Page 61 - Read Online

Page 14 of 20 Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12

compared to Amuc_1100. In addition, the results show that the mechanism of activating CTL by
Amuc_1100 and Amuc_2172 may be different, because CTL can be activated by Amuc_1100 directly, while
the activation of CTL by Amuc_2172 requires the involvement of cancer cells. Specifically, Amuc_2172
promotes the secretion of HSP70 from cancer cells, which in turn indirectly promotes the activation of CTL.
However, whether Amuc_2172 can inhibit the development of intestinal-associated metabolic diseases as
Amuc_1100 has not been reported and the mechanism of Amuc_2172 in intestinal-related diseases still
needs further exploration. Altogether, as a probiotic enzyme, Amuc_2172 could regulate the function of
eukaryotic cells and serve as a potential drug by catalyzing eukaryotic protein targets.

The effect of other components
In addition to the above components, other active ingredients of Akk are also important in intestinal-related
diseases. Pasteurized Akk can alleviate the progress of intestinal-related diseases by enhancing intestinal
[21]
barrier function and regulating intestinal immunity, as mentioned above . The metabolite of Akk, SCFA,
- -
can act on G-protein-coupled receptor 43 (GPR43). Compared with WT enteritis mice, Gpr43 / enteritis
mice showed higher expression of IL-6 and IL-22 and more tissue damage. After SCFA supplementation, it
binds to GPR43 on neutrophils and subsequently induces their apoptosis, which alleviates the progression
of enteritis in WT mice , whereas no remission was seen in Gpr43 / mice. SCFA can also affect glucose
[102]
- -
metabolism to improve type II diabetes, and it regulates intestinal microbial composition and metabolism to
inhibit liver injury [81,103] . Moreover, a recent study found that another probiotic enzyme Amuc_2109, a
metabolic enzyme (β- N-acetyl hexosaminidase) secreted by Akk, had a significant protective effect against
DSS-induced colitis mainly by improvement of the intestinal epithelial barrier function and regulation of
[89]
intestinal microbiota homeostasis , as Amuc_2109 reshaped intestinal microbiota and inhibited the
overexpression of TNF-α, IL-6, and NLRP3 in DSS-induced colitis, as well promoting the expression of tight
junction protein. However, Amuc_2109 was not detected in Akk grown on mucin ; its role in intestinal-
[104]
related diseases needs to be further explored. Furthermore, a recent study identified a new protein secreted
by Akk, named protein 9 (P9), which stimulates human intestinal endocrine L cells to secrete glucagon-like
peptide-1 (GLP-1) in vitro and causes a modest increase in circulating GLP1 levels of obese mice, thereby
reducing insulin resistance and improving glucose metabolism. The process may be associated with the
activation of intercellular adhesion molecule 2 (ICAM2), as the ICAM2 antibody partially abrogated the
[90]
effect of P9 on GLP1 in vitro . Moreover, the expression of ICAM2 may require the involvement of IL-6.
The study illustrates the new mechanism by which Akk-derived proteins act on intestinal endocrine cells to
affect the occurrence and development of metabolic diseases. However, the signal pathways through which
P9 protein interacts with ICAM-2, and the downstream signal transduction through which ICAM-2 induces
GLP-1 secretion are unclear, and the specific molecular mechanism still needs to be explored by more
experiments. In addition, ornithine lipid, a lipid component produced by Akk in the intestines of mice and
humans, was also reported to have anti-inflammatory effect, which can prevent LPS-induced inflammatory
reaction, inhibit the production of pro-inflammatory cytokines, and increase the level of anti-inflammatory
[105]
cytokine IL-10 .

PATHOGENESIS OF AKK IN INTESTINAL-RELATED DISEASES
The above research shows the beneficial effect of Akk in intestinal-related diseases. On the other hand, some
studies have also found that the application of Akk aggravated intestinal inflammation in mice. A study in
mice with secondary metastatic colitis (AdTr-colitis) also found that the abundance of Akk was positively
[106]
correlated with the degree of colonic inflammation and histopathological score . In 2013, the results of a
study showed that commensal Akk exacerbated intestinal inflammation in Salmonella typhimurium-infected
germ-free mice , and then in 2017, Seregin et al. reported that repeated gavage of Akk could induce
[107]
increased severity of colitis in IL10 / mice . There are many possible reasons for the controversial role of
- -
[108]
Akk in intestinal inflammation. These include the use of various mouse models in different experiments -