Ellagic acid alleviates ulcerative colitis in a GPR35-dependent manner associated with SDH restoration.

Abstract

BACKGROUND: Ulcerative colitis (UC) is a nonspecific inflammatory bowel disease characterized by recurrent mucosal inflammation. Ellagic acid, a bioactive natural polyphenol, has shown efficacy in experimental UC models, yet its molecular mechanism remains unclear. PURPOSE: This study aimed to elucidate the molecular, cellular, and phenotypic mechanisms by which ellagic acid exerts its protective effects in UC. METHODS: A DSS-induced mouse model of colitis was used to evaluate the therapeutic effects of ellagic acid. Candidate molecular targets were prioritized by intersecting reported bioactive targets (PubChem) with colitis-related genes (GeneCards), followed by receptor pharmacological characterization using dynamic mass redistribution assays, NanoBRET-based competitive binding assays, and differential scanning fluorimetry. The role of GPR35 was validated via genetic inhibition. RESULTS: Ellagic acid alleviated DSS-induced colitis, reduced proinflammatory cytokine expression, and partially restored goblet cell-associated mucin staining as suggested by AB-PAS staining. Integrated target analysis and pharmacological assays identified GPR35 as a key receptor for ellagic acid in exerting its anti-IBD activity. GPR35 activation was associated with restoration of succinate dehydrogenase (SDH) subunit expression, whereas GPR35 deficiency impaired SDH expression and mitochondrial function. In addition to ellagic acid, hydrolyzable tannin metabolites, including sanguisorbic acid dilactone and gut-derived urolithins, also exhibited GPR35 agonistic activity. Dijincao, an ellagitannins-rich herb, recapitulated the therapeutic effects of ellagic acid in a GPR35-dependent manner. CONCLUSION: Ellagic acid ameliorates UC in a GPR35-dependent manner associated with restoration of SDH expression and improved mitochondrial function. These findings provide mechanistic insight into the therapeutic potential of ellagic acid and highlight ellagitannins as natural prodrug-like candidates with therapeutic potential through GPR35 activation.