A facile polysaccharide hydrogel activates PPARγ via the Gut-Kidney axis to ameliorate chronic kidney disease.

Chronic Kidney Disease (CKD) features gut microbiota dysbiosis, systemic inflammation, and impaired barrier function. The formation of such a triad of "microbiota-metabolite-barrier" dysregulation underscores the therapeutic potential of a Gut-Kidney Axis intervention strategy. Traditional Chinese medicine highlights plant-derived polysaccharides as renoprotective modulators of the Gut-Kidney Axis, yet free polysaccharides suffer from limited colonic exposure, single-function delivery, and proximal-skewed fermentation. Thus, this study engineered a Morinda officinalis polysaccharide (MOPs)/Inulin composite hydrogel (MI Gel) via a simple, green hydrothermal process to achieve colon-targeted, sustained release with mucosal adhesion for CKD therapy via the Gut-Kidney Axis. This hydrogel exhibited degradation resistance and prolonged retention in the intestinal tract of CKD model mice, while effectively reshaping the gut microbiota community structure by increasing the abundance of Muribaculaceae and Allobaculum, elevating serum propionate and butyrate levels, and activating GPCRs and PPARγ signaling pathways. As a result, the gel treatment reduced the levels of intestinal inflammatory cytokines (TNF-α, IL-6, and IL-1β) and reactive oxygen species (ROS). MI Gel further improved glomerular function and attenuated renal fibrosis compared to free polysaccharides. This colon-targeted, acid-resistant platform utilizes synergistic fermentation of MOPs and Inulin to restore Gut-Kidney Axis homeostasis, providing a viable long-term approach for CKD management.