About the beneficial human fungal microbiome in the gut

Good news! Not to be confused with the more familiar bacterial microbiome!

"... In experiments in mice, a fungus that lives in our digestive system helped fend off non-alcoholic fatty liver disease.

Before the team could investigate how gut-dwelling fungi might be beneficial, they had to grow them—a notoriously tricky task. So they turned to FiChips, small devices that mimic the intestinal environment. That allowed them to culture 161 fungi from more than 2100 strains present in human fecal samples. And one—Fusarium foetens—popped up in gut microbiome datasets from around the world, suggesting it might be a symbiotic partner.

To test whether the fungus was actually helpful, the researchers fed mice a high-fat, choline-deficient diet, which gives the animals a liver condition similar to metabolic dysfunction-associated steatohepatitis (MASH). A single infusion of the animals’ digestive tracts with F. foetens notably reduced their symptoms, effects which largely stemmed from a single compound called FF-C1 produced by the fungus.

“The findings … point to the fungal microbiome as a rich, untapped source of compounds that may have therapeutic potential,” ..."

From the editor's summary and abstract:

"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. ...

Structured Abstract

INTRODUCTION

... 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.  ...

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."

ScienceAdviser

A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite–CerS6–ceramide axis (no public access)

Identification of gut fungi–mediated regulation of host metabolic disease.