Secreted NF-κB suppressive microbial metabolites modulate gut inflammation

Emerging evidence suggests that microbiome-host crosstalk regulates intestinal immune activity and predisposition to inflammatory bowel disease (IBD). NF-κB is a master regulator of immune function and a validated target for the treatment of IBD. Here, we identify five Clostridium strains that suppress immune-mediated NF-κB activation in epithelial cell lines, PBMCs, and gut epithelial organoids from healthy human subjects and patients with IBD. Cell-free culture supernatant from Clostridium bolteae AHG0001 strain, but not the reference C. bolteae BAA-613 strain, suppresses inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from Winnie mice. The in vivo responses to Clostridium bolteae AHG0001 and BAA-613 mirror the in vitro activity. Thus, using our in vitro screening of bacteria capable of suppressing NF-κB in the context of IBD and using an ex vivo organoid-based approach, we identify a strain capable of alleviating colitis in a relevant pre-clinical animal model of IBD. [Display omitted] •Select strains of Clostridium from human stool samples can suppress NF-κB activation•The immunomodulatory effect of bacteria can be strain- and media-specific•Inter-patient variation suggests possible development of personalized medicine•In vitro immunosuppression assays using organoids predict in vivo activity The ability of gut bacteria to modulate inflammation remains cryptic. Using anaerobic cultures, Giri et al. identify multiple Firmicutes-affiliated bacteria capable of reducing NF-κB-mediated inflammatory signaling in a strain-dependent manner. Cell-free culture supernatants reduce inflammation in patient-derived organoids and in a pre-clinical model of colitis.