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

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
• propionic acid
• intestinal epithelial barrier
• metformin
• histone acetylation

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 82020108024 and 82200596), the National Key Research and Development Program of China (2023YFE0109800), the China Postdoctoral Science Foundation (No. 2022M721014) and the Scientific and Technological Research Project of Henan Province (No. 232102311034).

Disclosure statement

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

Authors’ contributions

Yong-Ping Jian, Kai-Yue He, Xin-Yuan Lei, and Dan-Hui Wu designed the study, performed the experiments, and wrote the manuscript. Lei Zhang, Jun-Qi Li, Qiu-Tong Li, Wei-Tao Yin, Zi-Long Zhao, Huai Liu, Xiong-Yan Xiang, Ling-Jun Zhu, Cui-Yun Cui, Qian-Hui Sun, and Ke-Ke Wang performed the experiments. Zhi-Xiang Xu, Jin-Hua Wang, Lin Lv, and Guo-Long Liu contributed to the conception and writing. All authors read and approved the final manuscript.

Availability of data and materials

The authors declare that all the data supporting our findings in the study are available within the paper and its supplementary information files.

Abbreviations

A. muciniphila	=	Akkermansia muciniphila
Abx	=	microbiota-depleted
COX-2	=	cyclooxygenase-2
GRP	=	G-protein coupled receptor
IBD	=	inflammatory bowel disease
IHC	=	immunohistochemistry
IR	=	irradiation
MUC2	=	mucin 2
PAS	=	Periodic Acid-Schiff
SCFAs	=	short-chain fatty acids
TLR-2	=	toll like receptor 2
ZO-1	=	zonula occludens-1

Ethical approval and consent to participate

Protocols for animal usage were approved by the institutional animal care and use committee (IACUC) at Henan University, China. All animal experiments were conducted on the basis of the institutional guidelines, and were approved by the Laboratory Animal Center of Henan University. Collection and usage of patients’ feces were approved by the ethical committee of Jiangsu Cancer Institute and Henan University.

Consent for publication

All authors consent to submit and publish this article.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2293312.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82020108024 and 82200596), the National Key Research and Development Program of China (2023YFE0109800), the China Postdoctoral Science Foundation (No. 2022M721014) and the Scientific and Technological Research Project of Henan Province (No. 232102311034).