Gao Huihui, Bai Hangming, Su Yanyan, Gao Yuting, Fang Hui, Li Donghang, Yu Youren, Lu Xing, Xia Dasheng, Mao Daqing, Luo Yi
School of Medicine, Nankai University, Tianjin, 300071, China.
College of Environmental Sciences and Engineering, Nankai University, Tianjin, 300350, China.
J Transl Med. 2025 Jun 3;23(1):627. doi: 10.1186/s12967-025-06573-5.
Helicobacter pylori infection is common in patients with alcohol-related liver disease (ALD), and bismuth quadruple therapy (BQT) is widely used for eradication. However, its impact on ALD remains unclear. This study aims to characterize BQT-induced gut microbiota alterations in asymptomatic H. pylori carriers and evaluate their effect on an ALD mouse model.
Metagenomic sequencing was conducted to assess the gut microbiota composition of individuals before and after BQT. Fecal microbiota transplantation (FMT) from these donors was performed in an ALD mouse model. Gut microbiota in mice was analyzed by 16S rRNA sequencing. Liver and intestinal parameters were assessed using western blot, RT-qPCR, histopathology, ELISA, and flow cytometry.
BQT treatment significantly altered the gut microbiota in H. pylori carriers, increasing the abundance of opportunistic pathogens, including Klebsiella pneumoniae, Escherichia coli, Klebsiella quasipneumoniae, and Klebsiella variicola, while decreasing beneficial bacteria such as Bifidobacterium, Eubacterium, Bacteroides, Faecalibacterium, and Blautia. In ALD mice receiving FMT from post-BQT donors, exacerbated gut dysbiosis was observed, marked by an enrichment of Enterobacteriaceae and Escherichia-Shigella. These microbiota changes were associated with impairment of intestinal barrier integrity, as evidenced by reduced levels of mucins, tight junction proteins, and antimicrobial peptides, along with a decrease in Treg cells and an increase in Th17 and Th1 cells. Additionally, this dysbiosis led to elevated serum lipopolysaccharide (LPS) levels, which activated the hepatic NLRP3 inflammasome pathway and subsequently increased IL-18 and IL-1β levels. Furthermore, liver function and oxidative stress markers, including ALT, AST, MDA, GSSG/GSH ratio, and SOD, were significantly elevated, indicating severe liver dysfunction and increased oxidative stress. Finally, probiotic supplementation effectively mitigated the negative effects of BQT-induced gut microbiota remodeling on ALD in mice.
BQT markedly alters the gut microbiota in H. pylori carriers, promoting dysbiosis that exacerbates ALD in mice via LPS-mediated activation of hepatic inflammatory pathways. These findings highlight the need for careful consideration of BQT use in ALD patients.
幽门螺杆菌感染在酒精性肝病（ALD）患者中很常见，铋剂四联疗法（BQT）被广泛用于根除幽门螺杆菌。然而，其对ALD的影响仍不清楚。本研究旨在描述BQT诱导的无症状幽门螺杆菌携带者肠道微生物群的变化，并评估其对ALD小鼠模型的影响。
进行宏基因组测序以评估BQT治疗前后个体的肠道微生物群组成。将这些供体的粪便微生物群移植（FMT）到ALD小鼠模型中。通过16S rRNA测序分析小鼠的肠道微生物群。使用蛋白质免疫印迹、RT-qPCR、组织病理学、酶联免疫吸附测定和流式细胞术评估肝脏和肠道参数。
BQT治疗显著改变了幽门螺杆菌携带者的肠道微生物群，增加了包括肺炎克雷伯菌、大肠杆菌、准肺炎克雷伯菌和变异克雷伯菌在内的机会性病原体的丰度，同时减少了双歧杆菌、真杆菌、拟杆菌、粪杆菌和布劳特氏菌等有益细菌。在接受BQT治疗后供体FMT的ALD小鼠中，观察到肠道菌群失调加剧，其特征是肠杆菌科和埃希氏菌-志贺氏菌富集。这些微生物群变化与肠道屏障完整性受损有关，表现为粘蛋白、紧密连接蛋白和抗菌肽水平降低，以及调节性T细胞减少和辅助性T细胞17及辅助性T细胞1增加。此外，这种菌群失调导致血清脂多糖（LPS）水平升高，激活肝脏NLRP3炎性小体途径，随后增加白细胞介素-18和白细胞介素-1β水平。此外，肝功能和氧化应激标志物，包括谷丙转氨酶、谷草转氨酶、丙二醛、氧化型谷胱甘肽/还原型谷胱甘肽比值和超氧化物歧化酶，显著升高，表明严重肝功能障碍和氧化应激增加。最后，补充益生菌有效地减轻了BQT诱导的肠道微生物群重塑对小鼠ALD的负面影响。
BQT显著改变幽门螺杆菌携带者的肠道微生物群，促进菌群失调，通过LPS介导的肝脏炎症途径激活加重小鼠的ALD。这些发现凸显了在ALD患者中使用BQT时需要谨慎考虑。
