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Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12 Page 9 of 20

forming a vicious circle that may lead to the development of many liver and intestinal diseases. In this
context, the application of probiotics such as Akk to improve the intestinal microenvironment may be
effective in treating liver disease. A study using a streptozotocin high-fat diet (STZ-HFD) to induce mice
model of liver disease showed that the relative abundance of Akk was reduced in the STZ-HFD group of
mice compared to control mice . In 2017, administration of Akk to experimental mice was demonstrated
[67]
to reduce serum alanine transaminase and aspartate transaminase, attenuate liver damage induced by
concanavalin A (Con A), and decrease both pro-inflammatory cytokines such as IL-2 and IFNγ in the serum
[68]
of mice . Consistent with the serological results, IFNγ expression was significantly reduced in the liver of
Akk-treated mice . In the same year, another study showed that rhubarb extract could prevent hepatitis
[68]
caused by acute alcohol intake and increase the abundance of Akk in the intestine. Subsequent analysis
revealed that the abundance of Akk was positively correlated with the expression of the antimicrobial
peptide, regenerating islet-derived protein IIIγ (RegIIIγ), which restores the intestinal barrier function and
prevents alcohol-induced liver injury. It is speculated that rhubarb extract may promote the expression of
RegIIIγ by increasing the number of Akk . In addition, it has been reported that berberine reduced acute-
[69]
chronic alcoholic liver injury by altering the overall gut microbial community and promoting the
abundance of Akk . A study in 2018 found that Akk abundance in the feces of alcoholic hepatitis patients
[70]
was lower than that of healthy individuals, and the abundance of Akk was significantly reduced by alcohol
gavage in wild-type (WT) mice, while oral administration of Akk prophylactically reduced liver injury, fatty
liver, and neutrophil infiltration . Consistently, a clinical study showed that patients with either
[71]
hepatocellular carcinoma or cirrhosis showed a decrease in Akk abundance, along with an increase in
intestinal permeability and plasma LPS levels, suggesting that the hepatoprotective function of Akk may be
[72]
achieved by reducing intestinal-derived inflammation . Recently, it has been found that Akk can alleviate
the hepatotoxicity induced by sodium valproate , and oral application of Akk can alleviate the liver injury
[73]
induced by alcohol, increase the serum ornithine level, and reduce the oxalic acid level increased by alcohol
intake . In addition, the imbalance of intestinal microbiota and the decrease of SCFA production in
[74]
nonalcoholic steatohepatitis (NASH) animals may further act through the hepato-intestinal brain axis. It
may lead to the exhaustion of dopamine in the frontal cortex, increasing protein oxidation and lipid
peroxidation in the frontal cortex, which may eventually lead to mental illness. Akk has also been reported
to reduce microglia proliferation and inflammation and improve cognitive impairment induced by NASH,
including spatial working memory and new object recognition . The deletion of NOD-like receptor family
[75]
pyrin domain containing 6 (NLRP6) can enhance the progress of hepatitis, which may be related to the
increase of Muribaculum and the decrease of Akk abundance, while Akk supplementation can improve
intestinal barrier function, reduce the infiltration of myeloid-derived suppressor cells (MDSC), and inhibit
steatohepatitis activity . In addition, some studies have reported the correlation between Amuc_1100 and
[76]
liver disease in mouse model. Amuc_1100 significantly reduces serum ALT and AST levels and the body
weight of NAFLD mice, and ameliorates the blood lipid level. In the liver, Akk and Amuc_1100 significantly
reduced the mRNA expression levels of NOD-like receptor thermal protein domain associated protein 3
(NLRP3) and TLR4/nuclear factor κB (NF-κB), as well as the protein and mRNA expression levels of
inflammatory cytokines . The above evidence suggests that supplementation with Akk may be a new
[77]
effective approach for the prevention and treatment of liver injury [Figure 2].

THE POTENTIAL MECHANISM OF AKK AND ITS EFFECTIVE COMPONENTS IN
REGULATING INTESTINAL-RELATED DISEASES
In recent years, an increasing number of studies have focused on the potential mechanisms of the regulatory
role of Akk and the postbiotics from Akk, such as pasteurized cells and the effective components or
metabolites, aiming to provide probiotics in a more appropriate manner to promote the host health. The
main potential mechanisms and their effective components are discussed herein [Table 1 and Figure 3].