Publications by authors named "Jeremiah J Faith"

46 Publications

Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23.

Cell Metab 2021 May 11. Epub 2021 May 11.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Both genetic predisposition and environmental factors appear to play a role in inflammatory bowel disease (IBD) development. Genetic studies in humans have linked the interleukin (IL)-23 signaling pathway with IBD, but the environmental factors contributing to disease have remained elusive. Here, we show that the azo dyes Red 40 and Yellow 6, the most abundant food colorants in the world, can trigger an IBD-like colitis in mice conditionally expressing IL-23, or in two additional animal models in which IL-23 expression was augmented. Increased IL-23 expression led to generation of activated CD4 T cells that expressed interferon-γ and transferred disease to mice exposed to Red 40. Colitis induction was dependent on the commensal microbiota promoting the azo reduction of Red 40 and generation of a metabolite, 1-amino-2-naphthol-6-sulfonate sodium salt. Together these findings suggest that specific food colorants represent novel risk factors for development of colitis in mice with increased IL-23 signaling.
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http://dx.doi.org/10.1016/j.cmet.2021.04.015DOI Listing
May 2021

Maternal infection programmes offspring immunity.

Nat Rev Immunol 2021 Apr;21(4):207

OxMS Preprint Journal Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-021-00532-zDOI Listing
April 2021

Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms.

Gastroenterology 2021 06 4;160(7):2435-2450.e34. Epub 2021 Mar 4.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

Background & Aims: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance.

Methods: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions.

Results: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms.

Conclusions: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
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http://dx.doi.org/10.1053/j.gastro.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931673PMC
June 2021

Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales.

PLoS One 2021 4;16(1):e0244763. Epub 2021 Jan 4.

Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Background & Aim: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease.

Methods: The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome.

Results: There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales.

Conclusions: We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244763PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781477PMC
May 2021

Gastrointestinal involvement attenuates COVID-19 severity and mortality.

medRxiv 2020 Sep 9. Epub 2020 Sep 9.

Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.
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http://dx.doi.org/10.1101/2020.09.07.20187666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491532PMC
September 2020

SARS-CoV-2-specific IgA and limited inflammatory cytokines are present in the stool of select patients with acute COVID-19.

medRxiv 2020 Sep 5. Epub 2020 Sep 5.

Background And Aims: Immune dysregulation caused by SARS-CoV-2 infection is thought to play a pathogenic role in COVID-19. SARS-CoV-2 can infect a variety of host cells, including intestinal epithelial cells. We sought to characterize the role of the gastrointestinal immune system in the pathogenesis of the inflammatory response associated with COVID-19.

Methods: We measured cytokines, inflammatory markers, viral RNA, microbiome composition and antibody responses in stool and serum samples from a prospectively enrolled cohort of 44 hospitalized COVID-19 patients.

Results: SARS-CoV-2 RNA was detected in stool of 41% of patients and was found more frequently in patients with diarrhea than those without (16[44%] vs 5[19%], p=0.06). Patients who survived had lower median viral genome copies than those who did not (p=0.021). Compared to uninfected controls, COVID-19 patients had higher median fecal levels of IL-8 (166.5 vs 286.5 pg/mg; p=0.05) and lower levels of fecal IL-10 (678 vs 194 pg/mg; p<0.001) compared to uninfected controls. Stool IL-23 was higher in patients with more severe COVID-19 disease (223.8 vs 86.6 pg/mg; p=0.03) and we find evidence of intestinal virus-specific IgA responses, which was associated with more severe disease. Fecal cytokines and calprotectin levels were not correlated with gastrointestinal symptoms or with the level of virus detected.

Conclusions: Although SARS-CoV-2 RNA was detectable in the stools of COVID-19 patients and select individuals had evidence for a specific mucosal IgA response, intestinal inflammation was limited, even in patients presenting with gastrointestinal symptoms.
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http://dx.doi.org/10.1101/2020.09.03.20183947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480054PMC
September 2020

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

Fungal Trans-kingdom Dynamics Linked to Responsiveness to Fecal Microbiota Transplantation (FMT) Therapy in Ulcerative Colitis.

Cell Host Microbe 2020 05 15;27(5):823-829.e3. Epub 2020 Apr 15.

Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address:

Fecal microbiota transplantation (FMT) targeting gut microbiota has recently been successfully applied to ulcerative colitis. However, only a subset of patients responds to FMT, and there is a pressing need for biomarkers of responsiveness. Fungi (the mycobiota) represent a highly immunologically reactive component of the gut microbiota. We analyzed samples from a large randomized controlled trial of FMT for ulcerative colitis (UC). High Candida abundance pre-FMT was associated with a clinical response, whereas decreased Candida abundance post-FMT was indicative of ameliorated disease severity. High pre-FMT Candida was associated with increased bacterial diversity post-FMT, and the presence of genera was linked to FMT responsiveness. Although we detected elevated anti-Candida antibodies in placebo recipients, this increase was abrogated in FMT recipients. Our data suggest that FMT might reduce Candida to contain pro-inflammatory immunity during intestinal disease and highlight the utility of mycobiota-focused approaches to identify FMT responders prior to therapy initiation.
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http://dx.doi.org/10.1016/j.chom.2020.03.006DOI Listing
May 2020

Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation.

Cell Host Microbe 2020 Mar 18;27(3):467-475.e6. Epub 2020 Feb 18.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. Here, we assessed the IgA-inducing capacity of a diverse set of human gut microbial strains by monocolonizing mice with each strain. We identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied bimodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through the T cell-dependent B cell-activation pathway. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.
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http://dx.doi.org/10.1016/j.chom.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213796PMC
March 2020

Interleukin 22 disrupts pancreatic function in newborn mice expressing IL-23.

Nat Commun 2019 10 4;10(1):4517. Epub 2019 Oct 4.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Neonatal inflammatory diseases are associated with severe morbidity, but the inflammatory factors underlying them and their potential effector mechanisms are poorly defined. Here we show that necrotizing enterocolitis in neonate mice is accompanied by elevation of IL-23 and IL-22 and decreased production of pancreatic enzymes. These phenotypes are mirrored in neonate mice overexpressing IL-23 in CX3CR1 myeloid cells or in keratinocytes. The mice fail to grow and die prematurely, displaying systemic inflammation, nutrient malabsorption and decreased expression of intestinal and pancreatic genes mediating digestion and absorption of carbohydrates, proteins, and lipids. Germ-free environment improves, and genetic ablation of IL-22 restores normal growth in mice overexpressing IL-23. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (PTF1a). These results show that augmented production of IL-23 and IL-22 in early life has a negative impact on pancreatic enzyme secretion and food absorption.
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http://dx.doi.org/10.1038/s41467-019-12540-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778080PMC
October 2019

Challenges in IBD Research: Preclinical Human IBD Mechanisms.

Inflamm Bowel Dis 2019 05;25(Suppl 2):S5-S12

University of Chicago, Chicago, IL, USA.

Preclinical human IBD mechanisms is part of five focus areas of the Challenges in IBD research document, which also include environmental triggers, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the preclinical human IBD mechanisms manuscript is focused on highlighting the main research gaps in the pathophysiological understanding of human IBD. These research gap areas include: 1) triggers of immune responses; 2) intestinal epithelial homeostasis and wound repair; 3) age-specific pathophysiology; 4) disease complications; 5) heterogeneous response to treatments; and 6) determination of disease location. As an approach to address these research gaps, the prioritization of reverse translation studies is proposed in which clinical observations are the foundation for experimental IBD research in the lab, and for the identification of new therapeutic targets and biomarkers. The use of human samples in validating basic research findings and development of precision medicine solutions is also proposed. This prioritization aims to put emphasis on relevant biochemical pathways and humanized in vitro and in vivo models that extrapolate meaningfully to human IBD, to eventually yield first-in-class and effective therapies.
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http://dx.doi.org/10.1093/ibd/izz075DOI Listing
May 2019

Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.

Nat Commun 2019 05 1;10(1):2012. Epub 2019 May 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55902, USA.

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.
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http://dx.doi.org/10.1038/s41467-019-09964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494866PMC
May 2019

Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.

Gut 2020 01 29;69(1):42-51. Epub 2019 Apr 29.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Background And Aims: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome.

Methods: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines.

Results: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in and depletion in . Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon.

Conclusion: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.
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http://dx.doi.org/10.1136/gutjnl-2018-317855DOI Listing
January 2020

Microbial Engraftment and Efficacy of Fecal Microbiota Transplant for Clostridium Difficile in Patients With and Without Inflammatory Bowel Disease.

