Mycobiome Dysbiosis and Genetic Predisposition for Elevated IL-17A Contribute to Fibrosis in MASLD
Thielemann N, Leal Siliceo S, Rau M, Schöninger A, Reus N, Aldejohann AM, Shehata A, Behr IS, Nieuwenhuizen NE, Herz M, Hermanns HM, Mirhakkak M, Löffler J, Dandekar T, Hünniger-Ast K, Martin R, Panagiotou G, Geier A, Kurzai O 2025 Mycobiome Dysbiosis and Genetic Predisposition for Elevated IL-17A Contribute to Fibrosis in MASLD JHEP Reports , 101721.
Abstract
Background & Aims
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 inflammatory processes including Th17 activation. We aimed to investigate the role of intestinal fungi in MASH-mediating Th17-associated signaling.
Materials & Methods
Blood samples of MASLD patients (n=451), including n=141 histology-proven MASH patients, were genotyped for IL17A rs2275913. Microbiome composition was assessed by ITS1 and 16S rRNA analysis of MASLD patient stool samples (n=221), including n=79 histology-proven MASH patients and additionally n=25 healthy controls. Highly abundant fungi in MASH patients were used to stimulate IL17A rs2275913-genotyped T cells ex vivo and cytokine levels were measured (n=9 per genotype). Th17/resting regulatory T cell (Th17/rTreg) ratios were associated to MASLD patients´ IL17A rs2275913 genotype (n=58) including n=31 histology-proven MASH patients and additionally n=28 healthy controls.
Results
In this study, we identified 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. By integrating genetic risk predisposition and mycobiome composition, we demonstrated in ex vivo T cell stimulation assays, that donors carrying the minor allele variant of IL17A rs2275913 secreted significantly higher levels of IL-17A in response to CTG species. Additionally, MASH patients carrying the IL17A rs2275913 risk allele had elevated Th17/Treg ratios in peripheral blood.
Conclusions
Genetic predisposition for enhanced Th17 responses in the context of mycobiome dysbiosis could trigger MASH progression and liver fibrosis.
Impact and implications
Liver inflammation and fibrosis are central elements for BS-to-MASH transition. Our results provide a combinatory mechanism of genetic IL-17A predisposition and gut mycobiome dysbiosis contributing to MASH development. These findings emphasize the importance for further studies investigating targeted IL-17A dysregulation intervention strategies in MASLD patients.