Fig.1 An overview of gut-liver-brain axis.
2.1 Gut-liver axis
The gut-liver axis is a hot topic in recent decades. There exists a delicate relationship between gut and liver for their anatomical and functional intimacy. After partially absorbed by the gastrointestinal tract, some xenobiotics such as oral drugs are subject to the liver for further metabolism through the portal vein and some of the metabolites accompanied with bile are recycled into the intestine via enterohepatic circulation (Roberts et al., 2002), indicating the intimate relationship between gut and liver (Fig.1). Hence, ever since gut microbiota was highlighted decades ago, scholars have been connecting gut microbiota with liver diseases which gains much progress in this field. Gut dysbiosis has been associated with the pathogenesis of a wide spectrum of liver diseases including alcoholic liver disease, non-alcoholic liver disease (NAFLD), hepatocellular carcinoma, autoimmune hepatitis, autoimmune cholangiopathies, acute liver injury, and liver fibrosis/cirrhosis (Hartmann et al., 2019). Notably, its role in initiating, perpetuating, and exacerbating NAFLD enables us to understand the etiology of the agnogenic and intricate liver disease and facilitates therapy of it (Leung et al., 2016). Mechanisms involved in gut microbiota related NAFLD include enterohepatic circulation of bile acids, increased intestinal permeability, systemic inflammation, altered immunity, and microbiota-derived metabolites, and so far as we know, manipulation of gut microbiota is fruitful in improving NAFLD with supplemental antibiotics and pre/pro/synbiotics, FMT, specific diet and exercise intervention having been demonstrated effective in NAFLD treatment, some of which are already in clinical trial phase (Wiest et al., 2017; Aron-Wisnewsky et al., 2020). Targets involved in gut microbiota mediated NAFLD locate in the gut lumen, gut mucosa, portal system, and liver/adipose tissue and gut dysbiosis modulates NAFLD negatively through microbiota-gut-liver axis by activating or inhibiting relevant receptors, cytokines or metabolites production therein (Leung et al., 2016) (Fig.2). Among the numerous metabolites engaged in the axis, bile acids are considered a common language of gut and liver with farnesoid X receptor (FXR) playing as a mediator. Primary bile acids are produced in the liver from cholesterol and are then subject to gut microbiota to form secondary bile acids. FXR, a nuclear receptor situated both in ileal enterocytes and hepatocytes, receives stimuli from liver secreted bile acids and activates expression of fibroblast growth factor (FGF) 19 in ileal enterocytes, which enters the liver via portal vein and activates FGF4/b-klotho complex in hepatocytes and further inhibits cholesterol 7α-hydroxylase (CYP7A1) expression, leading to suppression of bile acids synthesis (Wiest et al., 2017). Reversely, bile acids produced from liver to gut also influence gut microbial composition and function, constituting an important part in gut-liver bidirectional communication.