Inflamm Bowel Dis 2019 05;25(6):969-979

Icahn Institute for Genomics & Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York NY, USA.

Background: Recurrent and severe Clostridium difficile infections (CDI) are treated with fecal microbiota transplant (FMT). Uncertainty exists regarding FMT effectiveness for CDI with underlying inflammatory bowel disease (IBD) and regarding its effects on disease activity and effectiveness in transferring the donor microbiota to patients with and without IBD.

Methods: Subjects with and without IBD who underwent FMT for recurrent or severe CDI between 2013 and 2016 at The Mount Sinai Hospital were followed for up to 6 months. The primary outcome was CDI recurrence 6 months after FMT. Secondary outcomes were (1) CDI recurrence 2 months after FMT; (2) frequency of IBD flare after FMT; (3) microbiota engraftment after FMT; (and 4) predictors of CDI recurrence.

Results: One hundred thirty-four patients, 46 with IBD, were treated with FMT. Follow-up was available in 83 and 118 patients at 6 and 2 months, respectively. There was no difference in recurrence in patients with and without IBD at 6 months (38.7% vs 36.5%; P > 0.99) and 2 months (22.5% vs 17.9%; P = 0.63). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. Pre-FMT microbiota was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment, with no difference in engraftment based on CDI recurrence or IBD endoscopic severity at FMT.

Conclusions: Inflammatory bowel disease did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiota was not predictive of recurrence, and microbial engraftment was impacted in those requiring IBD treatment escalation, though not by CDI recurrence or IBD disease severity.
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http://dx.doi.org/10.1093/ibd/izy398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499938PMC
May 2019

Gut microbiota density influences host physiology and is shaped by host and microbial factors.

Elife 2019 01 22;8. Epub 2019 Jan 22.

The Dr. Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, United States.

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn's disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.40553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342524PMC
January 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

Specific Bacteria and Metabolites Associated With Response to Fecal Microbiota Transplantation in Patients With Ulcerative Colitis.

Gastroenterology 2019 Apr 6;156(5):1440-1454.e2. Epub 2018 Dec 6.

University of New South Wales, Sydney, Australia. Electronic address:

Background & Aims: Fecal microbiota transplantation (FMT) can induce remission in patients with ulcerative colitis (UC). In a randomized controlled trial of FMT in patients with active UC, we aimed to identify bacterial taxonomic and functional factors associated with response to therapy.

Methods: We performed a double-blind trial of 81 patients with active UC randomly assigned to groups that received an initial colonoscopic infusion and then intensive multidonor FMT or placebo enemas, 5 d/wk for 8 weeks. Patients in the FMT group received blended homogenized stool from 3-7 unrelated donors. Patients in the placebo group were eligible to receive open-label FMT after the double-blind study period. We collected 314 fecal samples from the patients at screening, every 4 weeks during treatment, and 8 weeks after the blinded or open-label FMT therapy. We also collected 160 large-bowel biopsy samples from the patients at study entry, at completion of 8 weeks of blinded therapy, and at the end of open-label FMT, if applicable. We analyzed 105 fecal samples from the 14 individual donors (n = 55), who in turn contributed to 21 multidonor batches (n = 50). Bacteria in colonic and fecal samples were analyzed by both 16S ribosomal RNA gene and transcript amplicon sequencing; 285 fecal samples were analyzed by shotgun metagenomics, and 60 fecal samples were analyzed for metabolome features.

Results: FMT increased microbial diversity and altered composition, based on analyses of colon and fecal samples collected before vs after FMT. Diversity was greater in fecal and colon samples collected before and after FMT treatment from patients who achieved remission compared with patients who did not. Patients in remission after FMT had enrichment of Eubacterium hallii and Roseburia inulivorans compared with patients who did not achieve remission after FMT and had increased levels of short-chain fatty acid biosynthesis and secondary bile acids. Patients who did not achieve remission had enrichment of Fusobacterium gonidiaformans, Sutterella wadsworthensis, and Escherichia species and increased levels of heme and lipopolysaccharide biosynthesis. Bacteroides in donor stool were associated with remission in patients receiving FMT, and Streptococcus species in donor stool was associated with no response to FMT.

