2. Academic Validation
  3. Gut mucosal mycobiome profiling in Crohn's disease uncovers an AMP-mediated anti-inflammatory effect of Cladosporium sphaerospermum

Gut mucosal mycobiome profiling in Crohn's disease uncovers an AMP-mediated anti-inflammatory effect of Cladosporium sphaerospermum

  • Nat Metab. 2026 Feb;8(2):389-409. doi: 10.1038/s42255-025-01420-9.
Ziyu Huang # 1 2 3 4,  Yunyun Liu # 5,  Yushan Wu # 6 7 8,  Feng Zhang 1 2 3 4,  Leyi Yu 9,  Shanshan Gao 1 2 10,  Weijie Wen 1 2 3 4,  Guannan Wang 1 2 3 4,  Runping Su 1 2 3 4,  Pei Xia 11,  Qiming Zhou 1 2 3 4,  Yiran Bie 1 2 3 4,  Peishan Hu 1 2 3 4,  Elke Burgermeister 12,  Ping Lan 1 2 3 4 13,  Xiaojian Wu 1 2 3 4 13,  Hu Zhang 14 15 16,  Fen Zhang 17,  Emad M El-Omar 18,  Tao Zuo 19 20 21 22
Affiliations

Affiliations

  • 1 Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.
  • 3 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4 Biomedical Innovation Centre, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 5 Jiangsu Province (Suqian) Hospital, Suqian, China.
  • 6 Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
  • 7 Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China.
  • 8 Lab of Inflammatory Bowel Disease, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
  • 9 School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China.
  • 10 Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, China.
  • 11 Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
  • 12 Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 13 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 14 Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 15 Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 16 Lab of Inflammatory Bowel Disease, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 17 Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China. [email protected].
  • 18 Microbiome Research Centre, St George, Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine, Health, University of New South Wales, Sydney, New South Wales, Australia. [email protected].
  • 19 Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 20 Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China. [email protected].
  • 21 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 22 Biomedical Innovation Centre, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41501528 DOI: 10.1038/s42255-025-01420-9
Abstract

Crohn's disease (CD) is a subtype of inflammatory bowel disease that most commonly affects the terminal ileum and is associated with abnormal gut microbiome composition. However, the fungi of the small bowel mucosa and their metabolic functions, particularly protective ones, remain largely unexplored. We enrolled patients with CD and healthy individuals from three independent cohorts and conducted multi-omics profiling of the ileal mucosal mycobiome and bacteriome, along with the faecal mycobiome, bacteriome and metabolome. We show that compared to a healthy mucosa, the fungus Cladosporium sphaerospermum is remarkably depleted in the mucosa of patients with CD, yet remains unchanged in faeces. Subsequent causality studies reveal that C. sphaerospermum occupies the intestinal crypt niche and counteracts intestinal inflammation partly by adenosine 5'-monophosphate (AMP) production, as demonstrated in mice, in vitro and in Fungal cultures. Mechanistically, C. sphaerospermum upregulates epithelial cell junctions and the Wnt signalling pathway. Our study unveils a mucosa-associated beneficial fungus, suggesting potential novel microbial intervention strategies for CD.

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