A role for microbiota metabolites in generation of mucosal dendritic cells (P3160)

Abstract

The gut mucosa normally exhibits tolerance towards the commensal microbiota by active suppression of inflammation. When homeostasis is disrupted, inflammatory bowel diseases may develop, during which microbiota dysbiosis may also occur. Resulting chronic inflammation induces loss of intestinal epithelial integrity, gastrointestinal (GI) distress, and colon cancer risk. We hypothesize that under normal conditions, the microbiota produce beneficial compounds that promote homeostasis. Previously, we reported that indole exerts immunomodulatory and anti-inflammatory effects on intestinal epithelial cells (IECs). We propose that indole, an abundant, freely diffusible, and strictly microbiota-derived molecule in the GI tract, conditions IECs and immune cells for optimal gut functions. Here, we report that indole potently modulates dendritic cell (DC) responses, which are central regulators of gut homeostasis. Specifically, indole-conditioned DCs produce decreased pro-inflammatory cytokines after microbial activation, and indole strongly synergizes with TGF-β for this effect. In addition, indole regulates the expression of the mucosal DC markers CCR9, B220, and aldh1a2. Furthermore, indole-treatment rescues host inflammation in a murine model of colitis. Given its availability and immunomodulatory properties, we suggest indole is a member of a novel class of microbiota compounds that regulate gut immune cells and may be a potential treatment of inflammatory bowel disease.