Exploring causal links in the gut–brain axis: a Mendelian randomization study of gut microbiota, metabolites, and cognition

The causal mediation effects of metabolites between gut microbiota and cognitive phenotypes remain unclear. Guided by the gut-brain axis mechanism, this study employed systematic Mendelian randomization (MR) to investigate these mediation pathways and their implications for functional food development. Univariate MR analysis was performed to estimate the causality of 211 gut microbial taxa (<i>n</i> = 18 340) and 452 serum metabolites (<i>n</i> = 7824) on general cognitive (<i>n</i> = 257 700), non-cognitive (<i>n</i> = 510 795), and specific cognitive phenotypes (<i>n</i> ≈ 2500) using genome-wide association study data. Inverse-variance weighted estimation was adopted as the primary method, with MR sensitivity analyses performed to complement the results. Metabolic pathway analysis was employed to enrich metabolic profiles, while two-step MR was used to screen mediation pathways. We revealed seven causal associations between microbiotas or metabolites and cognitive phenotypes (FDR < 0.05). Increased abundance of the order <i>Clostridiales id.1863</i> was associated with better cognitive traits (OR = 1.14, 95%CI = 1.06-1.22, <i>P</i> = 2.06 × 10^-4), while 1-linoleoylglycerophosphoethanolamine was also positively associated with cognitive traits (OR = 1.61, 95%CI = 1.33-1.95, <i>P</i> = 8.17 × 10^-7). Seven significant metabolic pathways were enriched, including alpha-linolenic acid and linoleic acid metabolism, highlighting the potential role of omega-3 and omega-6 fatty acids in cognitive health. We further identified two significant mediation pathways linking the gut microbiota to cognitive phenotypes through metabolites. Notably, homostachydrine (39.1%) was found to mediate a proportion of the impact of the genus <i>Turicibacter</i> on emotion recognition (indirect effect: <i>β</i> = 0.105, 95%CI = 0.006-0.259, <i>p</i> = 2.60 × 10^-2). This study provides evidence for causal relationships between gut microbiota, serum metabolites, and cognitive function, supporting the gut-brain axis mechanism. Our findings suggest potential targets for the development of functional food and personalized nutrition to improve cognitive health.