Slow transit constipation (STC) is a prevalent gastrointestinal disorder caused by colon dysfunction. Poly-γ-glutamic acid (γ-PGA), an anionic polymer known for its moisture retention, degradability, and food safety, was studied for its effects on loperamide-induced STC in mice. Treatment with γ-PGA for one week significantly increased both defecation frequency and fecal water content, with the high-dose group (10 g/kg/d) restoring fecal water content to 34.23%, outperforming the low- (16.16%) and medium-dose (27.08%) groups and exceeding the positive control, PEG, by 1.35 times. γ-PGA enhanced intestinal peristalsis and reduced the expression of inflammatory markers (IL-1β, IL-6, caspase-1, TLR2) and water-electrolyte transport genes (AQP3, AQP4, ENaC-β), while improving the expression of tight junction proteins (Claudin-1, Occludin, ZO-1) damaged by loperamide. Histopathological analyses confirmed γ-PGA's capacity to repair intestinal damage. Additionally, Western Blot analysis indicated reduced AQP3/4 levels in the colon, and molecular docking showed good binding affinity between γ-PGA and AQPs. γ-PGA also positively altered gut microbiota composition. Overall, γ-PGA shows promise in treating STC by modulating aquaporins and gut microbiota.
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