2025-05-19 北京大学(PKU)
<関連情報>
- https://newsen.pku.edu.cn/news_events/news/research/14940.html
- https://www.science.org/doi/10.1126/science.adp5540
腸内共生糸状菌が二次代謝産物-CerS6-セラミド軸を介してMASHを改善する A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite–CerS6–ceramide axis
Shuang Zhou, Meng Li, Pengcheng Wang, Chenghao Guo, […] , and Changtao Jiang
Science Published:1 May 2025
DOI:https://doi.org/10.1126/science.adp5540
Editor’s summary
Although fungi are prevalent in the mammalian gut, remarkably little is understood about their role in host metabolic function and disease. Zhou et al. undertook a large-scale survey of fecal and environmental fungi in humans across China (see the Perspective by Hooper and Koh). They identified a filamentous fungus called Fusarium foetens that negatively associated with the human metabolic disease phenotype metabolic dysfunction–associated steatohepatitis. Experiments in mice using cultured isolates of this species revealed that it produced diverse metabolites, including a small naphthoquinone molecule that inhibited the mammalian enzyme ceramide synthase. The metabolite and the presence of the fungus reduced ceramide accumulation and alleviated fatty liver disease in mice. —Caroline Ash
Structured Abstract
INTRODUCTION
Components of the gut microbiota are known to be associated with human metabolic diseases. Of microbial factors that influence human health, gut bacteria are the most highly relevant for metabolic diseases. Although fungi are increasingly recognized as important members of the gut community, the role of fungal symbionts in host health and diseases and the underlying molecular mechanisms are still unknown. Optimizing culture techniques and medium composition for gut fungi is essential for understanding intestinal microecology and will yield deeper insights into host-gut microbiota cross-talk.
RATIONALE
To identify the role of fungal gut symbionts, we developed a culture method based on in situ fecal environment incubation. We used this system to show that the filamentous fungi Fusarium spp. can acclimate to an anaerobic environment and establish stable colonization in mice. We discovered that this fungus was internationally ubiquitous in sequencing data of human feces. Hence, we investigated whether gut fungi play a role in host disease and particularly in metabolic dysfunction–associated steatohepatitis (MASH) progression in mouse models.
RESULTS
We designed a fungal isolation chip (FiChip)–based optimized in situ cultivation system for gut fungi (FOCUS-G), which helps obtain more unartificial and uncultured fungi. Using FOCUS-G, we systematically isolated 2137 fungal strains from fecal samples of volunteers from five different geographical areas within China. Using oxygen adaptability tests for gut fungal isolates, we characterized Fusarium spp. as a group of intestinal filamentous fungi that can acclimate to the anaerobic conditions that prevail in the colon. An analysis of internal transcribed spacer (ITS) data from global intestinal fungal studies confirmed that Fusarium foetens is commonly found in the gut of various human populations. We showed that the colons of germ-free and specific pathogen–free mice could be colonized by F. foetens with a single oral gavage.
We found that F. foetens gavage improves MASH progression in mice by altering ceramide metabolism through the inhibition of CerS6, a key enzyme in the ceramide biosynthetic pathway. We validated the role of CerS6 in F. foetens–mediated amelioration of MASH in mice by intestinal-specific Cers6 deletion and overexpression.
We used chromatographic analyses to show that F. foetens produces a secondary metabolite, FF-C1, that inhibits CerS6 activity through direct, noncompetitive binding. We showed that FF-C1 improves MASH progression and disease outcome in Cers6fl/fl mice but not in Cers6ΔIE mice.
CONCLUSION
We developed a culture method based on in situ fecal environmental incubation and identified Fusarium spp. as a group of intestinal filamentous fungi that can acclimate to an anaerobic environment. F. foetens colonization reverses MASH progression in mouse models through a secondary metabolite FF-C1, which inhibits intestinal CerS6 to reduce serum levels of ceramides. Collectively, our findings provide a deeper insight into the biology of host-commensal fungi interactions and indicate that a fungal secondary metabolite can influence clinically relevant host metabolic pathways, offering an investigative strategy for improving the therapeutic management of such diseases.
OPEN IN VIEWER
Identification of gut fungi–mediated regulation of host metabolic disease.
Identification of gut fungi is important to clarify their roles in health and disease. (A) FOCUS-G identified Fusarium spp. as symbiotic fungi that can acclimate to anaerobic conditions found in the host colon. (B and C) Intestinal tissue enzyme-activity analysis and bioactive-guided separation showed that F. foetens reverses metabolic dysfunction–associated fatty liver (MAFL)–MASH progression by producing the secondary metabolite FF-C1, which inhibited intestinal CerS6 activity and reduced serum levels of ceramides in mice.
Abstract
The gut microbiota is known to be associated with a variety of human metabolic diseases, including metabolic dysfunction–associated steatohepatitis (MASH). Fungi are increasingly recognized as important members of this community; however, the role of fungal symbionts in metabolic diseases is unknown. We have systematically isolated and characterized gut fungi, identifying Fusarium foetens as an intestinal symbiotic filamentous fungus in mice. F. foetens reverses MASH progression in mouse models through an intestinal ceramide synthetase 6 (CerS6)–ceramide axis. Moreover, we identified FF-C1, a secondary metabolite from F. foetens, as a CerS6 inhibitor that has an endogenous protective effect on MASH progression.
