嗜酸乳杆菌通过产生戊酸来抑制非酒精性脂肪性肝病相关的肝细胞癌。
Lactobacillus acidophilus suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma through producing valeric acid.
机构信息
State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
出版信息
EBioMedicine. 2024 Feb;100:104952. doi: 10.1016/j.ebiom.2023.104952. Epub 2024 Jan 4.
BACKGROUND
Gut probiotic depletion is associated with non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). Here, we investigated the prophylactic potential of Lactobacillus acidophilus against NAFLD-HCC.
METHODS
NAFLD-HCC conventional and germ-free mice were established by diethylnitrosamine (DEN) injection with feeding of high-fat high-cholesterol (HFHC) or choline-deficient high-fat (CDHF) diet. Orthotopic NAFLD-HCC allografts were established by intrahepatic injection of murine HCC cells with HFHC feeding. Metabolomic profiling was performed using liquid chromatography-mass spectrometry. Biological functions of L. acidophilus conditional medium (L.a CM) and metabolites were determined in NAFLD-HCC human cells and mouse organoids.
FINDINGS
L. acidophilus supplementation suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice. This was confirmed in orthotopic allografts and germ-free tumourigenesis mice. L.a CM inhibited the growth of NAFLD-HCC human cells and mouse organoids. The protective function of L. acidophilus was attributed to its non-protein small molecules. By metabolomic profiling, valeric acid was the top enriched metabolite in L.a CM and its upregulation was verified in liver and portal vein of L. acidophilus-treated mice. The protective function of valeric acid was demonstrated in NAFLD-HCC human cells and mouse organoids. Valeric acid significantly suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice, accompanied by improved intestinal barrier integrity. This was confirmed in another NAFLD-HCC mouse model induced by CDHF diet and DEN. Mechanistically, valeric acid bound to hepatocytic surface receptor GPR41/43 to inhibit Rho-GTPase pathway, thereby ablating NAFLD-HCC.
INTERPRETATION
L. acidophilus exhibits anti-tumourigenic effect in mice by secreting valeric acid. Probiotic supplementation is a potential prophylactic of NAFLD-HCC.
FUNDING
Shown in Acknowledgments.
背景
肠道益生菌耗竭与非酒精性脂肪性肝病相关的肝细胞癌（NAFLD-HCC）有关。在这里，我们研究了嗜酸乳杆菌对 NAFLD-HCC 的预防潜力。
方法
通过二乙基亚硝胺（DEN）注射并用高脂肪高胆固醇（HFHC）或胆碱缺乏高脂肪（CDHF）饮食喂养建立 NAFLD-HCC 常规和无菌小鼠。通过 HFHC 喂养肝内注射鼠 HCC 细胞建立 NAFLD-HCC 同种异体移植。使用液相色谱-质谱联用进行代谢组学分析。在 NAFLD-HCC 人细胞和小鼠类器官中确定嗜酸乳杆菌条件培养基（L.a CM）和代谢物的生物学功能。
结果
嗜酸乳杆菌补充剂抑制了 HFHC 喂养 DEN 处理的小鼠的 NAFLD-HCC 形成。在同种异体移植和无菌肿瘤发生小鼠中得到了证实。L.a CM 抑制了 NAFLD-HCC 人细胞和小鼠类器官的生长。嗜酸乳杆菌的保护功能归因于其非蛋白小分子。通过代谢组学分析，发现戊酸是 L.a CM 中含量最丰富的代谢物，并且在嗜酸乳杆菌处理的小鼠的肝脏和门静脉中得到了验证。戊酸在 NAFLD-HCC 人细胞和小鼠类器官中显示出保护功能。戊酸在 HFHC 喂养 DEN 处理的小鼠中显著抑制了 NAFLD-HCC 的形成，同时改善了肠道屏障的完整性。在另一种由 CDHF 饮食和 DEN 诱导的 NAFLD-HCC 小鼠模型中得到了证实。从机制上讲，戊酸与肝细胞表面受体 GPR41/43 结合，抑制 Rho-GTPase 通路，从而消除了 NAFLD-HCC。
结论
嗜酸乳杆菌通过分泌戊酸在小鼠中表现出抗肿瘤作用。益生菌补充剂是预防 NAFLD-HCC 的一种潜在方法。
资助
见致谢。
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