Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice.
Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice.
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DOI：
10.3389/fphys.2021.812882
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发表时间：
2021
影响因子：
4
通讯作者：
Kirpich IA
中科院分区：
文献类型：
--
作者：
Warner JB;Larsen IS;Hardesty JE;Song YL;Warner DR;McClain CJ;Sun R;Deng Z;Jensen BAH;Kirpich IA
酒精相关性肝病（ALD）是一种常见的肝脏疾病，是一种严重的全球医疗负担，有效的治疗选择有限。肠-肝轴是导致饮酒引起肝损伤的易感性的关键因素。在目前的研究中，我们测试了人类β防御素-2（hBD-2），一种小的抗微生物肽，是否能减弱实验性慢性ALD。给雄性C57 Bl/6 J小鼠喂食含乙醇（EtOH）的饮食6周，在最后一周期间通过口服管饲法每日施用hBD-2（1.2mg/kg）。使用具有不同基线肠道微生物群的两个独立的小鼠群组。口服hBD-2给药在两个队列中均减轻了肝损伤，如通过降低的血浆ALT活性所确定的。值得注意的是，hBD-2介导的减少EtOH相关的肝脂肪变性、肝细胞死亡和炎症的程度在队列之间是不同的，这表明微生物群特异性机制是hBD-2的有益作用的基础。事实上，我们观察到hBD-2在队列之间的不同机制，包括肝和小肠IL-17 A和IL-22的诱导，以及肠道和肠系膜淋巴结中T调节细胞丰度的增加。最后，hBD-2调节了两个队列中EtOH喂养小鼠的肠道微生物群组成，包括Barnesiella，Parabacteroides，Akkermansia和Alistipes在内的多个属的显著减少，以及Ruminococcaceae家族中几种细菌的丰度改变。总的来说，我们的结果表明hBD-2在与免疫调节和微生物群改变相关的实验性ALD中的保护作用。这些数据表明，虽然hBD-2对肝损伤的有益作用是一致的，但具体的作用机制与基线微生物群相关。
Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
4.6
作者：
Gulhane M;Murray L;Lourie R;Tong H;Sheng YH;Wang R;Kang A;Schreiber V;Wong KY;Magor G;Denman S;Begun J;Florin TH;Perkins A;Cuív PÓ;McGuckin MA;Hasnain SZ
通讯作者：
Hasnain SZ
DOI：
10.1002/hep.31321
发表时间：
2021-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Chu S;Sun R;Gu X;Chen L;Liu M;Guo H;Ju S;Vatsalya V;Feng W;McClain CJ;Deng Z
通讯作者：
Deng Z
影响因子：
13.5
作者：
Arab, Juan P.;Sehrawat, Tejasav S.;Shah, Vijay H.
通讯作者：
Shah, Vijay H.
影响因子：
4.4
作者：
Kao, CY;Chen, Y;Wu, R
通讯作者：
Wu, R