Pathobiont-triggered induction of goblet cell response drives regional susceptibility to inflammatory bowel disease.

Abstract

The gastrointestinal tract varies in structure and function by region, yet the drivers of region-specific inflammatory disease remain elusive. Here, a TNF-overexpressing murine model (TnfΔARE/+) of Crohn's disease (CD) was used to investigate how pathobionts interact with host immune susceptibilities to drive region-specific disease. We identified the pathobiont Chlamydia muridarum, an intracellular bacterium and murine counterpart to the human sexually transmitted C. trachomatis, as a necessary and sufficient trigger for disease manifestation in the proximal/ascending colon, a common site of CD. In genetically susceptible hosts, pathobiont-triggered proximal colonic inflammation is driven by goblet cell responses, including tryptophan metabolism via indoleamine 2,3-dioxygenase 1 (IDO1). Our findings translate to human disease, where we demonstrate upregulation of epithelia-derived IDO1 in actively inflamed ascending colon specimens, but not actively inflamed terminal ileum specimens, of patients with CD. Our findings mechanistically reveal how genetic and microbial factors drive the manifestation of disease in a region-specific manner and provide a unique model to study CD specific to the ascending colon.