Rifaximin prevents ethanol-induced liver injury in obese KK-Ay mice through modulation of small intestinal microbiota signature
Rifaximin prevents ethanol-induced liver injury in obese KK-Ay mice through modulation of small intestinal microbiota signature
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DOI：
10.1152/ajpgi.00372.2018
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发表时间：
2019-11-01
影响因子：
4.5
通讯作者：
Ikejima, Kenichi
中科院分区：
文献类型：
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作者：
Kitagawa, Ryuta;Kon, Kazuyoshi;Ikejima, Kenichi
酒精性肝炎(AII)合并代谢综合征的加重是一个新出现的临床问题，其中微生物区系在发病机制中起着重要作用。在这里，我们研究了利福昔明(RFX)对长期狂饮乙醇(Etoh)后KK-A(Y)小鼠肝脏损伤的影响，KK-A(Y)是一种代谢综合征的啮齿动物模型。8周龄雌性KK-A(Y)小鼠喂饲Lieber-DeCarli饲料(5%乙醇)10天，然后单次灌胃乙醇(4g/kg体重)。部分小鼠灌胃给予RFX(0.1g/L，流食)。收集小鼠的小肠内容物，但不暴食。利用好氧和厌氧培养技术对肠道微生物区系进行量化，并通过16S rRNA测序对其进行详细分析。暴饮暴食乙醇引起KK-A(Y)小鼠肝脏脂肪变性、氧化应激和炎性细胞因子的诱生，RFX治疗可显著阻止这些变化。肝脏分化簇14、TLR4、TLR2和NADPH氧化酶2的mRNA水平在乙醇灌胃/暴食后升高。给予RFX可完全抑制上述指标的升高。正如预期的那样，长期饲喂乙醇后，小肠细菌的净数量增加了三倍以上；然而，RFX并没有阻止这一净增加。有趣的是，在Etoh摄食后，小肠微生物区系的分布发生了巨大的变化，其中Erysipelotrichales在相对丰度上占优势。与之形成鲜明对比的是，RFX几乎完全钝化了乙醇诱导的白蜡虫数量的增加，并增加了类杆菌的比例。总之，RFX通过调节肥胖KK-A(Y)小鼠的肠道微生物区系/先天免疫反应来预防AH。值得注意的是，我们在这里证明了利福昔明(RFX)可以预防慢性酒精(Etoh)诱导的KK-A(Y)小鼠脂肪性肝炎。长期摄食乙醇导致小肠细菌过度生长，主要是白刺目的微生物区系发生了剧烈的变化。RFX通过增加类杆菌属中的取代基来最大限度地减少对白蜡虫的乙醇诱导。RFX还可阻止乙醇诱导的门静脉脂多糖、肝脏分化簇14、Toll样受体(TLR)2和TLR4mRNA水平的增加，表明微生物区系相关的先天免疫反应可能参与其中。
Exacerbation of alcoholic hepatitis (AII) with comorbid metabolic syndrome is an emerging clinical problem, where microbiota plays a profound role in the pathogenesis. Here, we investigated the effect of rifaximin (RFX) on liver injury following chronic-binge ethanol (EtOH) administration in KK-A(y) mice, a rodent model of metabolic syndrome. Female, 8-wk-old KK-A(y) mice were fed Lieber-DeCarli diet (5% EtOH) for 10 days, following a single EtOH gavage (4 g/kg body wt). Some mice were given RFX (0.1 g/L, in liquid diet) orally. Small intestinal contents were collected from mice without binge. Intestinal microbiota was quantified using aerobic and anaerobic culturing techniques and further analyzed by 16S rRNA sequencing in detail. EtOH feeding/binge caused hepatic steatosis, oxidative stress, and induction of inflammatory cytokines in KK-A(y) mice, which were markedly prevented by RFX treatment. Hepatic mRNA levels for cluster of differentiation 14, Toll-like receptor (TLR) 4. TLR2, and NADPH oxidase 2 were increased following EtOH feeding/binge. and administration of RFX completely suppressed their increase. The net amount of small intestinal bacteria was increased over threefold after chronic EtOH feeding as expected; however, RFX did not prevent this net increase. Intriguingly, the profile of small intestinal microbiota was dramatically changed following EtOH feeding in the order level, where the Erysipelotrichales predominated in the relative abundance. In sharp contrast, RFX drastically blunted the EtOH-induced increases in the Erysipelotrichales almost completely, with increased proportion of the Bacteroidales. In conclusion, RFX prevents AH through modulation of small intestinal microbiota/innate immune responses in obese KK-A(y) mice.NEW & NOTEWORTHY Here we demonstrated that rifaximin (RFX) prevents chronic-binge ethanol (EtOH)-induced steatohepatitis in KK-A(y) mice. Chronic EtOH feeding caused small intestinal bacterial overgrowth, with drastic alteration in the microbiota profile predominating the order Erysipelotrichales. RFX minimized this EtOH induction in Erysipelotrichales with substitutive increases in Bacteroidales. RFX also prevented EtOH-induced increases in portal lipopolysaccharide, and hepatic cluster of differentiation 14, toll-like receptor (TLR) 2, and TLR4 mRNA levels, suggesting the potential involvement of microbiota-related innate immune responses.