# Mycobiome dysbiosis and genetic predisposition to elevated IL-17A contribute to fibrosis in MASLD

## TL;DR

This study shows that a combination of genetic factors and gut fungal imbalances can worsen liver disease by increasing inflammation.

## Contribution

The study identifies a novel interaction between genetic predisposition and gut mycobiome dysbiosis in driving liver fibrosis in MASLD.

## Key findings

- The IL17A rs2275913 minor allele is a risk factor for fibrosis progression in MASLD.
- Fungal species like Candida albicans and Debaryomyces hansenii are more abundant in patients with advanced fibrosis.
- Donors with the IL17A rs2275913 minor allele secrete more IL-17A when exposed to CTG fungal species.

## Abstract

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 T helper 17 cell (Th17) activation. We aimed to investigate the role of intestinal fungi in MASH-mediating Th17-associated signaling.

Blood samples from patients with MASLD (n = 451), including 141 with histology-proven MASH, were genotyped for IL17A rs2275913. Microbiome composition was assessed by ITS1 and 16S rRNA sequencing of stool samples from patients with MASLD (n = 221), including 79 with histology-proven MASH, as well as 25 healthy controls. Highly abundant fungal species identified in patients with MASH 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 analyzed in relation to IL17A rs2275913 genotype in patients with MASLD (n = 58), including 31 with histology-proven MASH, and 28 healthy controls.

We identified the IL17A rs2275913 minor allele variant as a risk factor for fibrosis progression in patients with MASLD. 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 predisposition with mycobiome composition, ex vivo T-cell stimulation assays demonstrated that donors carrying the IL17A rs2275913 minor allele secreted significantly higher levels of IL-17A in response to CTG species. Additionally, patients with MASH carrying the IL17A rs2275913 risk allele had elevated Th17/Treg ratios in peripheral blood.

Genetic predisposition to enhanced Th17 responses, in the context of mycobiome dysbiosis, may promote MASH progression and liver fibrosis.

Liver inflammation and fibrosis are key drivers of the transition from bland steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Our findings identify a combinatorial mechanism in which genetic predisposition to enhanced IL-17A signaling, together with gut mycobiome dysbiosis, promotes MASH development and fibrosis progression. This work highlights the importance of host–mycobiome interactions in shaping inflammatory liver disease and supports further investigation into targeted strategies aimed at modulating IL-17A–mediated immune responses in patients with MASLD. Such approaches may offer novel opportunities for risk stratification and therapeutic intervention.

Image 1

•Genetic predisposition and gut mycobiome dysbiosis trigger BS-to-MASH transition.•Patients with advanced liver fibrosis have elevated intestinal CTG species abundance.•IL-17A secretion is dysregulated in patients with advanced liver fibrosis.•The IL17A rs2275913 A/A variant is a genetic risk factor for fibrosis progression.

Genetic predisposition and gut mycobiome dysbiosis trigger BS-to-MASH transition.

Patients with advanced liver fibrosis have elevated intestinal CTG species abundance.

IL-17A secretion is dysregulated in patients with advanced liver fibrosis.

The IL17A rs2275913 A/A variant is a genetic risk factor for fibrosis progression.