Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease
Abstract
Objective:
Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited.
Approach and Results
Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment.
Conclusions
Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.
Highlights
The suicide substrate inhibitor iodomethylcholine, which is nonlethal to gut microbes, selectively targets gut microbial choline trimethylamine-lyase activity and suppresses choline diet-induced trimethylamine, trimethylamine N-oxide, renal functional impairment (glomerular filtration rate and Cystatin C) and injury (albumin to creatinine ratio).
The gut microbial choline trimethylamine-lyase inhibitor, iodomethylcholine, suppresses choline diet-induced renal tubulointerstitial fibrosis, and profibrotic gene expression.
The present studies reveal a novel approach that targets the gut microbial trimethylamine N-oxide pathway and both prevents renal functional decline and tubulointerstitial fibrosis in vivo, while simultaneously limiting systemic exposure and potential for adverse side effects in the host.
Full text of this article is available at https://www.ahajournals.org/doi/10.1161/ATVBAHA.120.314139