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Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44 Page 5 of 14

and Alcaligenes, which are enriched in the gut microbiome of HE patients, produce neurotoxic substances
[39]
such as ammonia, mercaptan, benzodiazepine-like compounds , manganese, and lipopolysaccharide (LPS)
to levels exceeding the metabolic capacity of the liver in HE patients [40,41] . Subsequently, these pathogenic
conditions trigger the production of other metabolites and immune responses, which reciprocally alter the
gut microbiome . Ammonia is easily absorbed through the lipid membrane and enters the brain through
[42]
the blood-brain barrier, causing an impairment of the structure and function of the brain to contribute to
the pathogenesis of HE . Current clinical therapies targeting gut microbiota, such as the antibiotics
[43]
rifaximin and lactulose, can reduce blood ammonia and improve cognitive function in HE patients.
Furthermore, fecal microbiota transplantation (FMT) has also been shown to improve cognitive function
[26]
and reduce the recurrence rate of HE in patients .

BIOACTIVE MOLECULES AS MEDIATORS OF THE MICROBIOME-GUT-LIVER-BRAIN AXIS
Although HE is mainly caused by disorders of the liver, dysfunction of the gut microbiome, gut, brain, and
immune system is also involved in the disease progression. The gut microbiome is proposed to be an
endocrine organ that produces bioactive molecules that can interact with the host’s physiological functions
to trigger responses from the gut as well as other distant organs [44,45] . These molecules include a large
number of metabolites, such as various amino acid metabolites, short-chain fatty acids (SCFAs), secondary
bile acids (BAs), and lipids and lipid derivatives.

Amino acid metabolites
Intestinal bacteria directly or indirectly participate in tryptophan (Trp) metabolism, producing a series of
indole derivatives that are considered to be an important mediator for communication and exchange of
information between the microbiota and their host [46,47] . Some species of gut microbiota (for example,
Clostridium) directly metabolize Trp to bioactive substances, such as indole, indole acetic acid, indole
propionic acid, indole acetaldehyde, and indole propene. These substances can act as ligands for aromatic
hydrocarbon receptors and play an important role in immune homeostasis. Moreover, they are involved in
the production of neurotransmitters such as 5-hydroxytryptamine (5-HT) that mediate the function of the
central nervous system. Intestinal bacterial amino acid decarboxylase can transform phenylalanine, tyrosine,
lysine, and glutamic acid into neurotransmitters such as dopamine, acetylcholine, and γ-aminobutyric acid
(GABA) . GABA is implicated in the pathophysiology and clinical manifestations of neuropsychiatric
[48]
disorder in most HE patients. Research found that, in the early stage of HE, a high level of plasma ammonia
stimulates the consumption of glutamic acid to generate glutamine, which results in decreased GABA
synthesis. However, in the late stage, high plasma ammonia inhibits the hydrolysis of GABA, leading to an
accumulation of GABA in the brain. Thus, most HE patients exhibit clinical manifestations of anxiety,
insomnia, silent excitement and excitement in the early stage, but drowsiness and coma in the late stage.
Additionally, these aromatic amines can directly enter the brain when liver function is impaired, and
generate pseudo-neurotransmitters including phenylethanolamine and β-hydroxytyramine. These pseudo-
neurotransmitters cannot transmit nerve impulses [49,50] and, therefore, may cause brain dysfunction and liver
coma. Research on the influence of gut microbiota-derived metabolites on the pathophysiological
mechanisms of HE found that hyperammonemia plays an important role in the progression of HE. At
present, it is generally believed that ammonia diffuses into the brain through the blood-brain barrier. In the
brain, glutamine synthetase in astrocyte cells can catalyze the reaction between glutamate and free ammonia
to synthetize glutamine [43,51] , which is critical for detoxification of ammonia. In pathological conditions, the
capacity of astrocytic detoxification is weakened, and accordingly, the concentrations of brain ammonia are
increased. This is followed by astrocyte swelling and decreased nutrient availability and glutamate uptake,
[52]
which produces continuous stimulation of neurons . In addition, because the ability of the liver to convert
ammonia to urea is not sufficient in HE patients, making it difficult to keep the blood ammonia
concentration at a safe level, the patients are caught in a vicious cycle that exacerbates acute brain damage