To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17–516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman’s rho, 0.42; P < 10⁻⁵) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease.

为了验证非酒精性脂肪性肝病 (NAFLD) 患者的肠道微生物群产生足够的乙醇来驱动这种复杂疾病的发展和进展这一假设，我们进行了一项前瞻性临床研究和一项干预研究。对 146 人进行混合膳食测试 (MMT) 后 120 分钟和禁食时测量乙醇。在 37 个人的子集和外部验证队列中，在门静脉血液中测量了乙醇。在一项干预研究中，10 名患有 NAFLD 的人和 10 名超重但其他方面健康的对照组在 MMT 之前被输注了选择性乙醇脱氢酶 (ADH) 抑制剂。与空腹外周血相比，门静脉乙醇浓度中位数为 187（四分位数间距 (IQR)，17-516) 倍，并且随着疾病进展而增加，从无脂肪变性个体的 2.1 mM 到 NAFL 中的 8.0 mM，非酒精性脂肪性肝炎中的 21.0 mM。ADH 的抑制导致 NAFLD 患者外周血乙醇浓度增加 15 倍（IQR，1.6 至 20 倍），尽管这种效应在抗生素治疗后被消除。具体而言，乳杆菌科与餐后外周乙醇浓度相关（Spearman's rho，0.42；P  < 10 ^-5 ) 在前瞻性研究中。我们的数据表明，首过效应掩盖了内源性乙醇产生的水平，表明微生物乙醇可能被认为是这种高度流行的肝病的发病机制。