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

UDCA nonresponders exhibit persistent gut dysbiosis characterized by depletion of butyrate-producing bacteria and expansion of opportunistic fungi.

• Nonresponders showed depletion of beneficial butyrate-producing bacteria compared to responders
• Expansion of opportunistic fungi such as Candida albicans was observed in nonresponders
• A pro-inflammatory bacterial network centered on Collinsella was enriched in nonresponders
• This dysbiosis persisted longitudinally throughout the study period in nonresponders
• Study employed a longitudinal, multi-omics design with a small-sample human model

UDCA nonresponders showed enrichment of microbial virulence factors and impaired host energy metabolism.

• Nonresponders exhibited enrichment of microbial virulence factors including flagella
• Impaired host energy metabolism was observed, particularly mitochondrial tricarboxylic acid (TCA) cycle dysfunction
• TCA cycle dysfunction was supported by persistently elevated serum pyruvate levels in nonresponders
• These functional alterations were identified through multi-omics analysis

UDCA responders exhibited remodeling of the gut microbiota and improved mitochondrial function with significant enrichment of serum itaconate.

• Gut microbiota remodeling was observed longitudinally in UDCA responders
• Improved mitochondrial function distinguished responders from nonresponders
• Serum itaconate was significantly enriched in UDCA responders
• These findings contrast with the persistent dysbiosis and metabolic dysfunction seen in nonresponders

An integrated microbiota-metabolite predictive model showed potential in identifying UDCA nonresponders within the study cohort.

• The model was developed as a proof-of-concept using integrated microbiota and metabolite data
• The model demonstrated potential for identifying nonresponders within the study cohort
• Performance requires validation in independent cohorts and clinical utility remains unknown
• The model was built upon findings of gut dysbiosis and mitochondrial metabolic markers

UDCA nonresponse in primary biliary cholangitis may represent a distinct pathological state centered on persistent mitochondrial metabolic dysfunction.

• UDCA is the first-line therapy for PBC, yet a subset of patients responds inadequately
• The study proposes that gut microbiota-mitochondrial metabolic dysregulation influences heterogeneity of UDCA treatment response
• Persistent mitochondrial TCA cycle dysfunction is proposed as a central feature of the nonresponder state
• The gut-mitochondrion axis is identified as a potential target for personalized therapeutic strategies
• This was a longitudinal pilot study with a small sample size, described as a human model