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A gut microbial metabolite of dietary polyphenols reverses obesity-driven hepatic steatosis
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2022-11-23 , DOI: 10.1073/pnas.2202934119
Lucas J Osborn 1, 2, 3 , Karlee Schultz 1, 2, 4 , William Massey 1, 2, 3 , Beckey DeLucia 1, 2 , Ibrahim Choucair 1, 2 , Venkateshwari Varadharajan 1, 2 , Rakhee Banerjee 1, 2 , Kevin Fung 1, 2 , Anthony J Horak 1, 2 , Danny Orabi 1, 2, 3, 5 , Ina Nemet 1, 2 , Laura E Nagy 3, 6 , Zeneng Wang 1, 2 , Daniela S Allende 7 , Belinda B Willard 8 , Naseer Sangwan 1, 2 , Adeline M Hajjar 1, 2 , Christine McDonald 3, 6 , Philip P Ahern 1, 2, 3 , Stanley L Hazen 1, 2, 9 , J Mark Brown 1, 2, 3 , Jan Claesen 1, 2, 3
Affiliation  

The molecular mechanisms by which dietary fruits and vegetables confer cardiometabolic benefits remain poorly understood. Historically, these beneficial properties have been attributed to the antioxidant activity of flavonoids. Here, we reveal that the host metabolic benefits associated with flavonoid consumption hinge, in part, on gut microbial metabolism. Specifically, we show that a single gut microbial flavonoid catabolite, 4-hydroxyphenylacetic acid (4-HPAA), is sufficient to reduce diet-induced cardiometabolic disease (CMD) burden in mice. The addition of flavonoids to a high fat diet heightened the levels of 4-HPAA within the portal plasma and attenuated obesity, and continuous delivery of 4-HPAA was sufficient to reverse hepatic steatosis. The antisteatotic effect was shown to be associated with the activation of AMP-activated protein kinase α (AMPKα). In a large survey of healthy human gut metagenomes, just over one percent contained homologs of all four characterized bacterial genes required to catabolize flavonols into 4-HPAA. Our results demonstrate the gut microbial contribution to the metabolic benefits associated with flavonoid consumption and underscore the rarity of this process in human gut microbial communities.

中文翻译:

膳食多酚的肠道微生物代谢物可逆转肥胖驱动的肝脂肪变性

膳食水果和蔬菜赋予心脏代谢益处的分子机制仍然知之甚少。从历史上看,这些有益的特性归因于类黄酮的抗氧化活性。在这里,我们揭示了与类黄酮消耗相关的宿主代谢益处部分取决于肠道微生物代谢。具体而言,我们表明单一肠道微生物类黄酮分解代谢物 4-羟基苯乙酸 (4-HPAA) 足以减轻小鼠饮食诱导的心脏代谢疾病 (CMD) 负担。在高脂肪饮食中添加类黄酮可提高门脉血浆中 4-HPAA 的水平并减轻肥胖,持续输送 4-HPAA 足以逆转肝脂肪变性。抗脂肪变性作用显示与 AMP 活化蛋白激酶 α (AMPKα) 的激活有关。在对健康人类肠道宏基因组的一项大型调查中,略高于 1% 的基因组包含将黄酮醇分解代谢为 4-HPAA 所需的所有四种特征性细菌基因的同源物。我们的结果证明了肠道微生物对与类黄酮摄入相关的代谢益处的贡献,并强调了这一过程在人类肠道微生物群落中的罕见性。
更新日期:2022-11-23
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