Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence

Abstract

ObjectivesDysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNFdeltaARE mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement.DesignHeterozygous TNFdeltaARE mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis.ResultsGF-TNFdeltaARE mice were free of inflammation in the gut and antibiotic treatment of CONV-TNFdeltaARE mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNFdeltaARE mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNFdeltaARE recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNFdeltaARE mice with the human CD-related Escherichia coli LF82 did not induce ileitis.ConclusionsWe 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.

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

“…The effects on gut epithelial inflammation and inflammatory markers can also be studied using IBD mouse models. 40 Finally, mouse experiments can be used to investigate the metabolic effects of gut microbiota alterations. 41 Commonly used medication should be part of the core phenotype set for human gut microbiota research PPI use is overrepresented in many disorders and conditions, including obesity, non-alcoholic steatohepatitis (NASH), Irritable Bowel Syndrome (IBS), rheumatoid arthritis and IBD.…”

Paneth cell defects in Crohn’s disease patients promote dysbiosis

“…However, an alternative mechanism has recently been postulated in which dysbiosis may precede intestinal inflammation and subsequent Paneth cell dysfunction in genetically susceptible hosts. In a TNFΔARE mouse model, gut dysbiosis led to chronic intestinal inflammation that resulted in loss of Paneth cells (23). Thus, it is likely that there is a complex cross talk between Paneth cells and the gut microbiota.…”

La méthode Bayésienne pour aider à évaluer l’efficacité des thérapies personnalisées

“…La maladie de Crohn est souvent associée àune dysbiose spécifique avecappauvrissement de la diversité bactérienne [26][27][28].…”