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Войти в исследования Journal of the American Society of Nephrology : JASN · 2026
Targeted Inhibition of Gut Microbial Trimethylamine N -Oxide Production Fosters Regression of CKD Phenotypes.
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DiDonato Joseph A, Weeks Taylor L, Gupta Nilaksh, Mallela Deepthi P, Buffa Jennifer A, Wang Zeneng, Li Xinmin S, Anderson James T, Fu Xiaoming, Sangwan Naseer, Nemet Ina, Cameron Scott J, Hazen Stanley L
Аннотация
KEY POINTS: Inhibition of the gut microbial trimethylamine N -oxide (TMAO) pathway after CKD onset both halted disease progression and reversed pathophysiologic CKD features. Inhibition of TMAO formation in established CKD animals improved kidney function, proteinuria, fibrosis, and uremic toxins. In CKD models, a drug that suppressed gut microbial TMAO production yet remains in the intestinal lumen reversed kidney fibrosis and improved GFR.
BACKGROUND: Recent studies demonstrate gut microbial trimethylamine N -oxide (TMAO) is clinically and mechanistically linked to CKD development. Prior studies showed selective targeting of gut microbial TMAO production can prevent CKD initiation. A highly relevant clinical question is whether inhibiting TMAO generation can reverse established kidney dysfunction and fibrosis.
METHODS: CD1 mice were first randomized (phase 1) to unilateral nephrectomy (UNx) or sham surgery and fed a high-fat diet ±1% choline supplementation to document CKD through measures of multiple indices of kidney function, tissue remodeling/fibrosis, and uremic toxins. Mice were then randomized (phase 2) to continue the same diet±fluoromethylcholine (FMC), a mechanism-based gut microbial TMAO inhibitor, for 8 additional weeks, and the impact on CKD-related phenotypes was assessed.
RESULTS: After 12 weeks, choline-supplemented UNx mice exhibited 15-fold higher circulating TMAO levels. In parallel, multiple kidney dysfunction indices progressed, including 48% reduction in measured GFR (mGFR), elevated cystatin C and creatinine, 3.5-fold greater tubulointerstitial fibrosis, and upregulated profibrotic gene expression. After phase 2 (8 weeks±FMC), choline-supplemented (high-TMAO) UNx mice without FMC showed further elevation of circulating TMAO and multiple indices of progressive kidney function decline and fibrosis. Conversely, FMC-treated animals showed virtual elimination in circulating TMAO and significant improvements in all monitored CKD phenotypes, including >50% higher mGFR, and improved (decreased) creatinine, cystatin C, pseudouridine, urinary albumin/creatinine ratio, kidney fibrosis measures, and many uremic toxin levels ( e.g ., indoxyl sulfate and phenylacetylglycine). Beyond halting progression of kidney functional decline and fibrosis, there was frank regression in tubulointerstitial fibrosis (41% reduction) and significant improvement in mGFR (39% increase, end of phase 2 versus phase 1).
CONCLUSIONS: Pharmacologic targeting of gut microbial TMAO production after CKD establishment halted disease progression and promoted regression of key CKD pathophysiologic features.
BACKGROUND: Recent studies demonstrate gut microbial trimethylamine N -oxide (TMAO) is clinically and mechanistically linked to CKD development. Prior studies showed selective targeting of gut microbial TMAO production can prevent CKD initiation. A highly relevant clinical question is whether inhibiting TMAO generation can reverse established kidney dysfunction and fibrosis.
METHODS: CD1 mice were first randomized (phase 1) to unilateral nephrectomy (UNx) or sham surgery and fed a high-fat diet ±1% choline supplementation to document CKD through measures of multiple indices of kidney function, tissue remodeling/fibrosis, and uremic toxins. Mice were then randomized (phase 2) to continue the same diet±fluoromethylcholine (FMC), a mechanism-based gut microbial TMAO inhibitor, for 8 additional weeks, and the impact on CKD-related phenotypes was assessed.
RESULTS: After 12 weeks, choline-supplemented UNx mice exhibited 15-fold higher circulating TMAO levels. In parallel, multiple kidney dysfunction indices progressed, including 48% reduction in measured GFR (mGFR), elevated cystatin C and creatinine, 3.5-fold greater tubulointerstitial fibrosis, and upregulated profibrotic gene expression. After phase 2 (8 weeks±FMC), choline-supplemented (high-TMAO) UNx mice without FMC showed further elevation of circulating TMAO and multiple indices of progressive kidney function decline and fibrosis. Conversely, FMC-treated animals showed virtual elimination in circulating TMAO and significant improvements in all monitored CKD phenotypes, including >50% higher mGFR, and improved (decreased) creatinine, cystatin C, pseudouridine, urinary albumin/creatinine ratio, kidney fibrosis measures, and many uremic toxin levels ( e.g ., indoxyl sulfate and phenylacetylglycine). Beyond halting progression of kidney functional decline and fibrosis, there was frank regression in tubulointerstitial fibrosis (41% reduction) and significant improvement in mGFR (39% increase, end of phase 2 versus phase 1).
CONCLUSIONS: Pharmacologic targeting of gut microbial TMAO production after CKD establishment halted disease progression and promoted regression of key CKD pathophysiologic features.