Effects of prebiotics and phytochemicals on serum trimethylamine N-oxide reduction and gut microbiota: a systematic review and meta-analysis

Abstract

Serum trimethylamine N-oxide (TMAO) level has been considered as a potential biomarker linking gut microbiota to multiple diseases. Prebiotics and phytochemicals have emerged as promising non-pharmacological agents for regulating TMAO levels and promoting overall health, attracting significant interest in recent research. However, existing evidence on their efficacy remains inconsistent. To address this, we conducted a systematic analysis of 41 studies (from PubMed, Web of Science, Embase, and Cochrane Library up to May 19, 2025) evaluating the effects of prebiotics and phytochemicals on gut microbiota and TMAO level. Included studies had interventional and longitudinal designs, analyzed gut microbiota, reported diversity or abundance measures, and measured changes in trimethylamine (TMA) or TMAO levels. Hedge's g standardized mean difference (SMD) and heterogeneity (I²) were calculated to quantify the effects of prebiotics and phytochemicals on TMA, TMAO, and gut microbiota alpha-diversity. Microbial changes and beta-diversity were synthesized qualitatively. Our meta-analysis revealed that prebiotic and phytochemical interventions significantly reduced serum TMAO levels (SMD = - 2.31, 95% CI, - 2.75 to - 1.87; I² = 76.00%, p < 0.01) in animals, with clinical trials showing similar results (SMD = - 0.82, 95% CI, - 1.55 to - 0.08, I² = 91.00%, p < 0.01). In animals, TMA levels were also significantly reduced (SMD = - 1.53, 95% CI, - 2.04 to - 1.02; I² = 71.00%, p < 0.01). Phytochemical and prebiotic interventions significantly caused alteration in the alpha- and beta-diversity of gut microbiota. Despite heterogeneity, consistent changes were noted in genera such as Akkermansia and Bifidobacterium. In conclusion, phytochemical and prebiotic interventions appear effective in reducing serum TMAO levels and are associated with changes in the composition and diversity of the gut microbiota. While these findings highlight the therapeutic potential of microbiota-targeted dietary strategies for TMAO reduction, they should be interpreted with caution due to the substantial heterogeneity among studies and the potential for publication bias. Further high-quality, standardized trials are needed to confirm these effects and support clinical translation.

Keywords: Gut microbiota; Meta-analysis; Phytochemical; Prebiotic; TMA; TMAO.