Maccioni Luca, Guan Yukun, Kim Mariia, Parra Maria A, Peiffer Brandon, Fu Yaojie, Wang Yang, Lin Yu-Hong, Mackowiak Bryan, Feng Dechun, Cameron Andrew, Sun Zhaoli, Kunos George, Stärkel Peter, Gao Bin
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
Gut. 2025 Jul 7;74(8):1308-1320. doi: 10.1136/gutjnl-2024-334412.
Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure.
We examined the regulation of intestinal and intrahepatic CD8 T lymphocytes and their contribution to ALD.
ALD patients were recruited for evaluation of intestinal and liver T cells. Single-cell RNA sequencing (scRNA seq) was performed to analyse intrahepatic and peripheral T cells in ALD. Wildtype, CD8-specific transgenic ( ), and mice were subjected to chronic-plus-binge ethanol feeding.
In ALD patients, duodenal CD8 T cells were selectively reduced and negatively correlated with liver injury and bacterial translocation markers, while intrahepatic CD8 T cells were markedly increased. ScRNA seq analysis of ALD patient livers revealed several populations of CD8 T cells expressing activation and survival genes (eg, ). Transcriptomics and functional studies revealed a key role of prosurvival BCL2 in this opposite regulation of CD8 T cells. Mechanistically, chronic-plus-binge ethanol feeding reduced CD8 T cells specifically in the duodenum where ethanol levels are high. Inducing BCL2 in CD8 T cells reversed ethanol-induced loss of duodenal CD8 T cells, improved gut barrier function and ameliorated ALD, while CD8 deficiency was linked to enhanced neutrophil and macrophage infiltration in the liver, exacerbating ALD in mice.
ALD is associated with loss of duodenal CD8 T cells but elevation of intrahepatic CD8 T cells, which aggravates and ameliorates ALD, respectively. Restoration of survival and functions of intestinal and intrahepatic CD8 T cells may represent a novel therapeutic strategy for ALD patients.
肠-肝相互作用在酒精性肝病（ALD）发病机制中起重要作用；但其潜在机制仍不清楚。
我们研究了肠道和肝内CD8 T淋巴细胞的调节及其对ALD的作用。
招募ALD患者评估肠道和肝脏T细胞。进行单细胞RNA测序（scRNA seq）以分析ALD患者肝内和外周T细胞。对野生型、CD8特异性转基因（ ）和 小鼠进行慢性加暴饮乙醇喂养。
在ALD患者中，十二指肠CD8 T细胞选择性减少，且与肝损伤和细菌易位标志物呈负相关，而肝内CD8 T细胞明显增加。对ALD患者肝脏进行scRNA seq分析发现了几个表达激活和存活基因（如 ）的CD8 T细胞群体。转录组学和功能研究揭示了促存活BCL2在CD8 T细胞这种相反调节中的关键作用。机制上，慢性加暴饮乙醇喂养特异性减少了十二指肠中乙醇水平高的部位的CD8 T细胞。在CD8 T细胞中诱导BCL2可逆转乙醇诱导的十二指肠CD8 T细胞丢失，改善肠道屏障功能并减轻ALD，而CD8缺陷与肝脏中嗜中性粒细胞和巨噬细胞浸润增加有关，加重了小鼠的ALD。
ALD与十二指肠CD8 T细胞丢失但肝内CD8 T细胞升高有关，分别加重和减轻ALD。恢复肠道和肝内CD8 T细胞的存活和功能可能代表了ALD患者的一种新治疗策略。
