Department of Clinical Laboratory, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu, China.
Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, P.R. China.
BMC Cancer. 2024 Nov 6;24(1):1358. doi: 10.1186/s12885-024-13136-2.
Metabolic dysfunction-associated steatotic liver disease (MASLD) asscociated hepatocellular carcinoma (HCC) is becoming a growing concern in global healthcare. The early-life gut microbiota plays a crucial role in maintaining healthy. However, the impact of early-life gut microbiota dysbiosis on the advancement of MASLD-HCC remains inadequately understood.
In the present study, we investigated the role of early-life gut microbiota in the development of MASLD-HCC in streptozotocin and high-fat diet (STZ-HFD) induced mouse model. We recorded the body weight and lifespan, and dynamically monitored the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (T-CHO) and blood glucose in the serum monthly. In addition, we examined various immune cells present in the liver, such as T cells, B cells, NK cells, NKT cells, αβT cells, γδT cells, macrophage and MDSC cells by flow cytometry and conducted liquid chromatography mass spectrometry (LC-MS) based analysis on liver tissue from control and early-life antibiotic exposure mice (early-Abx) MASLD-HCC mice.
We found that early-Abx mice suffered from more severe tumor burden and further confirmed that hepatocytes and immune cells were all disturbed. Importantly, early-life antibiotic exposure alters the liver metabolic profiling especially glycerophospholipids and lipid accumulation. Furthermore, mice exposed to antibiotics in early-life showed disturbances in glucose metabolism and developed insulin resistance.
Collectively, our findings revealed that early-life antibiotic exposure accelerated the progression of MASLD-HCC by impairing the hepatocytes, immune homeostasis and metabolites persistently, highlighting the importance of the early-life microbiota in the development of MASLD-HCC.
代谢相关脂肪性肝病（MASLD）相关肝细胞癌（HCC）在全球医疗保健中日益受到关注。早期肠道微生物群在维持健康方面起着至关重要的作用。然而，早期肠道微生物群失调对 MASLD-HCC 进展的影响仍了解不足。
在本研究中，我们研究了早期肠道微生物群在链脲佐菌素和高脂肪饮食（STZ-HFD）诱导的小鼠模型中 MASLD-HCC 发展中的作用。我们记录了体重和寿命，并每月动态监测血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、甘油三酯（TG）、总胆固醇（T-CHO）和血糖水平。此外，我们通过流式细胞术检查了肝脏中存在的各种免疫细胞，如 T 细胞、B 细胞、NK 细胞、NKT 细胞、αβT 细胞、γδT 细胞、巨噬细胞和 MDSC 细胞，并对对照和早期抗生素暴露小鼠（早期-Abx）MASLD-HCC 小鼠的肝组织进行基于液相色谱质谱（LC-MS）的分析。
我们发现早期-Abx 小鼠的肿瘤负担更重，并进一步证实肝细胞和免疫细胞均受到干扰。重要的是，早期抗生素暴露改变了肝脏代谢谱，特别是甘油磷脂和脂质积累。此外，早期暴露于抗生素的小鼠表现出葡萄糖代谢紊乱并发展为胰岛素抵抗。
总之，我们的研究结果表明，早期抗生素暴露通过持续损害肝细胞、免疫稳态和代谢物，加速了 MASLD-HCC 的进展，强调了早期微生物群在 MASLD-HCC 发展中的重要性。
