Peripheral microbial metabolites as indicators of gut microbiome disruption: systematic review and meta-analysis

Gut microbiome disruption is often characterized by the loss of obligately anaerobic bacteria, which may lead to altered production of microbial metabolites that can be detected peripherally. The application of widely used sequencing-based microbiome analyses to clinical settings is limited by cost, turnaround time, and challenges with patients with very low stool output. Since some products of strictly bacterial metabolism are detectable in blood, peripheral metabolites may provide a rapid and scalable indicator of gut microbiome composition and function. We performed a systematic review and meta-analysis of studies reporting circulating microbial metabolites and gut microbiome composition to evaluate whether peripheral microbial metabolites could identify gut microbiome perturbation. Candidate metabolites were identified systematically across an independent set of studies reporting metabolite-microbiome associations, enabling the assessment of reproducibility across disease states and cohorts. We performed a meta-analysis of 19 human cohorts comprising 3,242 participants with paired blood metabolite and stool microbiome data. Anaerobe depletion (obligate anaerobe relative abundance <0.70) was associated with decreased plasma concentration of products of anaerobic microbial metabolism. Combinations of metabolites distinguished individuals with anaerobe-depleted microbiomes from those without. Circulating metabolite levels distinguished between cases and controls with similar performance as gut microbiome composition across a range of health/disease states and changed markedly within patients experiencing gut anaerobe depletion after antibiotic exposure. Circulating microbial metabolites are potentially informative indicators of gut microbiome disruption and may serve as a rapid and scalable method for patient stratification in clinical trials or acute care settings.IMPORTANCECirculating microbial metabolites represent a practical and scalable approach to detecting significant gut microbiome disruption, particularly the loss of obligate anaerobes. Our findings suggest that metabolites capture compositional consequences of microbiome collapse, with performance comparable to direct microbiome profiling in distinguishing disease states. Enabling diagnostic enrichment and real-time monitoring of microbiome injury (e.g., during antibiotic use or critical illness) has potential implications for both clinical care and research, including the selection of patients for investigation of microbiome-targeted therapies. With further validation, circulating metabolites could provide an accessible surrogate for gut microbiome composition in settings where sequencing is impractical.