Inulin and Lycium barbarum polysaccharides mitigate the diabetic inflammatory response by modulating bile acid metabolism to enhance regulatory T cell (Treg) activation in a rat model of diabetes

Hai Xia Lu^1,2*Hongyan Luo^1,2Peiling Li^1,2Yan Yang^1,2Shilu Cao¹Zhang Yanfang^1,2Hongxia Ma^1,2Qian Zhao^1,2*Yali Zheng^1,2*Hao Wang^1*

• ¹Ningxia medical university, Yinchuan, China
• ²People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that poses a serious threat to human health. Currently, there are still no completely effective treatment options. Modulating the intestinal flora and its metabolites may represent a promising new approach for diabetes therapy. Regulating the intestinal microbiota and its metabolites through prebiotics, mediated by regulatory T (Treg) cells. Objective: The purpose of this study was to investigate the improvement of diabetes-related chronic inflammation by examining the effects of inulin (INU) and Lycium barbarum polysaccharides (LBP) in diabetic rats. This was achieved by modulating the bile acids-metabolites of the intestinal flora through the FXR-FGF15-FGFR4 axis, thereby activating Treg cells in vivo and alleviating the inflammatory state associated with diabetes. Methods: A diabetic rat model was established by a high-fat diet and streptozotocin (STZ) injections. Sprague-Dawley rats were randomly allocated into four groups: type 2 diabetes mellitus (T2DM), T2DM with INU group (T2DM+INU), T2DM with LBP group (T2DM+LBP), and T2DM with INU and LBP group (T2DM+INU+LBP). Results: INU and LBP treatments significantly decreased the levels of inflammatory cytokines, including MCP-1, IL-18, NF-κB, NLRP3, superoxide dismutase (SOD), and malondialdehyde (MDA). Moreover, these alleviations of the inflammatory state of diabetes were partially attributed to an increased proportion of Treg cells. We found the abundance of Tauro β-muricholic acid (TβMCA) was reduced following INU and LBP treatment, while the relative abundances of chenodeoxycholic acid (CDCA), lithocholic acid (LCA), and hyocholic acid (HCA) were all increased compared to the untreated group. Mechanically, INU and LBP significantly influenced the negative feedback regulation of the FXR-FGF15-FGFR4 axis via intestinal bile acids, thereby increasing the proportion of Treg cells in the periphery of diabetic rats. Intriguingly, an increase of Treg cells after INU and LBP intervention was notably correlated with the improvement of the inflammatory state of diabetes. Conclusions: INU and LBP modulate bile acids derived from the intestinal flora to improve the chronic inflammatory status of diabetic rats, specifically, both of which exert their effectiveness by regulating gut microbial bile acids metabolites through the FXR-FGF15-FGFR4 axis to activate Treg cells.