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.

中文翻译：

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肠微生物三甲胺N-氧化物生产的有针对性的抑制作用减少了慢性肾病小鼠模型中的肾小管间质纤维化和功能障碍。

目的饮食胆碱（一种在西方饮食中富含的营养物）的肠道微生物代谢会产生三甲胺（TMA）以及促进动脉粥样硬化和纤维化的代谢产物TMA-N-氧化物（TMAO）。最近的临床和动物研究表明，TMAO水平升高与心血管疾病和慢性肾脏疾病发展的风险增加有关。尽管如此，以治疗为目标的肠道微生物群依赖型TMAO产生及其对保持肾功能的影响的研究仍然有限。方法和结果：在本文中，我们研究了在慢性肾脏疾病模型中，药理抑制胆碱饮食诱导的肠道微生物群依赖性TMA产生的产物，进而导致TMAO对肾小管间质纤维化和功能损害的影响。对基于肠道微生物胆碱TMA裂解酶机制的抑制剂碘甲基胆碱的初步研究证实，TMA生成具有明显的抑制作用，因此抑制了TMAO水平，并且选择性靶向肠道微生物区隔（即，药物在肠道微生物中的蓄积和宿主体内的全身暴露受限）。膳食补充胆碱或TMAO可以显着增加与慢性皮下注射异丙肾上腺素有关的肾功能损害和纤维化的多个指标。然而，肠道菌群靶向抑制剂碘甲基胆碱的存在阻止了胆碱饮食引起的TMAO升高，并且两者均显着改善了肾功能的下降，并显着减弱了肾小管间质纤维化的多个指标。碘甲基胆碱治疗还逆转了许多胆碱饮食诱导的与TMAO和肾功能损害相关的盲肠微生物群落组成的变化。结论肠道微生物群依赖的TMAO产生的选择性靶向可以预防处于慢性肾脏疾病风险中的受试者的不良肾脏结构和功能改变。