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Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12 Page 13 of 20

and degrades Muc2 secreted by colon cancer cells. Amuc_1434 also promotes the mutual adhesion of colon
[99]
cancer cells with high Muc2 expression . Subsequently, Amuc_1434 was shown to upregulate the
expression of p53, an oncogene that controls cell cycle initiation, which resulted in the arrest of CRC cells in
the G0/G1 phase of the cell cycle and inhibited the proliferation of colon cancer cells. Furthermore,
Amuc_1434 also induced apoptosis in CRC tumor cells by activating the mitochondrial apoptosis pathway
[40]
associated with TNF-related apoptosis-inducing ligand .
The effect of Amuc_1100
Another protein from Akk is Amuc_1100, which was widely studied and purified from the outer membrane
of Akk. Amuc_1100 was isolated and identified for the first time in 2017, and it was demonstrated to
[20]
improve the metabolism of obese and diabetic mice . The study investigated the potential mechanism of
the protective role of Amuc_1100, and confirmed that Amuc_1100 was associated with the formation of
[20]
Akk pili and was capable of interacting directly with TLR2. Activated TLR2 increased the expression of tight
junction protein between IECs, and enhanced the anti-apoptosis ability of IECs mediated by
phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway through myeloid differentiation factor
88 (MyD88). Furthermore, it was also found that Amuc_1100 and LPS from Akk all bound TLR2 or TLR4
on peripheral blood mononuclear cells (PBMCs) and activated the NF-κB signaling pathway to produce
[86]
high levels of IL-10, thereby regulating the host immune response . In addition, another study in 2020
further investigated the mechanism of Amuc_1100 in intestinal-related diseases, which found that
pasteurized Akk or Amuc_1100 can reduce the infiltration of pro-inflammatory macrophages and CTL in
the spleen and MLN of mice with colitis, reduce histological damage in the proximal colon, and alleviate
[21]
colitis . In addition, it was found that pasteurized Akk or Amuc_1100 attenuated DNA damage, reduced
apoptosis, and abnormal proliferation in colonic epithelial cells of colitis-associated CRC mice induced by
AOM/DSS. Moreover, Akk or Amuc_1100 significantly increased the number of CTL in MLN and inhibited
the expression of PD-1 on pro-inflammatory macrophages and CTL of MLN and spleen , which effectively
[21]
increased the immune effect of the host against CRC. Furthermore, a study in 2021 found that Amuc_1100
can increase the expression of aryl hydrocarbon receptor (AhR)-targeted genes such as IL-10 and CYP1A1
to alleviate colonic inflammation by regulating tryptophan metabolism and activating AhR signaling , and
[100]
this is a novel mechanism by which Amuc_1100 relieved intestinal inflammation. Another study in 2021
found that Amuc_1100 can promote the expression of 5-hydroxytryptamine (5-HT) synthesis rate-limiting
enzyme Tph1 and reduce the expression of 5-HT reuptake transporter (SERT) in Caco-2 cells through the
direct interaction with TLR2, thus improving the biosynthesis and level of 5-HT. As 5-HT is a
neurotransmitter and an important signal molecule for regulating gastrointestinal function, Amuc_1100 can
improve the gastrointestinal peristalsis function of mice by regulating the biosynthesis of 5-HT . Although
[101]
there is no research about the role of Amuc_1100 in IBS, we still infer from this research that Amuc_1100
may have the potential to improve IBS, and this effect may be related to 5-HT.

The effect of Amuc_2172
Amuc_2172 is a newly discovered protein derived from Akk, which is a probiotic enzyme secreted by
bacteria that can improve the function of host cells and has been shown to modulate the tumor immune
microenvironment and thus inhibit a variety of CRC models and other tumor models such as melanoma.
The researchers used proteases to identify Amuc_2172 as a protein from AmEVs. The mechanism of its
tumorigenesis inhibition is that Amuc_2172, as a prokaryotic-derived acetyltransferase, can enter colorectal
cells via macropinocytosis and acetylate the Lys14 site on histone H3 of the HSP70 gene, thus promoting
HSP70 secretion, activating CTLs, and promoting IFN-γ expression to play a role of tumor-killing . The
[4]
application of macrophage membrane-coated Amuc_2172 nanoparticles can promote the targeted delivery
of Amuc_2172 to tumor cells, thus enhancing its antitumor effect. Importantly, it was found that
Amuc_1100 protein was not detected in AmEVs and that Amuc_2172 had more potential to activate CTL