Secreted microbial metabolites modulate gut immunity and inflammatory tone

Evidence is emerging that microbiome–immune system crosstalk regulates the tenor of host intestinal immunity and predisposition to inflammatory bowel disease (IBD). We identified five NF-κB suppressive strains affiliated with clusters IV, XIVa and XV that independently suppressed secretion of the chemokine IL-8 by peripheral blood mononuclear cells and gut epithelial organoids from healthy human subjects, as well as patients with the predominant IBD subtypes, Crohn’s disease and ulcerative colitis. The NF-κB suppressive AHG0001, but not BAA-613, suppressed cytokine-driven inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from mice that develop spontaneous colitis. This predicted responses thereby validating a precision medicine approach to treat colitis and suggesting the microbiome may function as an extrinsic regulator of host immunity. Finally, we identified a novel molecule associated with NF-κB suppression indicating gut bacteria could be harnessed to develop new therapeutics.