Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis

Area of Science:

• Microbiome research
• Immunology
• Gastroenterology

Background:

• Gut microbiota metabolites significantly influence inflammatory responses in inflammatory bowel disease (IBD).
• Specific metabolites can either promote or suppress inflammation, highlighting their therapeutic potential.

Purpose of the Study:

• To identify specific gut microbiota-derived metabolites driving inflammation in ulcerative colitis (UC).
• To elucidate the mechanism by which these metabolites activate immune cells and exacerbate colitis.
• To explore potential therapeutic strategies targeting these metabolites or their pathways.

Main Methods:

• Analysis of gut microbiota composition and metabolite levels in colitis models and UC patients.
• Investigating the role of succinate in activating T helper 9 (Th9) cells.
• Utilizing bacterial colonization, receptor antagonists, and antibody neutralization in preclinical models.

Main Results:

• Succinate-producing bacteria and luminal succinate levels are increased in colitis and UC.
• Succinate activates colitogenic Th9 cells, exacerbating intestinal inflammation.
• Administration of succinate-metabolizing bacteria, succinate receptor antagonists, or anti-IL-9 antibodies reduced inflammation.

Conclusions:

• Gut microbiota-derived succinate is a key driver of colitogenic Th9 cell responses in UC.
• Targeting succinate metabolism or signaling pathways presents a promising therapeutic avenue for IBD.