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Page 2 of 14 Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44

INTRODUCTION
Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities
caused by complications stemming from liver dysfunction, including hyperammonemia and portal
hypertension . As the disease progresses, many patients experience neurological symptoms including sleep
[1]
disorders, personality changes, depression, coma, and even death. Once HE is developed in patients with
liver disease, it takes a long time for them to recover cognitive function, even with successful treatments.
Additionally, secondary HE may recur during the recovery period, which can seriously affect the prognosis
[2]
and quality of life of the patients . Various factors that cause acute liver failure and cirrhosis can induce
HE, for example, hepatitis viruses such as HBV, HCV, HEV, drugs, or liver toxic substances such as alcohol,
chemical agents, etc. Generally, some neurotoxic molecules should be effectively metabolized while passing
through the liver before entering the systemic circulation. Otherwise, it will result in pathological
neurological disorder syndromes. Additionally, abnormal functioning of the urea cycle enzymes or any
other factors, for example, congenital urea cycle disorders, can lead to elevated blood ammonia
(hyperammonemia), which is believed to be a major contributor to the neurological sequelae following
severe liver disease. Depending on the underlying liver disease, HE is divided into three types: Type A,
caused by acute liver failure, accompanied with relatively minor changes in consciousness at first, and then
rapidly falling into deep coma and even death; Type B, caused by portocaval shunting, without any apparent
liver disease; Type C, caused by liver cirrhosis, characterized by chronic recurrent personality and
behavioral changes, cognitive impairment, and even numbness and coma. HE is a continuous process
constantly changing from normal cognitive function, clear consciousness, to coma . Clinical treatment
[3]
mainly focuses on supportive therapies and the treatment of symptoms. HE has become an urgent issue for
medical research due to the poor effectiveness of treatment and high mortality rate. Currently, early
prediction, early identification, and timely treatment are highly effective strategies to prevent and treat HE.
Reports indicate that early diagnosis and treatment for patients at high risk of HE is associated with
improvement in the prognosis of HE .
[4]
The close connection between the physiological functions of the gut-liver axis and the gut-brain axis ,
[6]
[5]
both of which are in part mediated by gut microbiota, has become an increasingly important topic for HE
medical research. Although HE is caused by liver failure, accumulating evidence suggests that there are
bidirectional links among the intestine, the liver, and the brain, known as the gut-liver-brain axis, which
[7,8]
involves the exchange of information via hormones, cytokines, and nutritional metabolites . Most HE
patients display an increased permeability of the blood-cerebrospinal fluid barrier, which renders their
brains vulnerable to toxins and the toxic effects of neurotoxins. In addition, artificial liver support for HE
patients has been shown to improve the prognosis, shorten disease course, and reduce mortality .
[9]
The human gastrointestinal tract harbors a wide variety of microbes, the so-called gut microbiome - the
second genome [10,11] . From birth, the coevolution of gut microbiota and the host shapes a unique pattern of
gene expression and regulation, which has become the focus of precision medicine research in the 21st
century. Gut microbiota is involved in the digestion and metabolism of nutrients and various drugs, and
also regulates immune responses [12-14] . Furthermore, it makes an important contribution to the regulation of
development, maturation, and physiological functions of the gut, liver, and central nervous system . Since
[15]
gut microbiota has been shown to be involved in regulating central nervous system activities such as brain
development, stress response, anxiety, depression, and cognitive function , further exploration of the
[16]
molecular interaction between the intestinal microbiome and the gut-liver-brain axis is of great significance
for the clinical prevention, treatment, and prognosis of HE. This review focuses on the communication
network between gut microbiota and the gut-liver-brain axis, which is referred to as the gut microbiota-
liver-brain axis, and the role and significance of this network in the occurrence, prognosis, prevention, and
treatment of HE.