Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Hong Kong SAR, China.
Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China; Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
J Hepatol. 2023 Dec;79(6):1352-1365. doi: 10.1016/j.jhep.2023.07.005. Epub 2023 Jul 17.
BACKGROUND & AIMS: Recent studies have highlighted the role of the gut microbiota and their metabolites in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). We aimed to identify specific beneficial bacterial species that could be used prophylactically to prevent NAFLD-HCC.
The role of Bifidobacterium pseudolongum was assessed in two mouse models of NAFLD-HCC: diethylnitrosamine + a high-fat/high-cholesterol diet or + a choline-deficient/high-fat diet. Germ-free mice were used for the metabolic study of B. pseudolongum. Stool, portal vein and liver tissues were collected from mice for non-targeted and targeted metabolomic profiles. Two human NAFLD-HCC cell lines (HKCI2 and HKCI10) were co-cultured with B. pseudolongum-conditioned media (B.p CM) or candidate metabolites.
B. pseudolongum was the top depleted bacterium in mice with NAFLD-HCC. Oral gavage of B. pseudolongum significantly suppressed NAFLD-HCC formation in two mouse models (p < 0.01). Incubation of NAFLD-HCC cells with B.p CM significantly suppressed cell proliferation, inhibited the G1/S phase transition and induced apoptosis. Acetate was identified as the critical metabolite generated from B. pseudolongum in B.p CM, an observation that was confirmed in germ-free mice. Acetate inhibited cell proliferation and induced cell apoptosis in NAFLD-HCC cell lines and suppressed NAFLD-HCC tumor formation in vivo. B. pseudolongum restored heathy gut microbiome composition and improved gut barrier function. Mechanistically, B. pseudolongum-generated acetate reached the liver via the portal vein and bound to GPR43 (G coupled-protein receptor 43) on hepatocytes. GPR43 activation suppressed the IL-6/JAK1/STAT3 signaling pathway, thereby preventing NAFLD-HCC progression.
B. pseudolongum protected against NAFLD-HCC by secreting the anti-tumor metabolite acetate, which reached the liver via the portal vein. B. pseudolongum holds potential as a probiotic for the prevention of NAFLD-HCC.
Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an increasing healthcare burden worldwide. There is an urgent need to develop effective agents to prevent NAFLD-HCC progression. Herein, we show that the probiotic Bifidobacterium pseudolongum significantly suppressed NAFLD-HCC progression by secreting acetate, which bound to hepatic GPR43 (G coupled-protein receptor 43) via the gut-liver axis and suppressed the oncogenic IL-6/JAK1/STAT3 signaling pathway. Bifidobacterium pseudolongum holds potential as a novel probiotic for NAFLD-HCC prevention.
最近的研究强调了肠道微生物群及其代谢物在非酒精性脂肪性肝病相关肝细胞癌（NAFLD-HCC）中的作用。我们旨在确定特定的有益细菌种类，可用于预防性预防 NAFLD-HCC。
在两种 NAFLD-HCC 小鼠模型中评估了假双歧杆菌的作用：二乙基亚硝胺+高脂肪/高胆固醇饮食或+胆碱缺乏/高脂肪饮食。使用无菌小鼠进行假双歧杆菌的代谢研究。收集粪便、门静脉和肝组织进行非靶向和靶向代谢组学分析。将两种人 NAFLD-HCC 细胞系（HKCI2 和 HKCI10）与假双歧杆菌条件培养基（B.p CM）或候选代谢物共培养。
假双歧杆菌是 NAFLD-HCC 小鼠中最明显减少的细菌。口服假双歧杆菌显著抑制了两种小鼠模型中的 NAFLD-HCC 形成（p < 0.01）。将 B.p CM 孵育于 NAFLD-HCC 细胞中可显著抑制细胞增殖，抑制 G1/S 期转变并诱导细胞凋亡。鉴定出乙酸盐是 B.p CM 中源自假双歧杆菌的关键代谢产物，在无菌小鼠中得到了证实。乙酸盐可抑制 NAFLD-HCC 细胞系的增殖并诱导细胞凋亡，并抑制体内 NAFLD-HCC 肿瘤的形成。假双歧杆菌恢复了健康的肠道微生物群组成并改善了肠道屏障功能。在机制上，假双歧杆菌产生的乙酸盐通过门静脉到达肝脏，并与肝细胞上的 G 蛋白偶联受体 43（G 蛋白偶联受体 43）结合。GPR43 的激活抑制了 IL-6/JAK1/STAT3 信号通路，从而阻止了 NAFLD-HCC 的进展。
假双歧杆菌通过分泌抗肿瘤代谢产物乙酸盐来预防 NAFLD-HCC，乙酸盐通过门静脉到达肝脏。假双歧杆菌有望作为预防 NAFLD-HCC 的益生菌。
非酒精性脂肪性肝病相关肝细胞癌（NAFLD-HCC）是全球日益严重的医疗保健负担。迫切需要开发有效的药物来阻止 NAFLD-HCC 的进展。在此，我们表明，益生菌假双歧杆菌通过分泌乙酸盐显著抑制了 NAFLD-HCC 的进展，乙酸盐通过肠道-肝脏轴与肝脏上的 G 蛋白偶联受体 43（G 蛋白偶联受体 43）结合，并抑制了致癌的 IL-6/JAK1/STAT3 信号通路。假双歧杆菌有望成为预防 NAFLD-HCC 的新型益生菌。
