Puerarin Regulates Gut Homeostasis in T2DM Rats Involving Structural and Functional Alterations of Gut Microbiota and Paneth Cell Function.

objectiveTo investigate the impact of puerarin on gut microbiota and epithelial integrity and glucose metabolism on a type 2 diabetes mellitus (T2DM) rat model.

methodsA total of 20 male Sprague-Dawley rats were randomly divided into 4 groups, including the normal control (NC), high-fat diet (HFD), diabetes mellitus (DM), and puerarin-treated (Pue) groups (n=5). Except for the NC group, the rats in the other groups were fed a HFD. Additionally, rats in the DM group were injected with streptozotocin (STZ) to induce diabetes. Rats in the Pue group were fed an HFD, injected with STZ and treated with puerarin via intraperitoneal injection at a dosage of 100 mg/kg daily for 4 weeks. Glucose metabolism indicators, including glycated hemoglobin (HbA1c) and area under the curve (AUC) of glucose tolerance test (GTT) were measured through blood sampling. Gut microbiota was analyzed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing, and the expression of free fatty acid receptors 2 and 3 (FFAR2/FFAR3) was detected by quantitative polymerase chain reaction. Paneth cell function and epithelial integrity were evaluated by analyzing antimicrobial peptide gene expression and tight-junction proteins (zonula occludens-1 and occludin).

resultsPuerarin treatment significantly reduced prolonged glucose exposure, as evidenced by decreased HbA1c and AUC of GTT (P<0.05). Insulin level was increased after puerarin treatment. The gut microbiota composition was significantly altered, with a decrease in Firmicutes/Bacteroidetes ratio. At the class level, puerarin significantly decreased abundance of Desulfovibrionia and Firmibacteria compared to the DM group (P<0.05). At the order level, puerarin reduced abundance of Desulfovibrionales and Negativicutes within Firmibacteria, while increasing abundance of Bifidobacteriales, Enterobacterales, Clostridiales, and Peptococcales (P<0.05). The production of FFAR2 and FFAR3, which was diminished in the DM and HFD groups, was restored after puerarin treatment (P<0.05 or P<0.01). Additionally, puerarin reversed diabetes-associated loss of Paneth cell antimicrobial peptides and restored epithelial tight-junction protein expressions, thus enhanced barrier integrity.

conclusionsPuerarin administration significantly ameliorates glucose metabolism, modulates gut microbiota toward a beneficial profile, and improves Paneth cell function and epithelial integrity in T2DM rats. These findings highlight puerarin's potential as a multi-target therapeutic agent for T2DM by modulating the gut-pancreas-immune axis.