Song YJ, Yang B, Feng QS, Ma FF, Xing B, Bin XL, Ha XQ. Gut microbiota-derived trimethylamine N-oxide exacerbates diabetic nephropathy by promoting renal fibrosis. World J Nephrol 2025; 14(4): 112066 [DOI: 10.5527/wjn.v14.i4.112066]
Corresponding Author of This Article
Xiao-Qin Ha, Chief Physician, Clinical Laboratory, The 940th Hospital of Joint Logistics Support Force of People’s Liberation Army, No. 333 Binhe Middle Road, Lanzhou 730050, Gansu Province, China. songyuejuan410@163.com
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Dec 25, 2025 (publication date) through Dec 23, 2025
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World Journal of Nephrology
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Song YJ, Yang B, Feng QS, Ma FF, Xing B, Bin XL, Ha XQ. Gut microbiota-derived trimethylamine N-oxide exacerbates diabetic nephropathy by promoting renal fibrosis. World J Nephrol 2025; 14(4): 112066 [DOI: 10.5527/wjn.v14.i4.112066]
World J Nephrol. Dec 25, 2025; 14(4): 112066 Published online Dec 25, 2025. doi: 10.5527/wjn.v14.i4.112066
Gut microbiota-derived trimethylamine N-oxide exacerbates diabetic nephropathy by promoting renal fibrosis
Yue-Juan Song, Bo Yang, Qiang-Sheng Feng, Fei-Fei Ma, Bang Xing, Xi-Liang Bin, Xiao-Qin Ha
Yue-Juan Song, Bo Yang, Qiang-Sheng Feng, Fei-Fei Ma, Bang Xing, Xi-Liang Bin, Xiao-Qin Ha, Clinical Laboratory, The 940th Hospital of Joint Logistics Support Force of People’s Liberation Army, Lanzhou 730050, Gansu Province, China
Author contributions: Song YJ has primary responsibility for the final content; Song YJ, Yang B, and Ha XQ conceived and designed the research; Song YJ and Yang B wrote the manuscript; Feng QS and Bin XL analyzed the data; Ma FF and Xing B collected the data; and all authors have read and approved the final manuscript.
Supported by the Chinese People’s Liberation Army, No. 2021yxky056.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Research Ethics Committee of 940th Hospital of the Logistics Support Force, approval No. 2023KYL419.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data included in this study are available upon request by contacting the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Qin Ha, Chief Physician, Clinical Laboratory, The 940th Hospital of Joint Logistics Support Force of People’s Liberation Army, No. 333 Binhe Middle Road, Lanzhou 730050, Gansu Province, China. songyuejuan410@163.com
Received: July 17, 2025 Revised: August 18, 2025 Accepted: November 21, 2025 Published online: December 25, 2025 Processing time: 159 Days and 23 Hours
Abstract
BACKGROUND
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.
AIM
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.
METHODS
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.
RESULTS
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).
CONCLUSION
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.
Core Tip: Diabetic nephropathy (DN) is characterized by significant renal dysfunction and gut microbiota dysbiosis, which enhances the microbiota’s capacity to produce trimethylamine N-oxide (TMAO). In Zucker diabetic fatty rats, elevated TMAO levels were associated with aggravated renal injury, fibrosis, and upregulated P-smad3 expression. Fecal microbiota transplantation from DN rats further increased TMAO production, confirming TMAO as a key microbiota-derived mediator in DN progression.
