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.

Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

“…Our results tie well with those of previous studies demonstrating that alterations of specific gut microbial composition and metabolites have an essential role in hypertension development [ 9 , 10 ]. Given that inhibition of the TMA-TMAO metabolic pathway has been reported to protect adult offspring against hypertension programmed by early life insult and CKD progression [ 31 , 32 , 33 ], outcomes from targeting the TMA-TMAO pathway to protect against CKD-related adverse pregnancy and offspring need further research.…”

Unraveling the Effects of Trimethylamine N-Oxide on Stroke: “The lower, the better?”

“…Therapeutic approaches have emerged for reducing TMAO levels, including the use of prebiotics, probiotics, and antibiotics to elicit a favorable impact on gut microbiota, 3,3-dimethyl-1-butanol or iodomethylcholine by suppressing the activity of microbial choline trimethylamine (TMA) lyase 5,10) , and diet modification to reduce the intake of choline and carnitine Trimethylamine (TMA) is generated from choline (derived from egg, shrimp, and milk); betaine (vegetable and mushroom); and carnitine (red meat) by three specific TMA lyases; namely, choline TMA lyase, betaine reductase, and carnitine monooxygenase, respectively. Produced TMA is metabolized by liver host enzyme and is changed to TMAO.…”

Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease

“…Studies have shown that TMAO is independently related to cardiovascular events and that a relationship between TMAO levels and ischemic cardiovascular events exists, especially in CKD Stages 3b and 4 [ 30 ]. For these reasons, selective inhibition of TMAO prevents renal damage and cardiovascular events in patients with CKD [ 31 ].…”