Gut permeability and cognitive decline: A pilot investigation in the Northern Manhattan Study

BACKGROUND: Gut microbiota may impact cognitive function and decline, though data are limited. This pilot study examines the associations between gut dysbiosis products, plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14), with cognitive decline and immune molecule activation among 40 participants in the longitudinal population-based Northern Manhattan Study. METHODS: We selected stroke- and dementia-free participants at baseline with high activation levels of core components of the immune signaling pathways underlying microbiota metabolite-cognitive associations (IL-1, IL-17, TNF). Participants were followed with up to three complete neuropsychological assessments, at least 5 years apart. RESULTS: Elevated sCD14 was associated with high levels of IL-1 pathway activation (p ​< ​0.05), whereas in samples where only those molecules within the IL-17 and TNF pathways were increased, LPS and sCD14 levels were not elevated. LPS was associated with decline in global cognitive performance over 2–3 assessments (adjusted β ​= ​-0.023 per SD per year, 95% CI:-0.036, −0.010). The association between sCD14 and cognitive decline was marginal (adjusted β ​= ​-0.018 per SD per year, 95% CI:-0.040, 0.004). CONCLUSIONS: These preliminary data support the hypothesis that gut dysbiosis leads to systemic and neuro-inflammation, and subsequently cognitive decline. Further large targeted and untargeted gut microbiota-derived metabolomic studies are needed.