Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL, USA.
Hepatol Commun. 2022 Jan;6(1):133-160. doi: 10.1002/hep4.1793. Epub 2021 Aug 28.
Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.
酒精相关性肝病（ALD）是一个严重的临床问题，其最有效的治疗方法是戒酒。本研究的两个目的是，首先，确定在酒精性肝损伤高峰期以及在 ALD 早期和晚期恢复过程中，肝脏转录组、粪便微生物组和门脉血清代谢组；其次，整合它们的相互作用，更好地了解 ALD 的发病机制。为了引发酒精性肝损伤，雌性和雄性野生型小鼠分别用对照或乙醇 Lieber-DeCarli 饮食喂养 6 周。为了研究早期和晚期恢复，从饮食中去除酒精，分别在 3 天和 14 天后处死小鼠。在酒精性肝损伤高峰期，信号转导和转录激活因子 3（Stat3）、Rho-GTPases、Tec 激酶和糖蛋白 VI（Gp6）增加，过氧化物酶体增殖物激活受体信号减少。在 ALD 恢复过程中，维生素 D 受体/视黄酸 X 受体、 Toll 样受体、p38 和 Stat3 上调，肝 X 受体信号下调。雌性表现出分解代谢途径的显著变化，而雄性增加细胞应激、损伤和免疫反应途径，这些途径在恢复过程中减少。细菌属 Alistipes 和代谢物二肽甘氨酰-L-亮氨酸在两性中均在高峰期增加，但在 ALD 恢复过程中减少。丝裂原活化蛋白激酶（Map3k1）在肝中的诱导与微生物组和代谢组在高峰期的变化相关，但在 ALD 恢复过程中得到恢复。抑制 MAP3K1 可防止小鼠发生 ALD。结论：戒酒以性别特异性的方式恢复肝脏转录组、粪便微生物组和门脉血清代谢组。多组学数据的整合确定了 Map3k1 是驱动 ALD 发病机制和恢复的关键基因。
