Gut Microbiota‐Derived 3‐Hydroxybutyrate Blocks GPR43‐Mediated IL6 Signaling to Ameliorate Radiation Proctopathy

Author:

Ge Zhenhuang1,Chen Chun23,Chen Junyi1,Jiang Zhou1,Chen Lingming4,Wei Yingqi2,Chen Haiyang5,He Lei67,Zou Yi1,Long Xiaoxuan1,Zhan Hongyu1,Wang Huaiming28,Wang Hui28,Lu Yongjun1ORCID

Affiliation:

1. Run Ze Laboratory for Gastrointestinal Microbiome Study, School of Life Sciences Sun Yat‐sen University Guangzhou 510275 China

2. Department of Colorectal Surgery, The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 China

3. Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University Shanghai 201620 China

4. School of Medical Technology Guangdong Medical University Dongguan 523808 China

5. Department of Radiation Oncology, The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 China

6. Affiliated Cancer Hospital & Institute of Guangzhou Medical University Guangzhou 510095 China

7. Key Laboratory for Cell Homeostasis Cancer Research of Guangdong Higher Education Institutes Guangzhou 510095 China

8. Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases Supported by National Key Clinical Discipline Guangzhou 510655 China

Abstract

AbstractRadiation proctopathy (RP) is a common complication of radiotherapy for pelvic malignancies with high incidence. RP accompanies by microbial dysbiosis. However, how the gut microbiota affects the disease remains unclear. Here, metabolomics reveals that the fecal and serous concentrations of microbiota‐derived 3‐hydroxybutyrate (3HB) are significantly reduced in RP mice and radiotherapeutic patients. Moreover, the concentration of 3HB is negatively associated with the expression of proinflammatory IL6 that is increased along with the severity of radiation damage. 3HB treatment significantly downregulates IL6 expression and alleviates IL6‐mediated radiation damage. Irradiated cell‐fecal microbiota co‐culture experiments and in vivo assays show that such a radioprotection of 3HB is mediated by GPR43. Microbiome analysis reveals that radiation leads to a distinct bacterial community compared to untreated controls, in which Akkermansia muciniphila is significantly reduced in RP mice and radiotherapeutic patients and is associated with lower 3HB concentration. Gavage of A. muciniphila significantly increases 3HB concentration, downregulates GPR43 and IL6 expression, and ameliorates radiation damage. Collectively, these results demonstrate that the gut microbiota, including A. muciniphila, induce higher concentrations of 3HB to block GPR43‐mediated IL6 signaling, thereby conferring radioprotection. The findings reveal a novel implication of the gut‐immune axis in radiation pathophysiology, with potential therapeutic applications.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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