Conclusions: In an analysis of fecal and colonic mucosa samples from patients receiving FMT for active UC and stool samples from donors, we associated specific bacteria and metabolic pathways with induction of remission. These findings may be of value in the design of microbe-based therapies for UC. ClinicalTrials.gov, Number NCT01896635.
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http://dx.doi.org/10.1053/j.gastro.2018.12.001DOI Listing
April 2019

Diet Modifies Colonic Microbiota and CD4 T-Cell Repertoire to Induce Flares of Colitis in Mice With Myeloid-Cell Expression of Interleukin 23.

Gastroenterology 2018 10 15;155(4):1177-1191.e16. Epub 2018 Jun 15.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background & Aims: Several studies have shown that signaling via the interleukin 23 (IL23) receptor is required for development of colitis. We studied the roles of IL23, dietary factors, alterations to the microbiota, and T cells in the development and progression of colitis in mice.

Methods: All mice were maintained on laboratory diet 5053, unless otherwise noted. We generated mice that express IL23 in CX3CR1-positive myeloid cells (R23FR mice) upon cyclic administration of tamoxifen dissolved in diet 2019. Diets 2019 and 5053 have minor differences in the overall composition of protein, fat, fiber, minerals, and vitamins. CX3CR1 mice (FR mice) were used as controls. Some mice were given antibiotics, and others were raised in a germ-free environment. Intestinal tissues were collected and analyzed by histology and flow cytometry. Feces were collected and analyzed by 16S rDNA sequencing. Feces from C57/Bl6, R23FR, or FR mice were fed to FR and R23FR germ-free mice in microbiota transplant experiments. We also performed studies with R23FR/Rag, R23FR/Mu, and R23FR/Tcrd mice. R23FR mice were given injections of antibodies against CD4 or CD8 to deplete T cells. Mesenteric lymph nodes and large intestine CD4 cells from R23FR or FR mice in remission from colitis were transferred into Rag mice. CD4 cells were isolated from donor R23FR mice and recipient Rag mice, and T-cell receptor sequences were determined.

Results: Expression of IL23 led to development of a relapsing-remitting colitis that was dependent on the microbiota and CD4 T cells. The relapses were caused by switching from the conventional diet used in our facility (diet 5053) to the diet 2019 and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota but did not alter levels of IL23 in intestinal tissues compared with mice that remained on the conventional diet. Mesenteric lymph nodes and large intestine CD4 cells from R23FR mice in remission, but not from FR mice, induced colitis after transfer into Rag mice, but only when these mice were placed on the diet 2019. The CD4 T-cell receptor repertoire of Rag mice with colitis (fed the 2019 diet) was less diverse than that from donor mice and Rag mice without colitis (fed the 5053 diet) because of expansion of dominant T-cell clones.

Conclusions: We developed mice that express IL23 in CX3CR1-positive myeloid cells (R23FR mice) and found that they are more susceptible to diet-induced colitis than mice that do not express IL23. The R23FR mice have a population of CD4 T cells that becomes activated in response to dietary changes and alterations to the intestinal microbiota. The results indicate that alterations in the diet, intestinal microbiota, and IL23 signaling can contribute to pathogenesis of inflammatory bowel disease.
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http://dx.doi.org/10.1053/j.gastro.2018.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174107PMC
October 2018

Metagenomic binning and association of plasmids with bacterial host genomes using DNA methylation.

Nat Biotechnol 2018 01 11;36(1):61-69. Epub 2017 Dec 11.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Shotgun metagenomics methods enable characterization of microbial communities in human microbiome and environmental samples. Assembly of metagenome sequences does not output whole genomes, so computational binning methods have been developed to cluster sequences into genome 'bins'. These methods exploit sequence composition, species abundance, or chromosome organization but cannot fully distinguish closely related species and strains. We present a binning method that incorporates bacterial DNA methylation signatures, which are detected using single-molecule real-time sequencing. Our method takes advantage of these endogenous epigenetic barcodes to resolve individual reads and assembled contigs into species- and strain-level bins. We validate our method using synthetic and real microbiome sequences. In addition to genome binning, we show that our method links plasmids and other mobile genetic elements to their host species in a real microbiome sample. Incorporation of DNA methylation information into shotgun metagenomics analyses will complement existing methods to enable more accurate sequence binning.
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http://dx.doi.org/10.1038/nbt.4037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762413PMC
January 2018

Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice.

