Role of Microbial Metabolites of Histidine in the Development of Colitis

SCOPE: Colitis is a chronic relapsing inflammatory disease of colon. Clinical studies show that meat-rich diet plays a critical role in the relapse of colitis. However, it is unclear whether the microbial metabolites of histidine, which is an amino acid widely found in meat, have an impact on the health of the intestine. METHODS AND RESULTS: Six metabolites of histidine are given to IEC-6 cells. The cell activity measurement shows that imidazole propionate (IMP) is the most detrimental metabolite. Then, IMP is injected to mice by rectal administration, with blood and colon tissues collected for the measurement of colitis related parameters. The results show that treatment with IMP significantly increased NF-κB, iNOS, and IL-6, decreased number of goblet cell, and inhibited expressions of miR-146b. However, overexpression of miR-146b in mice rescues the decline of the physical condition. Additionally, Notch receptor 1 (Notch1) is identified as a target gene of miR-146b. Further analysis shows that miR-146b restored the abundance of goblet cells by regulating Notch1 signaling pathway. CONCLUSION: IMP is able to induce intestinal inflammation, impairs the intestinal barrier, and affects the proliferation of goblet cells. The underlined mechanism may partially contribute to the dysregulation of miR-146b/Notch1 axis.