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Page 6 of 20 Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12

In recent years, the role of the components of Akk in intestinal tumors has attracted considerable attention.
In an in vitro cellular assay in 2020, the Akk aspartate protease Amuc_1434 was demonstrated to inhibit the
[40]
viability of human CRC LS174T cells . Furthermore, oral administration of pasteurized Akk or its purified
membrane protein Amuc_1100 increased the number of CTL in the colon and mesenteric lymph nodes
(MLN) and inhibited azoxymethane (AOM)/DSS-induced colitis and CRC in mice . Recently,
[21]
extracellular vesicles from Akk were shown to inhibit the development of CRC associated with colitis. The
researchers identified a new protein from AmEV, named Amuc_2172, that promotes the activity of CTL to
[4]
inhibit CRC .
In recent years, a cancer vaccine preparation with extracellular vesicles mixed with lipid nanovesicles
(Lipo@HEV) was constructed by using exosomes derived from tumor cells as antigen sources, and outer
membrane vesicles from Akk (Akk-OMV) as natural adjuvants. It can enhance preventive and therapeutic
vaccination by promoting the maturation of dendritic cells (DC) in lymph nodes and activating CTL
reaction, and enhance the therapeutic effect of PD-1 blocking by loading PD-L1 trap plasmids [Figure 3].
[41]

Akk and functional gastrointestinal disorders
Akk has also been reported to be associated with functional gastrointestinal disorders such as IBS. In 2012, a
study discovered that the relative abundance of Akk in the feces of children with diarrhea-predominant
irritable bowel syndrome was significantly reduced .
[42]

Another study in 2017 found that the traditional Chinese medicine Wujiwan can effectively reduce
abdominal pain and diarrhea in rats with post-inflammatory irritable bowel syndrome (PI-IBS), and its
effect may be related to significantly improving the abundance of Akk . Furthermore, fecal microbiota
[43]
transplantation (FMT) was shown to effectively relieve gastrointestinal symptoms and relieve depression
and anxiety in 30 patients with refractory IBS. The analysis of the fecal microbiota showed that the
abundance of Akk was significantly increased one month after FMT . Another study in 2018 also obtained
[44]
similar results and found that the abundance of Akk is related to the extent of symptom relief of patients,
[45]
and we speculate that the mechanism may lie in the decreased sensitivity of visceral pain caused by short
[46]
chain fatty acid (SCFA), one of the metabolites of Akk and other probiotics . Furthermore, in a clinical
study, the researchers stimulated biopsied intestinal mucosa of PI-IBS and healthy people with Akk and
found that the release of anti-inflammatory cytokine IL-13 in PI-IBS patients increased significantly after
Akk stimulation, which was higher than that in the healthy control group, further explaining the anti-
[47]
inflammatory effect of Akk in IBS . In addition, a study assessing the changes of intestinal mucosa and
microbiota associated with air pollution of UC and IBS patients in Ukraine found that the intestinal mucosa
of patients in areas with low air pollutants particulate matter 2.5 (PM2.5) was less damaged than that in high
PM2.5, and the level of Akk in feces of patients in low PM2.5 was even significantly higher than that in the
healthy control group, further suggesting the protective effect of Akk in IBS . In addition, several studies
[48]
found that the relative abundance of Akk in the intestines of patients with constipation-predominant
irritable bowel syndrome(C-IBS) increased , which is different from previous studies finding that the
[49]
abundance of Akk decreased in patients compared with the healthy population. However, Gobert et al.,
using the model of human microbiota-related rats (HMAR) and experimental colitis induced by DSS, found
that animals carrying C-IBS-related microbiota had milder colitis after DSS treatment . Compared with
[18]
the control group, in mice pretreated with Akk or HMAR, the expression of IL-17, IFN-γ, and TNF-α genes
was inhibited, revealing that although the abundance of Akk in the intestines of C-IBS patients increased, its
effect was still beneficial, that is, the anti-inflammatory effect of intestinal microbiota in C-IBS patients
could have been mediated by Akk to some extent. In addition, another study on intestinal microbial changes
in patients with enteritis and IBS shows that there is no significant difference in Akk abundance between
IBS patients and the healthy population, which may be due to the limitation of sample size, because it only