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Original research
Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists
  1. Xiaokui Huo1,2,
  2. Dawei Li1,3,
  3. Fan Wu1,2,
  4. Shenghui Li4,
  5. Yanling Qiao1,2,
  6. Chao Wang1,
  7. Yan Wang1,
  8. Changjiang Zhou5,
  9. Liqun Sun5,
  10. Zhilin Luan1,
  11. Qiulong Yan1,
  12. Jiayue Wang1,2,
  13. Yu Zhang1,2,
  14. Ting Zhao1,2,
  15. Yue An2,
  16. Baojing Zhang1,
  17. Xiangge Tian1,2,
  18. Zhenlong Yu1,
  19. Xiaochi Ma1,2
  1. 1 Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
  2. 2 Second Affiliated Hospital of Dalian Medical University, Dalian, China
  3. 3 First Affiliated Hospital of Dalian Medical University, Dalian, China
  4. 4 College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
  5. 5 Dalian University Affiliated Xinhua Hospital, Dalian, China
  1. Correspondence to Professor Xiaochi Ma, Dalian Medical University, Dalian, China; maxc1978{at}163.com; Chao Wang, Dalian Medical University, Dalian, China; wach_edu{at}sina.com

Abstract

Objective Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice.

Design Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo.

Results The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1–F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice.

Conclusion This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.

  • Intestinal fungus
  • inflammatory bowel disease
  • Candida metapsilosisM2006B
  • FXR
  • secondary metabolite

Data availability statement

The whole-metagenome shotgun sequencing data of human faeces and the whole-genome sequences of cultivated human intestinal fungi were deposited in the China National GeneBank database under the accession nos. CNP0001845 (IBD patients), CNP0001821 (healthy subjects) and CNP0001822 (whole-genomes). The datasets generated and analysed in this study are available from the corresponding author on reasonable request.

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Data availability statement

The whole-metagenome shotgun sequencing data of human faeces and the whole-genome sequences of cultivated human intestinal fungi were deposited in the China National GeneBank database under the accession nos. CNP0001845 (IBD patients), CNP0001821 (healthy subjects) and CNP0001822 (whole-genomes). The datasets generated and analysed in this study are available from the corresponding author on reasonable request.

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Footnotes

  • XH, DL, FW and SL contributed equally.

  • Contributors XH and FW contributed toward the animal studies and wrote the manuscript. DL, XT, JW and ZY investigated the metabolites. YW, YQ, ZL, TZ and YZ participated in the inflammation evaluation experiments. SL and QY analysed and interpreted data. CZ, LS, YZ, YA, BZ and XM collected fresh human stools. CW and XM conceived and designed the experiments, interpreted the data and wrote the manuscript. XM acts as guarantor for the present study. All authors discussed the results and approved the final manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China (81930112 and 81872970), the Dalian Science and Technology Leading Talents Project (2019RD15, 2020RJ09), the Distinguished Professor of Liaoning Province (XLYC2002008), the Liaoning Provincial Natural Science Foundation (20180550761), and the Liaoning Revitalisation Talents Programme (XLYC1907017).

  • Competing interests The authors were granted patents related to the preparation and use of the novel fungus (Candida metapsilosis M2006B and GDMCC 61628) and metabolites (F1–F7) as probiotics and prebiotics, respectively.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.