Said Imaad, Ahad Hassan, Said Adnan
Brown University, Providence, RI 02912, United States.
Kansas University, Lawrence, KS 66045, United States.
World J Gastrointest Oncol. 2022 May 15;14(5):947-958. doi: 10.4251/wjgo.v14.i5.947.
Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.
非酒精性脂肪性肝病（NAFLD）等代谢性疾病的发病率正在上升，并且日益成为肝硬化和肝细胞癌（HCC）的常见病因。肠道微生物群与肝脏通过门静脉紧密相连，最近已被确定为肝脏疾病状态的一个预测指标。对非酒精性脂肪性肝病、肝硬化和肝细胞癌的研究已经确定了与这些疾病相关的某些微生物特征，与疾病相关的微生物群变化统称为生态失调。这些观察结果的病理生理学基础是一个正在进行研究的领域，目前的证据表明肠道微生物群可以影响肝脏疾病和致癌作用，其作用途径包括对肠道通透性（肠漏）的影响以及先天免疫系统的激活。在先天免疫系统中，驻留肝细胞和巨噬细胞上的病原体识别受体（Toll样受体）会引发肝脏炎症、纤维化、肝细胞增殖并降低抗肿瘤免疫力，从而导致慢性肝病和致癌作用。与生态失调相关的变化包括次级胆汁酸增加和FXR（核受体）表达降低，这也与进行性肝病相关的脂质和碳水化合物代谢的有害影响有关。需要在不同人群中开展纵向实验和临床研究，以进一步探讨这些问题。调节微生物群的治疗方法的作用是一个新兴领域，实验研究表明饮食、益生菌、粪便微生物群移植和益生元在改善实验模型中的肝病方面具有潜力。临床研究正在进行中，初步证据显示肝酶和脂肪变性有所改善。包括肝癌在内的癌症免疫治疗应答者的微生物谱有所不同，但微生物群的操控是否可用于影响应答正在研究之中。
