S2136 The Role of Gut Microbiota in Cognitive Decline: A Taxonomic-Level Meta-Analysis of Mendelian Randomization Studies

Introduction: Cognitive decline (CD) is a growing health concern, especially among the elderly. Gut microbiota (GM) affects brain function through metabolic and immune pathways. It produces short-chain fatty acids that regulate inflammation and protect the blood-brain barrier. GM also synthesizes neurotransmitters like GABA and serotonin, which mediate neural signaling. Alterations in GM balance can trigger inflammatory pathways, leading to cognitive dysfunction. Methods: We searched PubMed, Scopus, and Google Scholar using relevant keywords to examine the potential causal role of GM phyla in cognitive outcomes. We pooled data from 12 Mendelian randomization studies that used MiBioGen consortium and GWAS datasets, including UK Biobank. Inverse variance weighted analysis was used to estimate the causal link between GM and CD. Leave-one-out sensitivity analyses confirmed the robustness of the results. Results: The analysis showed that GM has both causative and protective roles to play in cognitive decline. Among the causative phyla, Melainabacteria showed a 2-fold increase in the risk of CD (odds ratio [OR] 2.25; 95% confidence interval [CI] 1.45–3.49; P < 0.01) with no heterogeneity (I² = 0%). Thermodesulfobacteriota and Myxococcota were also associated with higher odds of CD, with varying degrees of heterogeneity. In addition, Pseudomonadota showed a borderline risk. On the other hand, Lentisphaerae (OR 0.76; 95% CI 0.7-0.83; P < 0.01) showed a strong protective association with moderate heterogeneity (I² = 29.98%). Phylum Bacillota showed mixed associations: with one analysis reporting a protective effect (OR = 0.90, 95% CI: 0.87–0.92, P < 0.01; I² = 82.57%), and another showing increased odds of CD (OR = 1.11, 95% CI: 1.08–1.14, P < 0.01; I² = 82.23%). Actinomycetota also demonstrated a significant causative association in one analysis (OR = 1.16, 95% CI: 1.09–1.23, P < 0.01; I² = 77.34%) and a non-statistically significant protective trend in another (OR = 0.81, 95% CI: 0.64–1.02, P = 0.07; I² = 67.9%). Conclusion: Our study supports a phylum-specific relationship between GM and CD. Melainabacteria emerged as a consistent risk factor for CD, while Lentisphaerae was found to be protective. Phylum Bacillota exhibits both protective and causative effects on CD. This emphasizes the complexity of the role of GM in CD. Future research should focus on the mechanisms by which bacteria at the lower taxonomic levels exert this effect. High heterogeneity in most estimates also highlights the need for more standardized protocols.