Role of Gut Microbiota in the Development and Treatment of Diabetic Kidney Disease

Abstract

Background: The role of gut microbiota in the pathogenesis of Diabetes Mellitus (DM) and its complications has garnered significant scientific interest. Our research highlights intestinal dysbiosis as a hallmark of DM, characterized by an altered Bacteroidetes-to-Firmicutes ratio, key phyla that dominate the gut microbiome. Emerging evidence suggests that fecal microbiota transplantation (FMT), the transfer of fecal matter from healthy donors into recipients, restores microbial balance and alleviates disease symptoms. We hypothesize that modulating gut microbiota via FMT could mitigate the progression of diabetic kidney disease (DKD) and serve as a potential therapeutic strategy.

Methods: We used FVB/NJ control mice and non-obese type 2 diabetic MKR transgenic mice. Mice were assigned to three groups: sham, FMT-treated with stool from healthy donors, and FMT-treated with stool from Type 2 Diabetes Mellitus (T2DM) donors. Prior to treatment, gut microbiota was depleted using an antibiotic cocktail. FMT was administered orally twice weekly for 8 weeks. Urine and kidney samples were collected for functional, histological, and molecular analyses.

Results: Our results demonstrate a significant decline in kidney function in the control group treated with T2DM-derived FMT, as evidenced by a marked increase in the urinary albumin-creatinine ratio (UACR). This functional impairment was accompanied by pronounced histological abnormalities, including increased sclerosis and collagen deposition, as well as elevated production of reactive oxygen species (ROS). These findings underscore the critical role of gut dysbiosis in exacerbating renal deterioration. Notably, similar pathological changes were observed in the T2DM group, which exhibited elevated UACR, heightened NOX expression, amplified ROS production, and intensified inflammatory responses, further linking dysbiosis to renal injury. Of interest, these adverse effects were significantly mitigated in the T2DM group treated with FMT from healthy control mice. This therapeutic intervention resulted in the reversal of renal dysfunction, characterized by reduced UACR, attenuation of sclerosis and collagen deposition, and a marked decrease in ROS production. Furthermore, this group exhibited suppressed NADPH oxidase activity and a substantial reduction in pro-inflammatory cytokine levels, highlighting the ability of healthy FMT to restore microbial balance, alleviate oxidative stress, and dampen inflammation.

Conclusion: This study underscores the critical role of gut microbiota in the pathogenesis of diabetes-associated renal injury. Our findings highlight the therapeutic potential of healthy FMT in restoring microbial balance, mitigating oxidative stress and inflammation, and improving kidney function in diabetic settings. These results pave the way for exploring microbiota-targeted therapies in DKD.