Abstract
The mouse pathobiont Helicobacter hepaticus can induce typhlocolitis in interleukin-10-deficient mice, and H. hepaticus infection of immunodeficient mice is widely used as a model to study the role of pathogens and commensal bacteria in the pathogenesis of inflammatory bowel disease. C57BL/6J Il10−/− mice kept under specific pathogen-free conditions in two different facilities (MHH and MIT), displayed strong differences with respect to their susceptibilities to H. hepaticus-induced intestinal pathology. Mice at MIT developed robust typhlocolitis after infection with H. hepaticus, while mice at MHH developed no significant pathology after infection with the same H. hepaticus strain. We hypothesized that the intestinal microbiota might be responsible for these differences and therefore performed high resolution analysis of the intestinal microbiota composition in uninfected mice from the two facilities by deep sequencing of partial 16S rRNA amplicons. The microbiota composition differed markedly between mice from both facilities. Significant differences were also detected between two groups of MHH mice born in different years. Of the 119 operational taxonomic units (OTUs) that occurred in at least half the cecum or colon samples of at least one mouse group, 24 were only found in MIT mice, and another 13 OTUs could only be found in MHH samples. While most of the MHH-specific OTUs could only be identified to class or family level, the MIT-specific set contained OTUs identified to genus or species level, including the opportunistic pathogen, Bilophila wadsworthia. The susceptibility to H. hepaticus-induced colitis differed considerably between Il10−/− mice originating from the two institutions. This was associated with significant differences in microbiota composition, highlighting the importance of characterizing the intestinal microbiome when studying murine models of IBD.
Highlights
The gram-negative ‘pathobiont’ Helicobacter hepaticus primarily colonizes the gastrointestinal tract of mice, and can colonize bile canaliculi and gallbladder of mice with chronic hepatitis [1]
Differential Susceptibility to H. hepaticus-associated Typhlocolitis of C57BL/6J Il102/2 mice Housed in Two Different Animal Facilities
H. hepaticus infected C57BL/6 Il102/2 mice were reported to develop typhlocolitis by the group of J.G.F. at Massachusetts Institute of Technology (MIT) [20,27], and similar findings have been reported by other groups [6] [28][29]
Summary
The gram-negative ‘pathobiont’ Helicobacter hepaticus primarily colonizes the gastrointestinal tract of mice, and can colonize bile canaliculi and gallbladder of mice with chronic hepatitis [1]. While H. hepaticus colonization causes no intestinal pathology in immunocompetent mice, it induces hepatobiliary inflammation and an increased incidence of hepatic cancer in a number of susceptible mouse strains [2,3,4]. The H. hepaticus genome [15] contains a gene cluster encoding a cytolethal distending toxin (CDT), a homolog of the Campylobacter jejuni CDT, which causes cell cycle arrest, chromatin fragmentation, and apoptosis [16]. It includes a pathogenicity island HHGI1, which encodes a functional type VI secretion system [17,18]. H. hepaticus lipopolysaccharide (LPS) has been shown to reduce Toll-like receptor 4 (TLR4) and TLR5-mediated innate immune responses of intestinal epithelial cells, and to inhibit development of endotoxin tolerance, affecting host responses to the resident microbiota and intestinal inflammatory conditions [21]
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