Dysbiotic Gut Microbiota Causes Transmissive Crohn´s Disease-like Ileitis Associated With Paneth Cell Failure

Background: Dysbiosis of the intestinal microbiota is associated with Crohn´s disease (CD). Functional evidence for a causal role of bacteria in chronic ileal inflammation development is lacking. Similar to human pathology, TNF^deltaARE mice develop a TNF-driven, CD-like transmural inflammation with predominant ileal involvement.

Methods and Results: Heterozygous TNF^deltaARE mice and WT littermates were housed under conventional (CONV), specific-pathogen-free (SPF) and germfree (GF) conditions. GF-TNF^deltaARE mice were free of inflammation in the gut and antibiotic treatment attenuated ileitis but not colitis, demonstrating that disease-severity and location is microbiota-dependent. SPF-TNF^deltaARE mice were free of colitis and developed distinct ileitis-phenotypes associated with gradual loss of Paneth cell function, as assessed by immunofluorescence analysis. Analysis of microbial communities by 16S gene sequencing and metaproteomes revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Monoassociation of GF-TNF^deltaARE mice with the human CD-related Escherichia coli LF82 did not induce ileitis. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF^deltaARE recipients and triggered Paneth cell failure.

Conclusion: We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.