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. 2023 Dec;15(2):2293312.
doi: 10.1080/19490976.2023.2293312. Epub 2023 Dec 12.

Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid

Kai-Yue He  1 , Xin-Yuan Lei  1 , Dan-Hui Wu  1 , Lei Zhang  1 , Jun-Qi Li  1 , Qiu-Tong Li  1 , Wei-Tao Yin  1 , Zi-Long Zhao  1 , Huai Liu  1 , Xiong-Yan Xiang  1 , Ling-Jun Zhu  1 , Cui-Yun Cui  2 , Ke-Ke Wang  3 , Jin-Hua Wang  3 , Lin Lv  4 , Qian-Hui Sun  1 , Guo-Long Liu  4 , Zhi-Xiang Xu  1 , Yong-Ping Jian  1
Affiliations

Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid

Kai-Yue He et al. Gut Microbes. 2023 Dec.

Abstract

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

Keywords: Irradiation-induced enteritis; akkermansia muciniphila; histone acetylation; intestinal epithelial barrier; metformin; propionic acid.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Abundance of A. muciniphila is reduced in stool from cervical cancer patients with radiotherapy.
Figure 2.
Figure 2.
Supplement of A. muciniphila mitigates IR-induced intestinal damage.
Figure 3.
Figure 3.
Viable A. muciniphila alleviates IR-induced intestinal damage.
Figure 4.
Figure 4.
A. muciniphila alleviates IR-induced intestinal damage by secreting propionic acid.
Figure 5.
Figure 5.
Propionic acid promotes the expression of occludin, ZO-1, and MUC2 through enhancing histone acetylation.
Figure 6.
Figure 6.
A. muciniphila is necessary and sufficient for metformin-induced radioprotection in intestine.
Figure 7.
Figure 7.
Metformin enhances intestinal barrier function.
See this image and copyright information in PMC

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