Gallic acid attenuates murine ulcerative colitis by promoting group 3 innate lymphocytes, affecting gut microbiota, and bile acid metabolism

Abstract

Gallic acid (GA), a plant phenol that is widely distributed in fruits and vegetables, and exhibits a protective role against ulcerative colitis (UC). UC is an inflammatory disease characterized by immune response disorders. However, the role and mechanism of action of GA in gut immunity remain unknown. Here, we observed that GA treatment improved enteritis symptoms, decreased the concentrations of cytokines TNF-α, IFN-γ, IL-6, IL-17A, and IL-23, increased the concentrations of cytokines IL-10, TGF-β and IL-22, and increased the proportion of group 3 innate lymphoid cells (ILC3) in mesenteric lymph nodes and lamina propria. However, GA did not upregulate ILC3 or impair UC in antibody-treated sterile mice. Notably, transplantation of fecal bacteria derived from GA-treated UC mice, instead of UC mice, increased ILC3 levels. Therefore, we analyzed the gut microbiota and related metabolites to elucidate the mechanism promoting ILC3. We determined that GA treatment altered the diversity of the gut microbiota and activated the bile acid (BA) metabolic pathway. We evaluated three BAs, namely, UDCA, isoalloLCA, and 3-oxoLCA that were significantly upregulated after GA treatment, improved UC symptoms, and elevated the proportion of ILC3 in vivo and in vitro. Collectively, these data indicate that GA attenuates UC by elevating ILC3 proportion, regulating the gut microbiota, and impacting BA metabolism. Additionally, we highlight the modulatory effects of BAs on ILC3 for the first time. Our findings provide novel insights into the multiple roles of GA in alleviating UC and provide a mechanistic explanation that supports the dietary nutrition in UC therapy.