Metagenomic alterations in gut microbiota precede and predict onset of colitis in the IL10 gene-deficient murine model

AbstractBackground & AimsInflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive biomarkers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined whether gut microbiota metagenomic profiles would provide more robust measures for predicting disease outcomes in colitis-prone hosts.MethodsUsing the IL-10 gene-deficient (IL-10 KO) murine model where early life dysbiosis from antibiotic (cefoperozone, CPZ) treated dams vertically-transferred to pups increases risk for colitis later in life, we investigated temporal metagenomic profiles in the gut microbiota of post-weaning offspring and determined their relationship to eventual clinical outcomes.ResultsCompared to controls, offspring acquiring maternal CPZ-induced dysbiosis exhibited a restructuring of intestinal microbial membership both in bacteriome and mycobiome that were associated with alterations in specific functional subsystems. Furthermore, among IL-10 KO offspring from CPZ-treated dams, several functional subsystems, particularly nitrogen metabolism, diverged between mice that developed spontaneous colitis (CPZ-colitis) versus those that did not (CPZ-no-colitis) at a time point prior to eventual clinical outcome.ConclusionsOur findings provide support that functional metagenomic profiling of gut microbes has potential and promise meriting further study for development of tools to assess risk and manage human IBD.SynopsisCurrently, predictive markers for the development and course of inflammatory bowel diseases (IBD) are not available. This study supports the notion that gut microbiome metagenomic profiles could be developed into a useful tool to assess risk and manage human IBD.

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Interleukin 1α-Deficient Mice Have an Altered Gut Microbiota Leading to Protection from Dextran Sodium Sulfate-Induced Colitis

mSystems ◽

10.1128/msystems.00213-17 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 11

Author(s):

Moran Nunberg ◽

Nir Werbner ◽

Hadar Neuman ◽

Marina Bersudsky ◽

Alex Braiman ◽

...

Keyword(s):

Gut Microbiota ◽

Clinical Outcomes ◽

Inflammatory Bowel Diseases ◽

Microbiota Composition ◽

Colon Inflammation ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Interleukin 1Α ◽

Deficient Mice ◽

Gut Microbiota Composition

ABSTRACT Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders of the intestine, with as-yet-unclear etiologies, affecting over a million people in the United States alone. With the emergence of microbiome research, numerous studies have shown a connection between shifts in the gut microbiota composition (dysbiosis) and patterns of IBD development. In a previous study, we showed that interleukin 1α (IL-1α) deficiency in IL-1α knockout (KO) mice results in moderate dextran sodium sulfate (DSS)-induced colitis compared to that of wild-type (WT) mice, characterized by reduced inflammation and complete healing, as shown by parameters of weight loss, disease activity index (DAI) score, histology, and cytokine expression. In this study, we tested whether the protective effects of IL-1α deficiency on DSS-induced colitis correlate with changes in the gut microbiota and whether manipulation of the microbiota by cohousing can alter patterns of colon inflammation. We analyzed the gut microbiota composition in both control (WT) and IL-1α KO mice under steady-state homeostasis, during acute DSS-induced colitis, and after recovery using 16S rRNA next-generation sequencing. Additionally, we performed cohousing of both mouse groups and tested the effects on the microbiota and clinical outcomes. We demonstrate that host-derived IL-1α has a clear influence on gut microbiota composition, as well as on severity of DSS-induced acute colon inflammation. Cohousing both successfully changed the gut microbiota composition and increased the disease severity of IL-1α-deficient mice to levels similar to those of WT mice. This study shows a strong and novel correlation between IL-1α expression, microbiota composition, and clinical outcomes of DSS-induced colitis. IMPORTANCE Here, we show a connection between IL-1α expression, microbiota composition, and clinical outcomes of DSS-induced colitis. Specifically, we show that the mild colitis symptoms seen in IL-1α-deficient mice following administration of DSS are correlated with the unique gut microbiota compositions of the mice. However, when these mice are exposed to WT microbiota by cohousing, their gut microbiota composition returns to resemble that of WT mice, and their disease severity increases significantly. As inflammatory bowel diseases are such common diseases, with limited effective treatments to date, there is a great need to better understand the interactions between microbiota composition, the immune system, and colitis. This study shows correlation between microbiota composition and DSS resistance; it may potentially lead to the development of improved probiotics for IBD treatment.

