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

BackgroundGut microbiome disruption is often characterized by loss of obligate 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 detectable in blood, peripheral metabolites may provide a potentially 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. ResultsCandidate metabolites were identified systematically across an independent set of studies reporting metabolite-microbiome associations, enabling assessment of reproducibility across disease states and cohorts. We performed a meta-analysis of 19 human cohorts comprising 3242 participants with paired blood metabolite and stool microbiome data. Anaerobe depletion (obligate anaerobe relative abundance <0.70 by sequencing) was associated with decreased 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. ConclusionsCirculating microbial metabolites are potentially informative indicators of gut microbiome disruption and may serve as a rapid and 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 loss of obligate anaerobes. Unlike stool-based sequencing, which can be logistically challenging and slow, blood-based metabolite profiling could be actionably integrated into existing clinical workflows. Our findings suggest 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 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.