Hippuric acid alleviates dextran sulfate sodium-induced colitis via suppressing inflammatory activity and modulating gut microbiota

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with metabolic disorder and gut dysbiosis. Decreased abundance of hippuric acid (HA) was found in patients with IBD. HA, metabolized directly from benzoic acid in the intestine and indirectly from polyphenols, serves as a marker of polyphenol catabolism. While polyphenols and benzoic acid have been shown to alleviate intestinal inflammation, the role of HA in this context remains unknown. Herein, we investigated the effects and mechanism of HA on DSS-induced colitis mice. The results revealed that HA alleviated clinical activity and intestinal barrier damage, decreased proinflammatory cytokine production. Metagenomic sequencing suggested that HA treatment restored the gut microbiota, including an increase in beneficial gut bacteria such as Adlercreutzia , Eubacterium , Schaedlerella and Bifidobacterium_pseudolongum . Furthermore, we identified 113 candidate genes associated with IBD that are potentially under HA regulation through network pharmacological analyses. 10 hub genes including ALB, IL-6, HSP90AA1, and others were identified using PPI analysis and validated using molecular docking and mRNA expression analysis. Additionally, KEGG analysis suggested that the renin-angiotensin system (RAS), NF- kappa B signaling and Rap1 signaling pathways were important pathways in the response of HA to colitis. Thus, HA may provide novel biotherapy options for IBD.