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The Gut Microbiome and Inflammatory Bowel Diseases

Annual Review of Medicine ◽

10.1146/annurev-med-042320-021020 ◽

2021 ◽

Vol 73 (1) ◽

Author(s):

Yue Shan ◽

Mirae Lee ◽

Eugene B. Chang

Keyword(s):

Gut Microbiota ◽

Inflammatory Bowel Diseases ◽

Gut Microbiome ◽

Annual Review ◽

Publication Date ◽

Bowel Diseases ◽

Microbe Interactions ◽

Inflammatory Bowel ◽

Host Microbe Interactions ◽

And Function

Inflammatory bowel diseases (IBD) arise from a convergence of genetic risk, environmental factors, and gut microbiota, where each is necessary but not sufficient to cause disease. Emerging evidence supports a bidirectional relationship between disease progression and changes in microbiota membership and function. Thus, the study of the gut microbiome and host–microbe interactions should provide critical insights into disease pathogenesis as well as leads for developing microbiome-based diagnostics and interventions for IBD. In this article, we review the most recent advances in understanding the relationship between the gut microbiota and IBD and highlight the importance of going beyond establishing description and association to gain mechanistic insights into causes and consequences of IBD. The review aims to contextualize recent findings to form conceptional frameworks for understanding the etiopathogenesis of IBD and for the future development of microbiome-based diagnostics and interventions. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Gut microbiota induce local and systemic CD4 T cell responses in healthy individuals that are altered in inflammatory bowel diseases

10.1055/s-0037-1604874 ◽

2017 ◽

Author(s):

AN Hegazy ◽

N West ◽

MJT Stubbington ◽

E Wendt ◽

K Suijker ◽

...

Keyword(s):

T Cell ◽

Gut Microbiota ◽

Inflammatory Bowel Diseases ◽

T Cell Responses ◽

Cd4 T Cell ◽

Healthy Individuals ◽

Cell Responses ◽

Bowel Diseases ◽

Inflammatory Bowel

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Gut microbiota in inflammatory bowel diseases: moving from basic science to clinical applications

Human Genetics ◽

10.1007/s00439-020-02218-3 ◽

2020 ◽

Author(s):

Valerie Collij ◽

Marjolein A. Y. Klaassen ◽

Rinse K. Weersma ◽

Arnau Vich Vila

Keyword(s):

Gut Microbiota ◽

Inflammatory Bowel Diseases ◽

Basic Science ◽

Clinical Applications ◽

Bowel Diseases ◽

Inflammatory Bowel

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The Use of Probiotic Therapy to Modulate the Gut Microbiota and Dendritic Cell Responses in Inflammatory Bowel Diseases

Medical Sciences ◽

10.3390/medsci7020033 ◽

2019 ◽

Vol 7 (2) ◽

pp. 33 ◽

Cited By ~ 2

Author(s):

Pablo Alagón Fernández del Campo ◽

Alejandro De Orta Pando ◽

Juan Ignacio Straface ◽

José Ricardo López Vega ◽

Diego Toledo Plata ◽

...

Keyword(s):

Gut Microbiota ◽

Inflammatory Bowel Diseases ◽

T Regulatory Cells ◽

Oxygen Species ◽

Regulatory Cells ◽

Population Status ◽

Cell Responses ◽

Bowel Diseases ◽

Tolerance Response ◽

Inflammatory Bowel

: Recent investigations have shown that different conditions such as diet, the overuse of antibiotics or the colonization of pathogenic microorganisms can alter the population status of the intestinal microbiota. This modification can produce a change from homeostasis to a condition known as imbalance or dysbiosis; however, the role-played by dysbiosis and the development of inflammatory bowel diseases (IBD) has been poorly understood. It was actually not until a few years ago that studies started to develop regarding the role that dendritic cells (DC) of intestinal mucosa play in the sensing of the gut microbiota population. The latest studies have focused on describing the DC modulation, specifically on tolerance response involving T regulatory cells or on the inflammatory response involving reactive oxygen species and tissue damage. Furthermore, the latest studies have also focused on the protective and restorative effect of the population of the gut microbiota given by probiotic therapy, targeting IBD and other intestinal pathologies. In the present work, the authors propose and summarize a recently studied complex axis of interaction between the population of the gut microbiota, the sensing of the DC and its modulation towards tolerance and inflammation, the development of IBD and the protective and restorative effect of probiotics on other intestinal pathologies.

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