Gut microbiota-derived trimethylamine N-oxide exacerbates diabetic nephropathy by promoting renal fibrosis

Background diabetic nephropathy (DN), a major complication of diabetes, is linked to gut microbiota dysbiosis. Elevated trimethylamine N-oxide (TMAO), a microbiota-derived metabolite, plays a central role in inducing renal injury during DN pathogenesis.

To investigate the role of TMAO in renal dysfunction and intestinal microbiota alterations associated with DN, hypothesizing that TMAO exacerbates renal injury and fibrosis through gut microbiota-dependent mechanisms.

A DN model was successfully established using Zucker diabetic fatty (ZDF) rats. Blood samples were analyzed for renal function parameters, and serum TMAO levels were quantified via high-performance liquid chromatography-tandem mass spectrometry. Renal tissue morphology and fibrosis were assessed using hematoxylin and eosin and Masson staining, respectively. Additionally, 16S rRNA sequencing was employed to profile fecal bacterial communities in rats with diabetes and DN. Fecal microbiota transplantation was conducted to verify alterations in TMAO production capacity in the gut microbiota of DN rats.

After 8 weeks of modeling, the ZDF rat model group exhibited blood glucose levels surpassing 16.7 mmol/L, and compared to the control group, renal function indicators, including β2-microglobulin, cystatin C, uric acid, and creatinine, were significantly elevated (P < 0.05). Renal fibrosis was more pronounced in the ZDF model group, accompanied by heightened P-smad3 expression, in contrast to the TMAO inhibition group. Although Masson staining results did not reach statistical significance (P > 0.05), notable alterations in intestinal flora structure were observed in DN rats, and fecal microbiota transplantation led to increased TMAO production within the intestinal flora of DN rats compared to controls (P > 0.05).

DN is associated with gut microbiota alterations that potentiate TMAO generation, contributing to renal injury and fibrotic progression. While TMAO's role in fibrosis warrants further validation, these findings implicate the gut-kidney axis in DN pathogenesis.