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Figure 1. Timeline of significant research milestones in Akk. Akk was first isolated, identified, and named in 2004. In the first five years,
there were few reports on it. After 2010, it gradually received more attention, and research on the relationship between Akk and human
health and diseases increased significantly. Since 2017, more and more research has focused on the mechanism of interaction between
Akk and the host to enhance disease management, with particular attention to the proteins and extracellular vesicles of Akk. Created
with BioRender.com. Akk: Akkermansia muciniphila.

studies observed that Akk affects the expression of genes involved in host lipid metabolism and epigenetic
activation, reduces the risk of gastrointestinal diseases , and that the application of Akk alters the
[15]
metabolic characteristics of nonalcoholic fatty liver disease (NAFLD) and obesity, thereby alleviating the
disease. In 2015, a study using a colorectal cancer (CRC) mouse model revealed that Akk colonization
significantly reduced the number of intestinal tumors, goblet cell density, and mucus layer thickness
compared to the control group, suggesting that Akk treatment plays a beneficial role in suppressing
[17]
intestinal tumors . A 2016 study first identified the outer membrane proteins of Akk, and another study
[16]
found that Akk is involved in the anti-inflammatory effects of the intestinal microbiota in constipated
irritable bowel syndrome (IBS) . In 2017, Guo et al. used whole-genome shotgun sequencing to isolate 39
[18]
new Akk strains from human and mouse fecal samples, followed by sequencing of the total DNA of all
[19]
microbes, assembly and annotation to identify 5,644 unique proteins . Another study found that purified
membrane protein Amuc_1100 isolated from Akk improved metabolism in diabetic and obese mice . In
[20]
the following five years, an increasing number of studies began to focus on the mechanisms by which Akk
interacted with the host to ameliorate disease, with particular attention to intestinal-related diseases, as well
as proteins and extracellular vesicles of Akk. In 2020, Wang et al. demonstrated that Akk or its purified
membrane protein Amuc_1100 could inhibit the occurrence of CRC associated with colitis by regulating
CD8 T cells . Furthermore, the researchers recently found a new protein of Akk named Amuc_2172,
+
[21]
which was derived from extracellular vesicles of Akk, can serve as acetyltransferase to inhibit the
development of CRC by reprogramming the tumor microenvironment, and was also effective in other
[4]
tumor models, such as melanoma . As Amuc_2172 is an enzyme secreted by bacteria that can improve the
function of host cells and alleviate the disease process of the host, we name it a probiotic enzyme.

THE THERAPEUTIC POTENTIAL OF AKK IN INTESTINAL-RELATED DISEASES
Akk and intestinal inflammation
Inflammatory bowel disease (IBD) is influenced by a complex interaction between immune, genetic,
environmental factors, and the intestinal microbiota. Multiple studies have shown that intestinal
inflammation is associated with changes in the abundance of Akk, most of which reveal that Akk may play a
beneficial role in controlling intestinal inflammation [Figure 2], as the occurrence of intestinal
inflammation is often accompanied by the reduction of Akk, but some findings are not completely