Gastroenterology 2018 03 23;154(4):1037-1046.e2. Epub 2017 Nov 23.

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

Background & Aims: It is not clear how the complex interactions between diet and the intestinal microbiota affect development of mucosal inflammation or inflammatory bowel disease. We investigated interactions between dietary ingredients, nutrients, and the microbiota in specific pathogen-free (SPF) and germ-free (GF) mice given more than 40 unique diets; we quantified individual and synergistic effects of dietary macronutrients and the microbiota on intestinal health and development of colitis.

Methods: C56BL/6J SPF and GF mice were placed on custom diets containing different concentrations and sources of protein, fat, digestible carbohydrates, and indigestible carbohydrates (fiber). After 1 week, SPF and GF mice were given dextran sulfate sodium (DSS) to induce colitis. Disease severity was determined based on the percent weight change from baseline, and modeled as a function of the concentration of each macronutrient in the diet. In unchallenged mice, we measured intestinal permeability by feeding mice labeled dextran and measuring levels in blood. Feces were collected and microbiota were analyzed by 16S rDNA sequencing. We collected colons from mice and performed transcriptome analyses.

Results: Fecal microbiota varied with diet; the concentration of protein and fiber had the strongest effect on colitis development. Among 9 fiber sources tested, psyllium, pectin, and cellulose fiber reduced the severity of colitis in SPF mice, whereas methylcellulose increased severity. Increasing dietary protein increased the density of the fecal microbiota and the severity of colitis in SPF mice, but not in GF mice or mice given antibiotics. Psyllium fiber reduced the severity of colitis through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary casein protein and psyllium fiber in parallel accounted for most variation in gut microbial density and intestinal permeability in unchallenged mice, as well as the severity of DSS-induced colitis; changes in 1 ingredient could be offset by changes in another.

Conclusions: In an analysis of the effects of different dietary components and the gut microbiota on mice with and without DSS-induced colitis, we found complex mixtures of nutrients affect intestinal permeability, gut microbial density, and development of intestinal inflammation.
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http://dx.doi.org/10.1053/j.gastro.2017.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847454PMC
March 2018

A functional genomics predictive network model identifies regulators of inflammatory bowel disease.

Nat Genet 2017 Oct 11;49(10):1437-1449. Epub 2017 Sep 11.

Thurston Arthritis Research Center and Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.
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http://dx.doi.org/10.1038/ng.3947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660607PMC
October 2017

Neutrophil ageing is regulated by the microbiome.

Nature 2015 Sep 16;525(7570):528-32. Epub 2015 Sep 16.

Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.
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http://dx.doi.org/10.1038/nature15367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712631PMC
September 2015

Metabolic labeling puts the microbiome under the microscope.

Nat Med 2015 Sep;21(9):977-8

Immunology Institute and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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http://dx.doi.org/10.1038/nm.3941DOI Listing
September 2015

Bridging the knowledge gap: from microbiome composition to function.

Authors:
Jeremiah J Faith

Mol Syst Biol 2015 Mar;11(3):793

Despite the wealth of metagenomic sequencing data, the functions of most bacterial genes from the mammalian microbiota have remained poorly understood. In their recent study (Yaung et al 2015), Wang, Gerber, and colleagues present a platform which allows functional mining of bacterial genomes for genes that contribute to fitness in vivo and holds great potential for forward engineering microbes with enhanced colonization abilities in the microbiota.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380927PMC
http://dx.doi.org/10.15252/msb.20156045DOI Listing
March 2015

Identifying strains that contribute to complex diseases through the study of microbial inheritance.

Proc Natl Acad Sci U S A 2015 Jan 9;112(3):633-40. Epub 2015 Jan 9.

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108

It has been 35 y since Carl Woese reported in PNAS how sequencing ribosomal RNA genes could be used to distinguish the three domains of life on Earth. During the past decade, 16S rDNA sequencing has enabled the now frequent enumeration of bacterial communities that populate the bodies of humans representing different ages, cultural traditions, and health states. A challenge going forward is to quantify the contributions of community members to wellness, disease risk, and disease pathogenesis. Here, we explore a theoretical framework for studies of the inheritance of bacterial strains and discuss the advantages and disadvantages of various study designs for assessing the contribution of strains to complex diseases.
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http://dx.doi.org/10.1073/pnas.1418781112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311841PMC
January 2015

Mining the human gut microbiota for effector strains that shape the immune system.

