Modulating effects of microbiota on synbiotic intervention outcomes for microbiota-derived trimethylamine, trimethylamine N-oxide and indoxyl sulfate in healthy young medical students: insights from a 12-week randomized clinical trial.

backgroundMicrobiota-derived metabolites, trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), have been implicated in cardiovascular, renal, and metabolic diseases. Synbiotic interventions are a promising strategy to modulate these metabolites, but their efficacy may vary depending on host-microbial characteristics. This study investigated whether a multi-strain synbiotic could reduce serum concentrations of trimethylamine (TMA), TMAO, and IS in healthy young adults, and whether baseline characteristics of the gut microbiota influence individual responses to the intervention.

methodsIn a 12-week, double-blind, randomized, placebo-controlled trial, 38 healthy young medical students received either a synbiotic or placebo. Serum levels of TMA, TMAO, and IS were measured at baseline, 6 weeks, and week 12, two hours after consuming two eggs. Gut microbiota composition and function were assessed using 16 S rRNA gene sequencing and predicted through metagenomic profiling (PICRUSt2). Weighted Gene Co-expression Network Analysis (WGCNA) was applied to identify groups of co-occurring bacterial taxa (ASVs) and functional orthologous groups - KEGG Orthologs (KOs).

resultsThe synbiotic intervention did not produce significant changes in TMA, TMAO, or IS levels across the entire study population. There were no significant changes in alpha diversity or microbiota composition during the intervention. However, baseline microbiota-related factors influenced individual responses to synbiotic therapy. Two taxonomic WGCNA modules, containing Lachnospiraceae and Ruminococcaceae, were associated with greater reductions in IS levels in participants receiving synbiotics. Also, a module containing Lachnospirales and Oscillospirales showed a potential modulatory effect on TMA levels. A KO module enriched in genes involved in bacterial secretion systems, sulfur metabolism, and methanogenesis pathways - including K14083 (mttB) and K14084 (mttC), both implicated in the conversion of TMA to methane - was significantly associated with reductions in TMA.

conclusionsIn this randomized, placebo-controlled trial in healthy young adults, the synbiotic did not produce a significant arm-wide effect on post-challenge serum TMA, TMAO, or indoxyl sulfate over 12 weeks. Exploratory moderation analyses suggest that baseline gut-microbiota features, taxonomic and functional, may modulate individual responses, particularly for IS and TMA, supporting a precision-nutrition framework. The translational significance of this study stems from the observation that primary prevention, which is particularly important in metabolic diseases, should be individualised based on the function of the microbiota.