Enteric fungi protect against intestinal ischemia-reperfusion injury via inhibiting the SAA1-GSDMD pathway

Yihui Chen; Ben Han; Xu Guan; Guangsheng Du; Baifa Sheng; Xiaoqi Tang; Quanchao Zhang; Huichao Xie; Xianhong Jiang; Qianshan Tan; Shuaishuai Chen; Jian Wang; Wei Chen; Weidong Xiao

doi:10.1016/j.jare.2023.09.008

Enteric fungi protect against intestinal ischemia-reperfusion injury via inhibiting the SAA1-GSDMD pathway

J Adv Res. 2023 Sep 16:S2090-1232(23)00258-8. doi: 10.1016/j.jare.2023.09.008. Online ahead of print.

Authors

Yihui Chen¹, Ben Han², Xu Guan³, Guangsheng Du¹, Baifa Sheng⁴, Xiaoqi Tang⁵, Quanchao Zhang³, Huichao Xie¹, Xianhong Jiang⁶, Qianshan Tan¹, Shuaishuai Chen¹, Jian Wang⁷, Wei Chen⁸, Weidong Xiao⁹

Affiliations

¹ Department of General Surgery, Xinqiao Hospital, Army Medical University(Third Military Medical University), Chongqing 400037, China.
² Department of Nutrition, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
³ Department of Nephrology, Army Medical University, Chongqing, 400037, China.
⁴ Department of General surgery, The General Hospital of Western Theater Command, Chengdu, Sichuan Province, 610036, China.
⁵ Department of Clinical Laboratory Medicine, Southwest Hospital, Army Medical University, Chongqing 400037, China.
⁶ Department of Laboratory Animal Science, College of Basic Medical Science, Army Medical University, Chongqing 400038, China.
⁷ Department of Nutrition, Xinqiao Hospital, Army Medical University, Chongqing 400037, China. Electronic address: wj_xqhospital@163.com.
⁸ Department of Nosocomial Infection Management, Xinqiao Hospital, Army Medical University, Chongqing 400037, China. Electronic address: chongqingchenwei@126.com.
⁹ Department of General Surgery, Xinqiao Hospital, Army Medical University(Third Military Medical University), Chongqing 400037, China. Electronic address: xiaoweidong@tmmu.edu.cn.

PMID: 37717911
DOI: 10.1016/j.jare.2023.09.008

Abstract

Introduction: Prophylactic antifungal therapy has been widely used for critical patients, but it has failed to improve patient prognosis and has become a hot topic. This may be related to disruption of fungal homeostasis, but the mechanism of fungi action is not clear. As a common pathway in critical patients, intestinal ischemia-reperfusion (IIR) injury is fatal and regulated by gut microbiota. However, the exact role of enteric fungi in IIR injury remains unclear.

Objectives: This is a clinical study that aims to provide new perspectives in clarifying the underlying mechanism of IIR injury and propose potential strategies that could be relevant for the prevention and treatment of IIR injury in the near future.

Methods: ITS sequencing was performed to detect the changes in fungi before and after IIR injury. The composition of enteric fungi was altered by pretreatment with single-fungal strains, fluconazole and mannan, respectively. Intestinal morphology and function impairment were evaluated in the IIR injury mouse model. Intestinal epithelial MODE-K cells and macrophage RAW264.7 cells were cultured for in vitro tests.

Results: Fecal fungi diversity revealed the obvious alteration in IIR patients and mice, accompanied by intestinal epithelial barrier dysfunction. Fungal colonization and mannan supplementation could reverse intestinal morphology and function impairment that were exacerbated by fluconazole via inhibiting the expression of SAA1 from macrophages and decreasing pyroptosis of intestinal epithelial cells. Clodronate liposomes were used to deplete the number of macrophages, and it was demonstrated that the protective effect of mannan was dependent on macrophage involvement.

Conclusion: This finding firstly validates that enteric fungi play a crucial role in IIR injury. Preventive antifungal treatment should consider damaging fungal balance. This study provides a novel clue to clarify the role of enteric fungi in maintaining intestinal homeostasis.

Keywords: Antifungal therapy; Enteric fungi; Intestinal ischemia–reperfusion injury; Mannan; Pyroptosis.