肠道菌群代谢产生的三甲胺促进酒精性肝病
创作:aluba 审核:aluba 02月11日
  • 相比于健康对照,酒精性肝炎患者的血浆三甲胺水平显著升高,并与肝脏三甲胺加氧酶FMO3的表达降低相关;
  • 利用细菌胆碱三甲胺裂解酶抑制剂(IMC或FMC)处理,可抑制小鼠在摄入酒精后的肠道菌群依赖性的三甲胺产生,并在酒精诱导的肝损伤中起保护性作用;
  • IMC或FMC处理可通过依赖于酒精的方式重塑小鼠的肠道菌群及肝脏转录组;
  • 在小鼠肝脏中,肠道菌群代谢产生的三甲胺可引发快速的激素样信号效应。
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aluba
来自eLife上发表的一项最新研究结果,发现在酒精性肝炎患者的血浆中,肠道菌群代谢产生的三甲胺显著增加。在小鼠中,抑制肠道菌群的三甲胺产生,可在酒精性肝病中起到保护性作用,并调节肠道菌群及肝脏转录组。
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eLife [IF:8.713]

Gut Microbial Trimethylamine is Elevated in Alcohol-Associated Hepatitis and Contributes to Ethanol-Induced Liver Injury in Mice

肠道菌群产生的三甲胺促进酒精诱导的小鼠肝损伤,并在酒精性肝炎患者中增加

10.7554/eLife.76554

01-27, Article

Abstract & Authors:展开

Abstract:收起
There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.

First Authors:
Robert N Helsley,Tatsunori Miyata,Anagha Kadam

Correspondence Authors:
Jonathan Mark Brown

All Authors:
Robert N Helsley,Tatsunori Miyata,Anagha Kadam,Varadharajan Venkateshwari,Naseer Sangwan,Emily C Huang,Rakhee Banerjee,Amanda L Brown,Kevin K Fung,William Massey,Chase Neumann,Orabi Danny,Lucas J Osborn,Rebecca C Schugar,Megan R McMullen,Annette Bellar,Kyle L Poulsen,Adam Kim,Vai Pathak,Marko Mrdjen,James T Anderson,Belinda Willard,Craig J McClain,Mack Mitchell,Arthur J McCullough,Svetlana Radaeva,Bruce Barton,Gyongyi Szabo,Srinivasan Dasarathy,Jose Carlos Garcia-Garcia,Daniel M Rotroff,Daniela S Allende,Zeneng Wang,Stanley L Hazen,Laura E Nagy,Jonathan Mark Brown

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