Debaryomyces is enriched in Crohn’s disease intestinal tissue and impairs healing in mice

• Published in: Science (American Association for the Advancement of Science) Vol. 371; no. 6534; pp. 1154 - 1159
• Main Authors: Jain, Umang, Ver Heul, Aaron M., Xiong, Shanshan, Gregory, Martin H., Demers, Elora G., Kern, Justin T., Lai, Chin-Wen, Muegge, Brian D., Barisas, Derek A. G., Leal-Ekman, J. Steven, Deepak, Parakkal, Ciorba, Matthew A., Liu, Ta-Chiang, Hogan, Deborah A., Debbas, Philip, Braun, Jonathan, McGovern, Dermot P. B., Underhill, David M., Stappenbeck, Thaddeus S.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12.03.2021
• Subjects: Amphotericin B - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Antifungal Agents - pharmacology; Cell culture; Chemokine CCL5 - metabolism; Colon - microbiology; Colon - pathology; Crohn Disease - immunology; Crohn Disease - microbiology; Crohn Disease - pathology; Crohn's disease; Debaryomyces - growth & development; Debaryomyces - isolation & purification; Debaryomyces - physiology; Debaryomyces hansenii; Digestive system; Female; Food industry; Food processing industry; Fungi; Gastrointestinal Microbiome; Gastrointestinal tract; Germ-Free Life; Gnotobiotic; Healing; Human subjects; Humans; Ileum - microbiology; Ileum - pathology; Inflammation; Inflammatory bowel diseases; Injuries; Interferon; Interferon Type I - metabolism; Intestinal microflora; Intestinal Mucosa - immunology; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine; Macrophages; Macrophages - immunology; Macrophages - microbiology; Male; Meat; Meat products; Mice; Mice, Inbred C57BL; Microbiota; Mucosa; Prokaryotes; Ripening; Salinity tolerance; Symbiosis; Tissues; Ulcerative colitis; Wound healing; Wounds
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abd0919

The gut microbiota includes not only prokaryotes, viruses, protists, and occasionally helminths, but also fungi. The role that fungi play in this symbiosis has long been overlooked. While investigating alterations to the gut microbiota in mice with mucosal damage and human subjects with Crohn's disease, Jain et al. discovered the fungus Debaryomyces hansenii localized to wounds in inflamed mucosal tissue (see the Perspective by Chiaro and Round). Impaired healing was associated with antibiotic treatment, overgrowth of the fungus, and subsequent induction of a type I interferon–CCL5 axis by macrophages. The fungus was observed within macrophages. Such persistent injury stimulus is a hallmark of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. It is not known whether this salt-tolerant fungus is a natural symbiont, but it is used in the food industry for surface ripening of cheese and meat products. Science , this issue p. 1154 ; see also p. 1102 A fungus associated with human intestinal ulcers impairs wound healing via type 1 interferon pathways. Alterations of the mycobiota composition associated with Crohn’s disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch’s postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell–specific type 1 interferon–CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.