Gut fungi exacerbates gallstone formation by activating neutrophil extracellular traps in the liver.

Patients with gallstones exhibited intestinal fungal dysregulation compared with healthy volunteers, marked by increased fungal biodiversity and compositional changes.

• Gallstone patients showed increased fungal biodiversity relative to healthy controls.
• Compositional changes in the gut fungal community were observed in gallstone patients.
• Gallstone patients also demonstrated alterations in fungal-bacterial interactions compared to healthy volunteers.

Fluconazole treatment reduced gallstone formation in C57 mice on a lithogenic diet.

• Fluconazole, described as a broad-spectrum antifungal drug, was administered to C57 mice maintained on a lithogenic diet.
• Mice treated with fluconazole showed reduced gallstone formation compared to untreated controls on the same diet.
• Liver transcriptome sequencing indicated that fluconazole may hinder gallstone formation by regulating multiple targets related to gallstones.

Gavage with Rhodotorula mucilaginosa promoted gallstone formation in mice.

• Mice were gavaged with Rhodotorula mucilaginosa to assess the specific effect of this fungal species on gallstone formation.
• Rhodotorula mucilaginosa administration was found to promote gallstone formation.
• This finding directly implicated a specific gut fungal species in the pathogenesis of gallstones.

Intestinal fungi promoted hepatic neutrophil infiltration and neutrophil extracellular trap (NET) formation to aggravate gallstone formation.

• Analysis included liver metabolism determination, liver immunohistochemistry, and immunofluorescence.
• Intestinal fungal dysbiosis was associated with increased neutrophil infiltration in the liver.
• Neutrophil extracellular trap (NET) formation was identified as a mechanism by which gut fungi aggravate gallstone formation.

Liver transcriptome sequencing revealed that fluconazole's effect on intestinal fungi may hinder gallstone formation through regulation of multiple gallstone-related targets.

• Liver transcriptome sequencing was performed to investigate the mechanistic basis of fluconazole's protective effect.
• The transcriptomic analysis identified multiple targets related to gallstones that were regulated by fluconazole treatment.
• The findings suggest a multi-target mechanism through which antifungal treatment may inhibit gallstone formation.