Dataset Information

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.

SUBMITTER: Gupta N

PROVIDER: S-EPMC7203662 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chronic kidney disease (CKD) increases the risk and prevalence of cardiovascular disease (CVD) morbidity and mortality. Recent studies have revealed marked changes in the composition of the microbiome and the metabolome and their potential influence in renal disease and CVD via the accumulation of microbial-derived uremic toxins. However, the effect of unilateral ureteral obstruction (UUO) on the gut microbiome and circulating metabolites is unknown. Male Sprague-Dawley rats were randomized to UUO and sham-operated control groups. Renal histology, colonic microbiota, and plasma metabolites were examined two weeks later. We employed 16S rRNA sequence and untargeted metabolomic analyses to explore the changes in colonic microbiota and plasma metabolites and their relationship with tubulointerstitial fibrosis (TIF). The UUO rats exhibited tubular atrophy and dilatation, interstitial fibrosis and inflammatory cell infiltration in the obstructed kidney. UUO rats showed significant colonic enrichment and depletion of genera. Significant differences were identified in 219 plasma metabolites involved in lipid, amino acid, and bile acid metabolism, which were consistent with gut microbiota-related metabolism. Interestingly, tryptophan and its metabolites kynurenine, 5-hydroxytryptophan and 5-hydroxytryptamine levels, which were linked with TIF, correlated with nine specific genera. Plasma tryptophan level was positively correlated with Clostridium IV, Turicibacter, Pseudomonas and Lactobacillales, and negatively correlated with Oscillibacter, Blautia, and Intestinimonas, which possess the genes encoding tryptophan synthase (K16187), indoleamine 2,3-dioxygenase (K00463) and tryptophan 2,3-dioxygenase (K00453) and their corresponding enzymes (EC:1.13.11.52 and EC:1.13.11.11) that exacerbate TIF. In conclusion, UUO results in profound changes in the gut microbiome and circulating metabolites, events that contribute to the pathogenesis of inflammation and TIF.

Dataset Information

Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease.

Objective

Conclusions

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