北大郑乐民团队突破:全新的促脂肪肝肠道菌群代谢产物!
创作:mildbreeze 审核:mildbreeze 03月01日
  • 肠道菌群代谢物N,N,N-三甲基-5-氨基戊酸(TMAVA)及其前体三甲基赖氨酸(TML),在脂肪肝患者血液中升高;
  • 粪肠球菌和铜绿假单胞菌可将TML代谢为TMAVA;
  • 小鼠TMAVA处理可加重高脂喂养诱导的脂肪肝、引起菌群失调和不耐寒;
  • TMAVA可结合并抑制γ-丁酰甜菜碱羟化酶(BBOX)抑制内源性肉碱合成,使小鼠体内肉碱水平降低,导致肝脏线粒体脂肪酸氧化减少,同时脂肪组织脂解增多,引起游离脂肪酸在肝脏积累;
  • BBOX敲除小鼠在高脂喂养下同样出现体内肉碱缺乏、脂肪肝;
  • 外源性补充肉碱可逆转TMAVA诱导的小鼠肝脏脂肪病变。
主编推荐语
mildbreeze
肠道菌群可影响非酒精性脂肪性肝病(NAFLD)的发生和发展,但其背后的机制(特别是菌群代谢产物在其中的作用)仍需深入揭示。Gastroenterology最新发表了来自北京大学郑乐民团队的研究,通过队列研究和小鼠试验发现,一种新的肠道菌群代谢产物TMAVA(N,N,N-三甲基-5-氨基戊酸)能通过影响肉碱合成和后续的脂肪酸氧化,来加重脂肪肝。这些发现为肠道菌群如何影响脂肪肝发生提供了一种新机制,也提示补充肉碱和靶向调节菌群或是治疗脂肪肝的新思路。
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Gastroenterology [IF:17.373]

TMAVA, a Metabolite of Intestinal Microbes, Is Increased in Plasma From Patients With Liver Steatosis, Inhibits γ-butyrobetaine Hydroxylase, and Exacerbates Fatty Liver in Mice

TMAVA,一种在脂肪肝患者血浆中升高的肠道微生物代谢物,可在小鼠中抑制γ-丁酰甜菜碱羟化酶并加剧脂肪肝

10.1053/j.gastro.2020.02.033

02-25, Article

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Background & Aims: Non-alcoholic fatty liver disease is characterized by excessive hepatic accumulation of triglycerides. We aimed to identify metabolites that differ in liver tissues of patients with liver steatosis vs healthy individuals (controls) and investigate the mechanisms by which these might contribute to fatty liver in mice.
Methods: We obtained blood samples from 15 patients with liver steatosis and 15 controls from a single center in China (discovery cohort). We performed untargeted liquid chromatography with mass spectrometry analysis of plasma to identify analytes associated with liver steatosis. We then performed targeted metabolomic analysis of blood samples from 2 independent cohorts of individuals who underwent annual health examinations in China (1157 subjects with or without diabetes and 766 subjects with or without liver steatosis; replication cohorts). We performed mass spectrometry analysis of plasma from C57BL/6J mice, germ-free, and mice given antibiotics. C57BL/6J mice with CRISPR-mediated disruption of the gene encoding γ-butyrobetaine hydroxylase (BBOX-knockout mice) were given 0.325% (m/v) N,N,N-trimethyl-5-aminovaleric acid (TMAVA) in their drinking water and placed on a 45% high fat diet (HFD) for 2 months. Plasma, liver tissues and fecal samples were collected; fecal samples were analyzed by 16S rRNA gene sequencing. Hepatic fatty acid oxidation (FAO) in liver tissues was determined by measuring liberation of 3H2O from [3H] palmitic acid. Liver tissues were analyzed by electron microscopy, to view mitochondria, and proteomic analyses. We used surface plasmon resonance analysis to quantify the affinity of TMAVA for BBOX.
Results: Levels of TMAVA, believed to be a metabolite of intestinal microbes, were increased in plasma from subjects with liver steatosis compared with controls, in the discovery and replication cohorts. In 1 replication cohort, the odds ratio for fatty liver in subjects with increased liver levels of TMAVA was 1.82 (95% CI, 1.14–2.90; P=.012). Plasma from mice given antibiotics or germ-free mice had significant reductions in TMAVA compared with control mice. We found the intestinal bacteria Enterococcus faecalis and Pseudomonas aeruginosa to metabolize trimethyllysine to TMAVA; levels of trimethyllysine were significantly higher in plasma from patients with steatosis than controls. We found TMAVA to bind and inhibit BBOX, reducing synthesis of carnitine. Mice given TMAVA had alterations in their fecal microbiomes and reduced cold tolerance; their plasma and liver tissue had significant reductions in levels of carnitine and acyl-carnitine and their hepatocytes had reduced mitochondrial FAO, compared with mice given only on a HFD. Mice given TMAVA on a HFD developed liver steatosis, which was reduced by carnitine supplementation. BBOX-knockout mice had carnitine deficiency and decreased FAO, increasing uptake and liver accumulation of free fatty acids and exacerbating HFD-induced fatty liver.
Conclusions: Levels of TMAVA are increased in plasma from subjects with liver steatosis. In mice, intestinal microbes metabolize trimethyllysine to TMAVA, which reduces carnitine synthesis and FAO to promote steatosis.

First Authors:
Mingming Zhao,Lin Zhao

Correspondence Authors:
Lemin Zheng

All Authors:
Mingming Zhao,Lin Zhao,Xuelian Xiong,Yuan He,Wei Huang,Zihao Liu,Liang Ji,Bing Pan,Xuefeng Guo,Leibo Wang,Si Cheng,Ming Xu,Hongyuan Yang,Yuxin Yin,Minerva T Garcia-Barrio,Y Eugene Chen,Xiangbao Meng,Lemin Zheng

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