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Page 8 of 20 Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12

antimicrobial peptide, as well as lowering serum endotoxin levels and islet Toll-like receptor (TLR)
[53]
expression, which suggested that Akk plays a protective role in T1D . The underlying mechanism may be
that Akk will increase the production of anti-inflammatory cytokines in pancreatic lymph nodes and
enhance the recruitment of Tregs in the pancreas, which will eventually delay the development of T1D [54,55] .
Akk can also promote mucus production and increase the expression of antimicrobial peptides, reduce the
level of serum endotoxin and the expression of islet TLRs, promote immune regulation, and delay the
development of diabetes .
[53]

[56]
The relative abundance of Akk is also significantly reduced during the development of type II diabetes. In
addition, a study found that the feces of healthy individuals contained more AmEV compared to those with
type II diabetes . The purified membrane protein Amuc_1100 from Akk also improved metabolic
[57]
[20]
disorders in obese and diabetic mice . These studies provide strong evidence that Akk regulates the
progress of diabetes. Furthermore, the abundance of Akk was also reduced in high-fat diet (HFD) mice and
the metabolic disorders of HFD mice could be reversed through the supplementation of Akk [57,58] . In 2013, a
study found that gavage of live Akk to HFD-induced obese mice reduced the level of plasma LPS by
increasing intestinal barrier function, lowered the insulin resistance index, and normalized the adipose
tissue marker CD11c, whereas heat-inactivated Akk could not exert such effects . Yet another study in
[20]
[58]
2017 found that pasteurized Akk also significantly improved insulin sensitivity indices and that mice treated
with pasteurized strains showed more significant reductions in body weight, plasma lipids, markers of
insulin resistance, and blood inflammatory markers, compared with live bacteria . There are many reasons
[20]
that may lead to the opposite results; for example, the amounts of Akk used in the two experiments are
different, and the medium used for bacterial culture is different. In addition, autoclaving Akk eliminated its
beneficial effects. However, recent research [59,60] showed that pasteurizing probiotics at 70 °C for 30 min,
which is a less extreme treatment method to limit the degeneration of their cell components, can partially or
completely retain its beneficial effects . We speculate that the less intense heat inactivation, such as
[20]
pasteurization, allows Akk to become more stable while retaining some of their beneficial properties, but the
dead bacteria after complete thermal inactivation do not have this function.

Furthermore, Akk significantly reduced adipose inflammation by inducing more Foxp3 regulatory T cells
+
[62]
[61]
in obese mice , Akk was significantly increased after treatment with metformin in obesity mouse model ,
[63]
and higher levels of Akk in patients contributed to the efficacy of metformin . It has been demonstrated
that intestinal microbes such as Akk may modulate the efficacy of metformin through the production of
[64]
SCFAs . In 2019, Depommier et al. conducted a pilot study on the administration of Akk in overweight
and obese human volunteers and found that oral administration of Akk for 3 months was completely safe
and well tolerated by all volunteers. Akk significantly enhanced insulin sensitivity in obese volunteer
patients, downregulated total cholesterol levels, and even improved liver tissue lesions, and the volunteers
experienced substantial weight loss . Furthermore, Akk has been shown to reduce gene expression
[65]
involved in adipocyte differentiation and lipid oxidation in mouse mesenteric adipose tissue, suggesting its
role in the regulation of lipid metabolism [Figure 2].
[58]

Akk and the “intestine-hepatic axis”
The liver is the detoxification organ of the body and is closely related to the intestine through the hepatic
portal system. Thus, the occurrence of liver diseases such as hepatitis and hepatic steatosis is also associated
with the intestine. The intestinal microbiota plays an important role in the interaction between the intestine
and the liver. When the intestinal barrier is damaged, intestinal pathogenic bacteria and LPS translocate and
enter the liver via the hepatic portal vein. Liver Kupffer cells phagocytose LPS and release cellular
inflammatory factors, which damage liver function . LPS further increases intestinal mucosal permeability,
[66]