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Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44 Page 3 of 14

THE MICROBIOME-GUT-LIVER-BRAIN AXIS: CONNECTING THE GUT MICROBIOME AND
HEPATIC ENCEPHALOPATHY
The microbiota-gut-brain axis is a communication network connecting the gut and the brain structurally
and functionally, and is operated through bioactive molecules, the vagus nerve, and the neuroendocrine and
immune pathway [Figure 1] . The intestinal microbiome plays a role in basic neurogenesis, such as the
[17]
formation of the blood-brain barrier, generation of myelin sheath, neurogenesis, and microglia
maturation . It also participates in regulating various behaviors . Recent studies have indicated that
[19]
[18]
dysbiosis of the gut microbiome is an important environmental factor that contributes to the induction and
[20]
development of nervous system dysfunction such as mental disease , central nervous system
degeneration [21,22] , and irritable bowel syndrome . Evidence suggests an association between the gut
[23]
[24]
microbiota and brain regions controlling sensory information . In particular, signals generated by the
brain can shape the composition of gut microbiota, and molecules produced by the gut microbiome can
affect the structure of the human brain, especially for false neurotransmitters. Therefore, neurotransmitters
produced from the brain and false neurotransmitters produced from the gut microbiome, through their
action on the gut and brain, respectively, play a critical role in the communication between the microbiome,
[25]
the gut, and the brain . A comprehensive understanding of the interaction between the gut microbiome
and the brain will provide us with new ideas for the development of clinical strategies to prevent and treat
[26]
HE . Additionally, a mutual communication exists between the liver and the gut through the bile duct,
portal vein, and systemic circulation. Liver metabolites affect the gut microbiome and the function of gut
barrier, and conversely, the gut microbiome participates in regulating bile acid synthesis and glycolipid
metabolism in the liver . Proinflammatory factors in the liver and intestines mediate the development of
[5]
[27]
liver fibrosis, cirrhosis, and hepatocellular carcinoma . Many studies on the pathogenesis of liver disease
confirmed the close relationship between intestinal dysbiosis and the development of liver disease [26,28] .

The gut microbiota is involved in the pathogenesis of HE through their participation not only in the
gut-liver axis, but also in the gut-brain axis. The gut-liver-brain axis was first proposed in the regulation of
liver glycogen metabolism and energy homeostasis . It is well-known that the vagus nerve plays a critical
[8]
role in communication among the gut, the liver, and the brain, as the hepatic vagal sensory afferent nerves
link the gut microenvironment to neuronal activity in the nucleus tractus solitarius . In addition, the
[29]
gut-liver-brain axis is involved in a number of processes including immune homeostasis. For example, it
regulates the differentiation of peripheral regulatory T cells, and affects the expression of aldehyde
[30]
dehydrogenase in the intestinal antigen-presenting cells and the synthesis of retinoic acid . Another
significance of the gut-liver-brain axis is found in the levels of N-acetyl aspartate and brain functions.
N-acetyl aspartate is considered a marker of brain dysfunction, and the level of this molecule may indicate
the severity of neuronal damage [31,32] , although it is synthesized by a mitochondrial enzyme expressed in the
liver and kidney . Interestingly, the levels of N-acetyl aspartate negatively correlate with the amounts of
[33]
Ruminococcus in the intestine, while they positively correlate with Butyricicoccus . Finally, the gut-liver-
[34]
brain axis is also involved in the homeostasis of nitric oxide (NO), which is related to gut-derived bacterial
translocation and portal hypertension in cirrhotic patients. Gut microbiome dysbiosis bidirectionally
influences the liver microenvironment and is associated with endotoxemia that causes the overproduction
of NO through an induction of NO synthase. NO is thought to act as a signaling molecule in the dorsal
vagal complex and contributes to autonomic reflex function and peripheral dilatation, which results in
[35]
portal hypertension in cirrhotic patients. Therefore, systemic NO overproduction and hepatic NO
underproduction are factors that contribute to arterial vasodilatation and portal hypertension . It is also
[36]
notable that serum NO level is a biomarker associated with disease severity . Importantly, changes in the
[37]