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Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44 Page 9 of 14

reducing and eliminating neurological, neuropsychiatric, and motor complications by eliminating triggers
and reducing the production and absorption of intestinal toxins. A number of clinical trials have been
[110]
conducted to explore possible treatments for HE . Currently, the main therapeutic strategies include
[111]
temporarily reducing or even prohibiting protein intake , oral administration of weakly acidic solutions,
for example, dilute acetic acid for catharsis , microbiota-targeted interventions such as lactulose,
[112]
probiotics, rifaximin, and FMT to reshape the gut microbiome to reduce the production of toxins [113-116] ,
glutamic acid tablets to promote free ammonia conversion , arginine to promote urea synthesis ,
[118]
[117]
ornithine to lower blood ammonia and correct symptoms of amino acid metabolism disorder , branched-
[119]
chain amino acids to suppress the formation of pseudo-neurotransmitters , naloxone or other opioid
[120]
receptor antagonists to improve brain dysfunction syndrome , and the use of an artificial liver support
[121]
[122]
system to eliminate all triggers . These therapeutic strategies are included in the guidelines on the
diagnosis and treatment of HE . Of these, microbiota and metabolomic-targeted strategies, in particular
[4]
[118]
lactulose, rifaximin, and probiotics , are well-received in the clinic for the treatment of covert/minimal
HE and to prevent HE reoccurrence . FMT, a newer modality of therapies targeting the gut microbiome
[123]
that has come into practice in the past decade, has been demonstrated to be safe and effective in preliminary
clinical trials on a small number of patients with HE . Before FMT, many procedures had to be strictly
[124]
performed to prevent the occurrence of adverse events, including selection of donors by questionnaire,
previous medical records, physical and stool examinations, evaluations of the potential risks and benefits for
the recipients in clinical situations, postoperative risks, etc., and preparations of the raw material in the
super-clean room under close microbiological control. After FMT, medical observation and periodic follow-
ups should be taken to monitor the clinical efficacy and short- and long-term adverse events, such as mild
and self-limiting abdominal discomfort, cramping, bloating, diarrhea or constipation, and, rarely, the
transmission of diseases that cannot be tested for by screening . However, there are still many challenges
[125]
that remain to be overcome clinically for personalized HE interventions that target the microbiota-gut-liver-
brain axis. For example, challenges include: how to accurately modify the gut microbiome and its
metabolites to give predictable clinical outcomes; how to maintain these outcomes; and how to anticipate
endogenous risks after the interventions. Randomized placebo-controlled multi-center trials on a large
cohort should be performed to validate the clinical outcomes of these preventive care interventions to
prevent symptoms in HE patients from progressing to severe neuropsychiatric dysfunction, such as coma.

CONCLUSION
As mentioned above, research on the microbiome-gut-brain axis and the microbiome-gut-liver axis has
proved that the gut microbiome is not only involved in the process of liver disease exacerbation, but also
closely related to cognitive impairment. These studies have allowed us to further understand the
microbiota-brain-gut-liver axis, providing new strategies to prevent and treat HE. While these previous
studies focused on identifying the differences in the amounts of microbes and small molecule metabolites
between HE patients and the control group, the exact dynamics of molecular networks that are involved in
gut microbiota-liver-brain axis in the context of HE disease progression from covert HE to coma is still
unclear. In addition, although the clinical efficacy of intestinal microbiota reconstruction therapy for HE,
including probiotics, prebiotics, and FMT, has been recognized, there is still a lack of strong biomarkers that
can be used to monitor the efficacy in real time and evaluate the prognosis.

DECLARATIONS
Authors’ contributions
Made substantial contributions to the conception and design of the review: Li L, Wu Z
Wrote the manuscript: Lu H