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A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis

Cellular & Molecular Immunology volume 20, pages 1156–1170 (2023)Cite this article

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Abstract

The gut microbiome is recognized as a key modulator of sepsis development. However, the contribution of the gut mycobiome to sepsis development is still not fully understood. Here, we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis, and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture (CLP)-challenged mice and Escherichia coli-challenged pigs. Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate (PPA) enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis. Mechanistically, PPA directly binds to sirtuin 2 (SIRT2) and increases reactive oxygen species (ROS) production for eventual bacterial clearance. Importantly, PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients. Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.

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Funding

Funding

This study was supported by the National Natural Science Foundation of China (32271230 and 32071124) to PC; the NIH Grant (P30DK120515) to BS; the National Natural Science Foundation of China (82270581) to YC; the National Key R&D Project of China (2018YFC0115301), the National Natural Science Foundation of China (81974070), the Shenzhen Science and Technology Program (JCYJ20210324131010027) and the Research Foundation of Shenzhen Hospital of Southern Medical University (PT2018GZR10) to WG.

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Author notes

  1. These authors contributed equally: Peng Gu, Ruofan Liu, Qin Yang, Li Xie, Rongjuan Wei.

Authors and Affiliations

  1. Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, China

    Peng Gu, Wei Gong & Ye Chen

  2. Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Peng Gu, Ruofan Liu, Qin Yang, Li Xie, Rongjuan Wei, Jiaxin Li, Fengyi Mei, Tao Chen, Yong Jiang & Peng Chen

  3. Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, China

    Qin Yang

  4. Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Zhenhua Zeng

  5. Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Yan He, Hongwei Zhou & Peng Chen

  6. Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China

    Hongjuan Peng

  7. Department of Environment and Biosciences, School of Business, Innovation and Sustainability, Halmstad University, Halmstad, Sweden

    Kutty Selva Nandakumar

  8. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Huikuan Chu

  9. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Bernd Schnabl

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  1. Peng Gu
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Contributions

PG, RL, QY, LX, RW, FM and TC performed the experiments and analyzed the data; JL, ZZ, YH and HZ collected all the clinical data; HP, HC and YJ provided technical support; KSN revised the manuscript; WG, YC, BS, and PC designed the study, interpreted the data, drafted and edited the manuscript, and supervised the study.

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Correspondence to Wei Gong, Ye Chen or Peng Chen.

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Gu, P., Liu, R., Yang, Q. et al. A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis. Cell Mol Immunol 20, 1156–1170 (2023). https://doi.org/10.1038/s41423-023-01070-5

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