Immunity 2014 Jun;40(6):815-23

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA. Electronic address:

The gut microbiota codevelops with the immune system beginning at birth. Mining the microbiota for bacterial strains responsible for shaping the structure and dynamic operations of the innate and adaptive arms of the immune system represents a formidable combinatorial problem but one that needs to be overcome to advance mechanistic understanding of microbial community and immune system coregulation and to develop new diagnostic and therapeutic approaches that promote health. Here, we discuss a scalable, less biased approach for identifying effector strains in complex microbial communities that impact immune function. The approach begins by identifying uncultured human fecal microbiota samples that transmit immune phenotypes to germ-free mice. Clonally arrayed sequenced collections of bacterial strains are constructed from representative donor microbiota. If the collection transmits phenotypes, effector strains are identified by testing randomly generated subsets with overlapping membership in individually housed germ-free animals. Detailed mechanistic studies of effector strain-host interactions can then be performed.
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http://dx.doi.org/10.1016/j.immuni.2014.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118768PMC
June 2014

Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice.

Sci Transl Med 2014 Jan;6(220):220ra11

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.

Identifying a scalable, unbiased method for discovering which members of the human gut microbiota influence specific physiologic, metabolic, and immunologic phenotypes remains a challenge. We describe a method in which a clonally arrayed collection of cultured, sequenced bacteria was generated from one of several human fecal microbiota samples found to transmit a particular phenotype to recipient germ-free mice. Ninety-four bacterial consortia of diverse size, randomly drawn from the culture collection, were introduced into germ-free animals. We identified an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells (T(regs)) and expansion of Nrp1(lo/-) peripheral T(regs), as well as strains that modulated mouse adiposity and cecal metabolite concentrations, using feature selection algorithms and follow-up monocolonizations. This combinatorial approach enables a systems-level understanding of microbial contributions to human biology.
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http://dx.doi.org/10.1126/scitranslmed.3008051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973144PMC
January 2014

Gut microbiota from twins discordant for obesity modulate metabolism in mice.

Science 2013 Sep;341(6150):1241214

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.

The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the U.S. diet. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes, were transmissible with uncultured fecal communities and with their corresponding fecal bacterial culture collections. Cohousing mice harboring an obese twin's microbiota (Ob) with mice containing the lean co-twin's microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cage mates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota and was diet-dependent. These findings reveal transmissible, rapid, and modifiable effects of diet-by-microbiota interactions.
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http://dx.doi.org/10.1126/science.1241214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829625PMC
September 2013

The long-term stability of the human gut microbiota.

Science 2013 Jul;341(6141):1237439

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.

A low-error 16S ribosomal RNA amplicon sequencing method, in combination with whole-genome sequencing of >500 cultured isolates, was used to characterize bacterial strain composition in the fecal microbiota of 37 U.S. adults sampled for up to 5 years. Microbiota stability followed a power-law function, which when extrapolated suggests that most strains in an individual are residents for decades. Shared strains were recovered from family members but not from unrelated individuals. Sampling of individuals who consumed a monotonous liquid diet for up to 32 weeks indicated that changes in strain composition were better predicted by changes in weight than by differences in sampling interval. This combination of stability and responsiveness to physiologic change confirms the potential of the gut microbiota as a diagnostic tool and therapeutic target.
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http://dx.doi.org/10.1126/science.1237439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791589PMC
July 2013

Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing.

Nat Methods 2013 Jan 2;10(1):57-9. Epub 2012 Dec 2.

Department of Viticulture and Enology, University of California, Davis, Davis, California, USA.

High-throughput sequencing has revolutionized microbial ecology, but read quality remains a considerable barrier to accurate taxonomy assignment and α-diversity assessment for microbial communities. We demonstrate that high-quality read length and abundance are the primary factors differentiating correct from erroneous reads produced by Illumina GAIIx, HiSeq and MiSeq instruments. We present guidelines for user-defined quality-filtering strategies, enabling efficient extraction of high-quality data and facilitating interpretation of Illumina sequencing results.
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http://dx.doi.org/10.1038/nmeth.2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531572PMC
January 2013