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Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

ABSTRACT: The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here, we fulfilled Koch's postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively reisolated them in culture. The bacteria colonized IBD-susceptible and -nonsusceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease, but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD.

SUBMITTER: Bloom SM

PROVIDER: S-EPMC3241010 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

Bloom Seth M SM Bijanki Vinieth N VN Nava Gerardo M GM Sun Lulu L Malvin Nicole P NP Donermeyer David L DL Dunne W Michael WM Allen Paul M PM Stappenbeck Thaddeus S TS

Cell host & microbe 20110501 5

The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here, we fulfilled Koch's postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common ...[more]

PMID: 21575910

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Project description:BackgroundInflammatory bowel diseases (IBD) may be caused in part by aberrant immune responses to commensal intestinal microbes including the well-characterized anaerobic gut commensal Bacteroides thetaiotaomicron (B. theta). Healthy, germ-free HLA-B27 transgenic (Tg) rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg) rats remain disease-free. However, the role of B. theta in causing disease in Tg rats is unknown nor is much known about how gut microbes respond to host inflammation.MethodsTg and nTg rats were monoassociated with a human isolate of B. theta. Colonic inflammation was assessed by histologic scoring and tissue pro-inflammatory cytokine measurement. Whole genome transcriptional profiling of B. theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA) software. Western Blots were used to determine adaptive immune responses to a differentially expressed B. theta gene.ResultsB. theta monoassociated Tg rats, but not nTg or germ-free controls, developed chronic colitis. Transcriptional profiles of cecal B. theta were significantly different in Tg vs. nTg rats. GSEA revealed that genes in KEGG canonical pathways involved in bacterial growth and metabolism were downregulated in B. theta from Tg rats with colitis though luminal bacterial concentrations were unaffected. Bacterial genes in the Gene Ontology molecular function "receptor activity", most of which encode nutrient binding proteins, were significantly upregulated in B. theta from Tg rats and include a SusC homolog that induces adaptive immune responses in Tg rats.ConclusionsB. theta induces colitis in HLA-B27 Tg rats, which is associated with regulation of bacterial genes in metabolic and nutrient binding pathways that may affect host immune responses. These studies of the host-microbial dialogue may lead to the identification of novel microbial targets for IBD therapies.

Project description:Inflammatory bowel disease (IBD) has become a global public health problem. Although the pathogenesis of the disease is unknown, a potential association between the gut microbiota and inflammatory signatures has been established. Probiotics, especially Lactobacillus or Bifidobacterium, are orally taken as food supplements or microbial drugs by patients with IBD or gastrointestinal disorders due to their safety, efficacy, and power to restore the gut microenvironment. In the current study, we investigated the comprehensive effects of probiotic bacterial consortia consisting of Lactobacillus reuteri, Lactobacillus gasseri, Lactobacillus acidophilus (Lactobacillus spp.), and Bifidobacterium lactis (Bifidobacterium spp.) or their metabolites in a dextran sodium sulfate (DSS)-induced colitis mouse model. Our data demonstrate that probiotic consortia not only ameliorate the disease phenotype but also restore the composition and structure of the gut microbiota. Moreover, the effect of probiotic consortia is better than that of any single probiotic strain. The results also demonstrate that mixed fermentation metabolites are capable of ameliorating the symptoms of gut inflammation. However, the administration of metabolites is not as effective as probiotic consortia with respect to phenotypic characteristics, such as body weight, disease activity index (DAI), and histological score. In addition, mixed metabolites led only to changes in intestinal flora composition. In summary, probiotic consortia and metabolites could exert protective roles in the DSS-induced colitis mouse model by reducing inflammation and regulating microbial dysbiosis. These findings from the current study provide support for the development of probiotic-based microbial products as an alternative therapeutic strategy for IBD. IMPORTANCE IBD is a chronic nonspecific inflammatory disease. IBD is characterized by a wide range of lesions, often involving the entire colon, and is characterized mainly by ulcers and erosions of the colonic mucosa. In the present study, we investigated the efficacy of probiotics on the recovery of gut inflammation and the restoration of gut microecology. We demonstrate that probiotic consortia have a superior effect in inhibiting inflammation and accelerating recovery compared with the effects observed in the control group or groups administered with a single strain. These results support the utilization of probiotic consortia as an alternative therapeutic approach to treat IBD.

Dataset Information

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

Publications

Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

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