Work

Longitudinal multi-omics pilot study: Small sample size human model of gut microbiota-mitochondrial metabolic dysregulation in primary biliary cholangitis

Year: 2026

Type: article

Abstract: Ursodeoxycholic acid (UDCA) is the first-line therapy for primary biliary cholangitis (PBC), yet a subset of patients responds inadequately, with the underlying mechanisms remaining unclear. In this longitudinal, multi-omics pilot study employing a small-sample human model, we investigated the role of gut microbiota-mitochondrial metabolic dysregulation in influencing the heterogeneity of UDCA treatment response. Our exploratory analysis revealed that UDCA nonresponders exhibit persistent gut dysbiosis, characterized by the depletion of beneficial butyrate-producing bacteria, the expansion of opportunistic fungi such as Candida albicans, and the enrichment of a pro-inflammatory bacterial network centered on Collinsella. Functionally, this dysbiosis in nonresponders is characterized by an enrichment of microbial virulence factors (e.g., flagella) and impaired host energy metabolism, particularly mitochondrial tricarboxylic acid (TCA) cycle dysfunction, as supported by persistently elevated serum pyruvate levels. Conversely, UDCA responders exhibit remodeling of the gut microbiota and improved mitochondrial function, with significant enrichment of serum itaconate. As a proof-of-concept, an integrated microbiota-metabolite predictive model showed potential in identifying nonresponders within our cohort.However, its performance requires validation in independent cohorts, and its clinical utility remains unknown. Overall, this pilot study proposes that UDCA nonresponse may represent a distinct pathological state centered on persistent mitochondrial metabolic dysfunction, offering preliminary insights for developing personalized therapeutic strategies that target the gut-mitochondrion axis.

Source: Microbiological Research

DOI: 10.1016/j.micres.2026.128465