria, and Roseburia abundance, and positively correlated with Escherichia abundance.

Conclusions: This study quantifies the effects of inflammation, antibiotic use, and biopsy location upon the microbiome and host transcriptome during pouchitis. Understanding these effects is essential for basic biological insights as well as for well-designed and adequately-powered studies. Additionally, our study provides a method for profiling host-microbe interactions with appropriate statistical power using high-throughput sequencing, and suggests that cross-sectional changes in gut epithelial transcription are not a major component of the host-microbiome regulatory interface during pouchitis.
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http://dx.doi.org/10.1186/s13059-015-0637-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414286PMC
April 2015
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