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Jiang et al. Microbiome Res Rep 2024;3:47 https://dx.doi.org/10.20517/mrr.2024.12 Page 5 of 20

[28]
significant reduction in Akk . Furthermore, extracellular vesicles of Akk (AmEV) were significantly
[14]
reduced in the intestine of mice with DSS-induced colitis .
In addition to these correlative studies, researchers have also attempted interventional studies with Akk or
its components. The application of Akk reduced the histopathological score of colitis mice by increasing the
thickness of the colonic mucus layer, which proved that Akk played a positive role in improving intestinal
[29]
barrier function and reducing intestinal inflammation . Furthermore, a study in 2020 showed that
Amuc_1100, the purified membrane proteins of Akk, attenuated DSS-induced colitis by reducing colon-
[21]
infiltrating macrophages and cytotoxic T lymphocytes (CTLs) . In addition, Bian et al. in 2019
demonstrated that the application of Akk improved intestinal inflammation in DSS-induced mice. It
reduced the levels of inflammatory cytokines such as TNF-α, IL-6, IL-1α, MIP-1A, IL-12A, and G-CSF,
while altering the intestinal microbiota of mice . In addition, in vitro treatment of colonic epithelial cells
[30]
with AmEVs reduced the production of IL-6, and oral administration of AmEV to mice alleviated DSS-
induced colitis phenotypes such as inflammatory cell infiltration, weight loss, and shortened colonic
length . Studies exploring the anti-inflammatory properties of two Akk strains against DSS-induced
[14]
[29]
chronic colitis in mice also obtained similar results .
Akk and intestinal tumors
Many studies have shown that the risk of developing CRC is two to four times higher in patients with IBD
than in normal subjects . The IBD-CRC model can destabilize the diversity of the intestinal microbiota .
[31]
[32]
According to a recent study, intestinal microbiota may be a driver of CRC development. The study proposes
a “driver-passenger” model in which the original gut bacteria act as drivers to attack the gut, causing DNA
damage and thus inducing CRC. Tumorigenesis causes changes in intestinal microbiota, which creates
[29]
favorable conditions for the propagation of “passenger” bacteria . In this context, the application of
probiotics may be a potential strategy to combat intestinal tumors [Figure 2]. In 2013, Grivennikov et al.
suggested that supplementation with Akk could prevent intestinal cancer by attenuating DNA damage and
inhibiting abnormal proliferation of tumor cells . Another study found that vitamin D supplementation
[33]
inhibited the development and progression of CRC and increased the integrity of the colonic barrier and the
abundance of Akk , which suggested that Akk may be a potential probiotic for the treatment of CRC.
[34]

Further studies revealed that Akk abundance was significantly reduced in the feces of patients and mice with
[35]
CRC . In addition, Akk was found to actively promote the response to chemotherapeutic agents and
[36]
immune checkpoint inhibitors in tumors . In 2017, researchers conducted a trial of 249 patients treated
[37]
with immune checkpoint inhibitor programmed cell death protein 1 (PD-1) antibodies , 69 of whom were
also treated with broad-spectrum antibiotics. It was observed that in the group of patients treated with
antibiotics, there was a higher probability of tumor recurrence and a shorter survival time. It was found that
the presence of Akk was associated with more effective immunotherapy in patients not treated with
antibiotics. To verify this correlation, the researchers transplanted feces from patients with good
immunotherapeutic effects into germ-free mice and found that the immune effects were higher than those
of non-transplanted mice. In mice given Akk by gavage, IL-12 levels increased and promoted the
recruitment of T lymphocytes to mouse tumors, which in turn restored the efficacy of the anti-PD-1
antibody, and the tumors almost completely disappeared . This study demonstrates for the first time the
[37]
role of Akk in the tumor immune response. In addition, Akk was significantly increased in individuals
treated with FOLFOX (oxaliplatin + fluorouracil + calcium folinate), the first-line chemotherapy regimen
[38]
for colon cancer treatment in clinical practice, and Akk was positively correlated with treatment efficacy .
In addition, it was found that Akk can inhibit tryptophan metabolism by inhibiting the AhR/β-catenin
signaling pathway, so as to inhibit the progress of CRC .
[39]