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Page 8 of 14 Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44

[99]
deteriorating pulmonary arterial hypertension . We speculate that this may deteriorate portal hypertension
in cirrhotic patients to contribute to the progression of HE. Further research is needed in humans to
identify UA-mediated pathways that are involved in the regulation of the microbiota-gut-liver-brain axis in
order to find a strategy to reduce the risks of HE.

IMPLICATIONS OF THE MICROBIOME-GUT-LIVER-BRAIN AXIS IN EARLY WARNING,
DIAGNOSIS, AND TREATMENT OF HEPATIC ENCEPHALOPATHY
Identification of high-risk cohorts, accurate diagnosis of HE, and timely interventions are all important
arms of the strategy to prevent and treat HE. During the progression of liver and neurological disease, the
communication networks are complex, and these networks involve both molecular communication between
organs and systems within the host, as well as communication between gut microbiota-derived metabolites
and the host. Furthermore, there is also the complex interaction between the host nervous and immune
system which includes neurotransmitters, interleukins, chemotactic factors, tumor necrosis factor, colony-
stimulating factor, interferons, other cytokines such as transforming growth factor β, vascular endothelial
cell growth factor, and many more. The high level of complexity suggests that uncovering the mechanisms
of various diseases will require high sensitivity/high-throughput technologies. With the recent introduction
of multi-omics approach into disease-associated microbiome studies, delineating the networks involved in
the pathogenesis of liver disease may identify key nodes that could be the targets for risk assessment of HE
progression, early warning signs, evaluation of treatment prognosis, and therapeutic strategies to prevent
disease complications and symptom progression.

The microbiome-gut-liver-brain axis as predictive and diagnosis tools for hepatic encephalopathy
Since the progression of HE, from the development of the disease to more advanced stages of the disease, is
inevitably accompanied by alterations in the structure and function of the microbiome and the metabolites,
it is likely that there are specific microbial genes and metabolites from the microbiome that can be used as
biomarkers for early warning and diagnosis of HE. Many studies have been performed to explore and
identify diagnostic indicators of HE in the clinical laboratory. The gut microbiome was first considered as a
unique non-invasive diagnostic biomarker for early- and late-stage liver cancer. This idea has been validated
[26]
by a study in a cross-regional cohort , which indicated that the diagnostic model for liver diseases using
microbiome was proven to be satisfactory in multi-regional Chinese populations. Promising gut microbiota
indicators to differentiate patients with higher HE progression risk from cirrhotic cohorts included: high
populations of urease enzyme-producing bacteria such as Alcaligenaceae, Streptococcaceae, and
Staphylococcus intermedius in fecal microbiota [100,101] ; low populations of butyric acid-producing bacteria
such as Faecalibacterium prausnitzii in colonic mucosal samples; and low populations of Ruminococcus,
Clostridium XIVb, Faecalibaterium, and Butyricoccus in stools [102-104] . In addition, α-ketoglutaramate, a
metabolite in the process of glutamine transamination, has been proposed to be a useful biomarker for early
prediction of HE . Serum homocysteine and BA levels were also identified as promising markers for the
[105]
[106]
diagnosis of HE . Additionally, it is possible to target brain dysfunction as a potential diagnostic criterion
in HE, as the brain default mode network based on resting-state functional magnetic resonance imaging
(MRI) scanning was shown to be a valuable method to identify HE . All of these diagnostic indicators for
[107]
clinical laboratory are closely related to the microbiome-gut-liver-brain axis.

The microbiome-gut-liver-brain axis as therapeutic and preventive targets for hepatic
encephalopathy
At present, HE therapies targeting the brain are still in the preclinical stage . For instance, gamma-
[108]
aminobutyric acid-benzodiazepine receptor agonists reduced peripheral inflammation and
neuroinflammation which was associated with improved cognitive and motor functions in
hyperammonemic rats . The principles of HE prevention and treatment emphasize the importance of
[109]