Biochemical controls: how fungus control host metabolism (Introduction)

by David Turell , Wednesday, May 07, 2025, 17:37 (1 day, 1 hours, 18 min. ago) @ David Turell

A fungus among us:

https://www.science.org/doi/10.1126/science.adx1789?utm_source=sfmc&utm_medium=emai...

"Zhou et al. (1) report a fungal species that resides in the human gut and produces a compound that protects against metabolic disease in mice. The findings point to intestinal fungi as a potentially rich source of beneficial chemical compounds that could be harnessed for human health.

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"One species—Fusarium foetens—was almost universally present in people from different geographic locales and readily grew under culture conditions that mimic conditions of the human gut, such as low oxygen. When inoculated into mice, F. foetens stably colonized the gastrointestinal tract without causing injury or invading deeper tissues. These characteristics suggest that F. foetens is not merely passing through from the environment but instead is well adapted to the mammalian intestine and leads a symbiotic rather than pathogenic lifestyle.

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"To investigate the effects of F. foetens on metabolic disease, Zhou et al. used a mouse model of metabolic dysfunction–associated steatohepatitis. This disorder is characterized by fatty liver and liver inflammation and can progress to cirrhosis or liver cancer. Similar symptoms can be induced in mice by feeding them a high-fat diet for several weeks. Unexpectedly, Zhou et al. found that F. foetens reduced symptoms of steatohepatitis when inoculated into mice. By contrast, inoculation with C. albicans failed to protect against this liver condition, suggesting that the effect is species specific.

"How does F. foetens protect against metabolic dysfunction–associated steatohepatitis? Using an in vitro activity-based assay, Zhou et al. found that F. foetens selectively reduced the activity of the enzyme ceramide synthetase 6 (CerS6). CerS6 is expressed in intestinal epithelial cells, where it catalyzes the synthesis of ceramides—an important class of endogenous lipids. Notably, ceramides are exported to the bloodstream and promote the progression of fatty liver disease to metabolic dysfunction–associated steatohepatitis. Colonizing mice with F. foetens decreased intestinal CerS6 activity and reduced ceramide amounts in both the intestine and the bloodstream, whereas supplementing F. foetens–colonized mice with ceramide blunted the beneficial effects on disease progression. Thus, F. foetens reduces symptoms by inhibiting ceramide synthesis in the intestine.

"A resident intestinal fungus protects against metabolic disease
Fusarium foetens a filamentous fungus that stably colonizes the mammalian gut, secretes a metabolite called F. foetens compound 1 (FF-C1). FF-C1 binds to and inhibits ceramide synthetase 6 (CerS6) in the gut epithelium. This reduces ceramide pools in the bloodstream and protects against the development of metabolic dysfunction–associated steatohepatitis in a mouse model. Intestinal symbiotic fungi may be an untapped reservoir of possible therapeutic chemical compounds.

"Investigating the mechanistic basis for this effect, Zhou et al. found that F. foetens culture medium contains a medley of secreted metabolites and was sufficient to inhibit CerS6 in vitro. Using biochemical fractionation methods to isolate metabolites from the conditioned medium, they found that F. foetens compound 1 (FF-C1) bound tightly to CerS6 and inhibited its activity. FF-C1 is a naphthoquinone, a class of aromatic small molecules produced by many fungi (13). Administering FF-C1 was sufficient to limit the progression of steatohepatitis in mice, even in the absence of F. foetens.

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"The findings of Zhou et al. suggest that the fungal microbiome may be a rich, untapped source of compounds with therapeutic potential. In addition to FF-C1, other compounds were isolated from F. foetens–conditioned culture medium that may selectively target different host pathways. It is also likely that other symbiotic fungi in the human gut produce compounds that interact with host pathways to promote health or limit disease. The results from this study should inspire further investigation of the human fungal microbiome to unlock the potential of these microscopic medicinal chemists.

Comment: the same evolutionary system that dhw derides as causing 99.9$ unnecessary organisms, produced this helpful one. It is obvious others will be found as god designed helpful forms for human support