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.