Project description:<p>Objective:</p><p>Metabolic associated fatty liver disease (MAFLD) affects approximately 25% of the global population, posing a serious threat to public health, and its pathogenesis remains largely unknown. Gut fungi play a significant role in the development of liver diseases, but the gut microbial community and its functions in MAFLD patients are not yet clear.</p><p>Methods:</p><p>We performed fungal ITS sequencing on fecal samples from 107 MAFLD patients and 120 healthy control (HC), matched for region, ethnicity, age, and sex. A high-fat diet-induced MAFLD mouse model was established and multi-omics techniques such as Liver transcriptome sequencing, qPCR, Western blot, and immunofluorescence were employed to validate the molecular mechanisms of key gut fungi involved in MAFLD. </p><p>Results:</p><p>MAFLD patients exhibited reduced species richness and diversity compared to HC. The gut microbiome of MAFLD patients was characterized by an increase in the harmful fungal genus Rhizopus, specifically the harmful fungi Rhizopus microsporus var. rhizopodiformis and Rhizopus microsporus var. chinensis, which positively correlated with the degree of steatosis and BMI. Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B amphotericin (AMP) administration alleviated disease progression. Gavage with Rhizopus microsporus var. rhizopodiformis significantly exacerbates gut microbiota dysbiosis and metabolic disorders, disrupted the intestinal barrier and activated liver SREBP-1c, thereby upregulating key lipid synthesis enzymes ACC1 and FASN. This activation occurred through a pro-inflammatory cascade involving the liver macrophage LPS-TLR4-NF-κB axis, amplification of inflammatory signals, and neutrophil degranulation.</p><p>Conclusion:</p><p>Rhizopus microsporus var. rhizopodiformis promotes hepatic lipid synthesis by upregulating hepatic neutrophil degranulation and facilitating SREBP-1c activation pathway.</p>
Project description:<p>Objective:</p><p>Metabolic associated fatty liver disease (MAFLD) affects approximately 25% of the global population, posing a serious threat to public health, and its pathogenesis remains largely unknown. Gut fungi play a significant role in the development of liver diseases, but the gut microbial community and its functions in MAFLD patients are not yet clear.</p><p>Methods:</p><p>We performed fungal ITS sequencing on fecal samples from 107 MAFLD patients and 120 healthy control (HC), matched for region, ethnicity, age, and sex. A high-fat diet-induced MAFLD mouse model was established and multi-omics techniques such as Liver transcriptome sequencing, qPCR, Western blot, and immunofluorescence were employed to validate the molecular mechanisms of key gut fungi involved in MAFLD. </p><p>Results:</p><p>MAFLD patients exhibited reduced species richness and diversity compared to HC. The gut microbiome of MAFLD patients was characterized by an increase in the harmful fungal genus Rhizopus, specifically the harmful fungi Rhizopus microsporus var. rhizopodiformis and Rhizopus microsporus var. chinensis, which positively correlated with the degree of steatosis and BMI. Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B amphotericin (AMP) administration alleviated disease progression. Gavage with Rhizopus microsporus var. rhizopodiformis significantly exacerbates gut microbiota dysbiosis and metabolic disorders, disrupted the intestinal barrier and activated liver SREBP-1c, thereby upregulating key lipid synthesis enzymes ACC1 and FASN. This activation occurred through a pro-inflammatory cascade involving the liver macrophage LPS-TLR4-NF-κB axis, amplification of inflammatory signals, and neutrophil degranulation.</p><p>Conclusion:</p><p>Rhizopus microsporus var. rhizopodiformis promotes hepatic lipid synthesis by upregulating hepatic neutrophil degranulation and facilitating SREBP-1c activation pathway.</p>
Project description:Rhizopus microsporus is one of the most common agents of mucormycosis, a severe and emerging infection caused by Mucorales fungi that poses a significant clinical challenge, particularly due to the growing population of immunocompromised individuals. An substantial proportion of clinical isolates harbor bacterial endosymbionts, which regulate key fungal functions, such asexual sporulation. The strict dependence on endosymbionts for spore formation has limited a comprehensive understanding of endosymbiosis in R. microsporus biology. Here, we demonstrate that sporulation in endosymbiont-cured strains of this fungus, which previously harbored Mycetohabitans bacteria, can be induced by light. Interestingly, both light and endosymbionts regulate sporulation through the same regulatory pathway, and a high proportion of the genes upregulated by these signals are known to be involved in asexual sporulation in other fungi, including Mucorales. Light-induced sporulation enabled comparative assays to assess the impact of symbiosis on fungal traits. In addition to previously known effects on fungal fitness, this study reveals that germination is independent of endosymbionts, although their presence accelerates the process. Furthermore, it shows that asexual spores lacking endosymbionts exhibit a reduced virulence in a mouse model of mucormycosis. The discovery of light-induced sporulation in endosymbiont-free strains of R. microsporus paves the way for future comparative studies using genetically identical backgrounds, advancing our understanding of fungal-bacterial symbiosis and its role in fungal biology and human pathogenesis.