Mycobiome Dysbiosis and Genetic Predisposition for Elevated IL-17A Drive Fibrosis in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in Western countries. Progression to metabolic dysfunction-associated steatohepatitis (MASH) occurs when fat accumulation in the liver triggers Th17 activation and other inflammatory processes. In this study, we identify the IL17A rs2275913 minor allele variant as a risk factor for fibrosis progression in MASLD patients. In patients with advanced fibrosis, we also observed an increased abundance of fungal CTG species including Candida albicans and Debaryomyces hansenii, which are potent triggers of Th17 responses. Integrating genetic risk-predisposition and mycobiome composition, we show in ex vivo T cell stimulation assays, that donors carrying the minor allele variant of IL17A rs2275913 secreted significantly higher IL-17A levels in response to CTG species. Additionally, MASH patients carrying the IL17A rs2275913 risk allele have elevated Th17/Treg ratios in peripheral blood. Taken together, our data indicate that genetic predisposition for enhanced Th17 responses in the context of mycobiome dysbiosis can trigger MASH progression and liver fibrosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/24315902v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@6527d5org.highwire.dtl.DTLVardef@11a1c6forg.highwire.dtl.DTLVardef@140e1eeorg.highwire.dtl.DTLVardef@b0e049_HPS_FORMAT_FIGEXP M_FIG C_FIG This Graphical Abstract was created with BioRender.com. Brief summaryIncreased antifungal immune responses triggered by gut mycobiome dysbiosis in genetically predisposed patients can lead to severe stages of metabolic dysfunction-associated steatotic liver disease.