Utilizing a filamentous fungus in the gut microbiome may provide a new strategy for treating metabolic dysfunction-associated steatohepatitis (MASH). Researchers have developed an innovative method for cultivating a prevalent gut fungus, Fusarium foetens, which can reverse progression of the chronic metabolic liver disease in mice.
The study, published in Science, was led by Shuang Zhou, PhD, and colleagues at Peking University. Their paper, titled “A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite–CerS6–ceramide axis,” describes how this fungus and its secreted metabolite, CerS6, work to reduce disease symptoms.
Metabolic dysfunction-associated fatty liver disease (MAFLD) affects roughly one in four adults globally. Its more advanced form, MASH, can lead to cirrhosis and liver cancer. Despite the condition’s widespread impact, only one approved drug therapy currently exists, resulting in a need for new treatment strategies.
While the bacterial microbiome has often been the center of gut research, the Chinese researchers turned their attention to gut fungi, whose role in metabolism remains poorly understood and not well studied.
“Of microbial factors that influence human health, gut bacteria are the most highly relevant for metabolic diseases,” wrote the authors. “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.”
One barrier to studying gut fungi is that many species do not grow well in traditional lab cultures. To address this, the team developed a cultivation platform they called fungal isolation chips (FiChips).
“We systematically isolated 2,137 fungal strains from fecal samples of volunteers from five different geographical areas within China,” they wrote in their paper. “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.”
Using FiChips, which mimic the intestinal environment in situ, the team was able to grow and identify 161 fungal species, including strains of Fusarium, many of which are capable of surviving in oxygen-poor environments like the colon.
Further, the team analyzed internal transcribed spacer data from global intestinal fungal studies and found that one species, F. foetens, is prevalent in the gut microbiome in datasets from around the world, suggesting a role in gut microbiome health.
To investigate the role that gut fungi play in intestinal health, the researchers utilized a mouse model for MASH. Mice were fed a high-fat, choline-deficient diet—a common model for inducing MASH—then were treated with F. foetens using a single oral gavage. Treated mice showed significant improvement in liver health, including reduced liver weight, lower liver enzyme and hepatic triglyceride levels, and decreased steatosis, inflammation, and fibrosis compared to untreated mice.
Seeking to understand how the fungus exerted these effects, the researchers identified a fungal metabolite, FF-C1, that inhibits CerS6, a ceramide synthase enzyme associated with metabolic dysfunction. Ceramides are lipid molecules that have been implicated in insulin resistance and liver disease.
The team “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.”
Using genetically engineered mice lacking functional CerS6, the role of FF-C1 was confirmed. FF-C1 binds to CerS6, reducing ceramide levels and alleviating MASH symptoms in mice. Mice without CerS6 did not benefit from FF-C1 treatment, confirming the metabolite’s mechanism of action.
“Collectively, our findings provide a deeper insight into the biology of host-commensal fungi interactions,” the authors wrote. They are encouraged by the utility of their work and the potential therapeutic applications.
In an accompanying Science Perspective, Lora Hooper, PhD, and Andrew Koh, MD, of UT Southwestern Medical Center, concurred.
“The findings of Zhou et al. point to the fungal microbiome as a rich, untapped source of compounds that may have therapeutic potential,” they wrote. “The results from this study should inspire further investigation of the human fungal microbiome to unlock the potential of these microscopic medicinal chemists.”
The post Gut Fungus Shows Promise in Reversing MASH in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.
The study, published in Science, was led by Shuang Zhou, PhD, and colleagues at Peking University. Their paper, titled “A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite–CerS6–ceramide axis,” describes how this fungus and its secreted metabolite, CerS6, work to reduce disease symptoms.
Metabolic dysfunction-associated fatty liver disease (MAFLD) affects roughly one in four adults globally. Its more advanced form, MASH, can lead to cirrhosis and liver cancer. Despite the condition’s widespread impact, only one approved drug therapy currently exists, resulting in a need for new treatment strategies.
While the bacterial microbiome has often been the center of gut research, the Chinese researchers turned their attention to gut fungi, whose role in metabolism remains poorly understood and not well studied.
“Of microbial factors that influence human health, gut bacteria are the most highly relevant for metabolic diseases,” wrote the authors. “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.”
Growing gut fungi
One barrier to studying gut fungi is that many species do not grow well in traditional lab cultures. To address this, the team developed a cultivation platform they called fungal isolation chips (FiChips).
“We systematically isolated 2,137 fungal strains from fecal samples of volunteers from five different geographical areas within China,” they wrote in their paper. “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.”
Using FiChips, which mimic the intestinal environment in situ, the team was able to grow and identify 161 fungal species, including strains of Fusarium, many of which are capable of surviving in oxygen-poor environments like the colon.
Further, the team analyzed internal transcribed spacer data from global intestinal fungal studies and found that one species, F. foetens, is prevalent in the gut microbiome in datasets from around the world, suggesting a role in gut microbiome health.
Fungal functionality
To investigate the role that gut fungi play in intestinal health, the researchers utilized a mouse model for MASH. Mice were fed a high-fat, choline-deficient diet—a common model for inducing MASH—then were treated with F. foetens using a single oral gavage. Treated mice showed significant improvement in liver health, including reduced liver weight, lower liver enzyme and hepatic triglyceride levels, and decreased steatosis, inflammation, and fibrosis compared to untreated mice.
Seeking to understand how the fungus exerted these effects, the researchers identified a fungal metabolite, FF-C1, that inhibits CerS6, a ceramide synthase enzyme associated with metabolic dysfunction. Ceramides are lipid molecules that have been implicated in insulin resistance and liver disease.
The team “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.”
Using genetically engineered mice lacking functional CerS6, the role of FF-C1 was confirmed. FF-C1 binds to CerS6, reducing ceramide levels and alleviating MASH symptoms in mice. Mice without CerS6 did not benefit from FF-C1 treatment, confirming the metabolite’s mechanism of action.
“Collectively, our findings provide a deeper insight into the biology of host-commensal fungi interactions,” the authors wrote. They are encouraged by the utility of their work and the potential therapeutic applications.
In an accompanying Science Perspective, Lora Hooper, PhD, and Andrew Koh, MD, of UT Southwestern Medical Center, concurred.
“The findings of Zhou et al. point to the fungal microbiome as a rich, untapped source of compounds that may have therapeutic potential,” they wrote. “The results from this study should inspire further investigation of the human fungal microbiome to unlock the potential of these microscopic medicinal chemists.”
The post Gut Fungus Shows Promise in Reversing MASH in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.