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Page 12 of 20 Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12

microbiota homeostasis is also an important part of the role of Akk per se.

In addition to directly inhibiting or promoting other bacteria, Akk also plays a beneficial role in intestinal-
related diseases by inhibiting the toxicity of harmful substances or promoting the effect of beneficial
substances [82,83,97] . Increasing evidence showed that some unabsorbed food additives, including the emulsifier
carboxymethyl cellulose (CMC) and polysorbate 80 (P80), can cause the destruction of the microbial
community, such as the depletion of Akk and the following chronic intestinal inflammation. Supplementing
exogenous Akk to mice can prevent the harmful effects of emulsifiers, such as hyper appetite, weight gain,
and blood glucose abnormalities. The administration of Akk also alleviated the slight intestinal
inflammation induced by CMC and P80 . Additionally, Akk supplementation can protect the intestinal
[82]
[82]
microbiota from the damaging effects of CMC and P80 . It is noteworthy that the study discovered that
CMC and P80 changed inflammation-related gene expression in the colon, which was prevented by Akk.
Moreover, it has been reported recently that the colonization of Akk. in the intestine can increase the
[97]
expression of intestinal cAMP reactive element-binding protein H (CREBH), thus promoting the
production of intestinal barrier tight junction protein. In addition, Akk. promotes the binding of CREBH to
microRNA-143/145 (miR-143/145), thus promoting intestinal epithelial cell (IEC) regeneration and wound
repair through insulin-like growth factor (IGF) and IGF-BP 5 signal transduction . The Amuc_1100
[97]
[97]
secreted by Akk can also cover this function of Akk cells in IECs . Another study designed a peptide of 9
amino acids named D3, which is a novel drug candidate for inhibiting diet-induced obesity as a non-toxic
and bioactive peptide. It was found that after administration of D3, the abundance of intestinal Akk in mice
increased by 100 times, which inhibited lipid absorption by downregulating the expression of CD36, thus
reducing diet-induced obesity .
[83]

The effect of AmEVs
The extracellular vesicles derived from probiotics are also beneficial in intestinal-related diseases [84,98] , and
AmEVs showed a similar effect as Akk in colitis mouse model induced by DSS . AmEVs significantly
[57]
decreased in the feces of obese patients and DSS-induced colitis mice. The application of AmEVs reduced
the weight gain and fat content induced by HFD, and lowered the production of IL-6 in colon epithelial
cells. Moreover, oral gavage of AmEVs reduced DSS-induced colitis by alleviating weight loss, colon length
reduction, and inflammatory cell infiltration. The underlying mechanism is that the administration of
[84]
AmEVs significantly reduced the expression of TLR4 and activated TLR2 in the colon of obese mice . On
the other hand, AmEVs have been found to enhance intercellular tight junctions by upregulating the
expression of occludin, ZO, and claudin-5. In liver diseases, AmEVs prevented chemical-induced liver
injury in mice via normalizing fecal bacterial composition, reducing intestinal permeability, and inhibiting
[6]
inflammatory reactions . Chelakkot et al. found that the administration of AmEVs reduced weight gain
and improved glucose tolerance in HFD-induced diabetic mice and illustrated the underscoring
[57]
mechanism that AmEVs improved intestinal barrier integrity in HFD-induced diabetic mice by inducing
adenylate-activated protein kinase (AMPK) phosphorylation, which increased the expression of tight
junction proteins in IECs. However, it is noteworthy that the administration of AmEVs reduced the daily
food intake of HFD mice, which may be another important factor in improving metabolism besides its own
direct effect. In addition, the dose of AmEVs in the experiment is not clear. Despite the aforementioned
beneficial effects of AmEVs in intestinal related disease, the components in AmEVs remain unclear and
whether these substances mediate the function of AmEVs in intestinal related disease requires further study.

The effect of Amuc_1434
Recent studies have focused on the mechanism of specific components from Akk, such as various proteins,
in intestinal-related diseases. It was found that Akk can directly promote apoptosis of tumor cells, and this
effect was associated with Amuc_1434, a protein from AmEV. Amuc_1434 binds with normal colon cells