Sedentary behavior (SB) is prevalent in daily life, with a growing number of studies reporting that higher SB exposure is associated with poorer cardiometabolic and brain health. Thus, in line with a broader paradigm shift, SB should be considered as a postural and low-contractile metabolic state, shaped by both total exposure and bout patterning, that is related to, but distinct from, physical activity (PA), rather than simply the absence of the latter. Regarding the gut microbiome, current evidence on the role of SB remains limited and indirect, as human studies have not yet experimentally manipulated the SB exposure. To generate novel, yet testable hypotheses on the role of SB on the gut microbiome and brain health, this article synthesizes the current evidence base by emphasizing limitations related to cross-sectional designs, measurement heterogeneity, potential confounding by diet, sleep, medications, and PA, and the absence of established quantitative thresholds for SB exposure. Building on broader microbiome, metabolic, inflammatory, and gut-brain axis literature, we outline candidate pathways through which SB exposure, especially prolonged uninterrupted sitting, may alter microbe-derived metabolites and host responses, focusing on short-chain fatty acids, bile acid signaling, and tryptophan-derived metabolism alongside barrier-immune activation and autonomic-vagal circuitry relevant for brain health. Thus, this review extends prior SB-brain health frameworks by positioning SB as a specific gut-brain metabolic state with potential unique effects on a range of brain health-related outcomes. To probe the prediction that changes in SB patterns can affect gut-derived metabolites and specific brain health domains, suitable study designs are discussed. More specifically, future studies should combine accurate measures of SB and PA exposure with gut microbiome and blood-based metabolite assessments, vascular and inflammatory markers, autonomic measures, and standardized tests of cognition and mood, collected at different times, such as after meals and across the day, to better quantify and understand temporal dynamics. Approaching the gut-brain axis by isolating the effects of SB exposure is likely to generate practically relevant and impactful insights that not only help to inform stakeholders, such as policymakers, but also provide the basis for more fine-grained lifestyle recommendations to preserve and improve brain health.
Gut-Brain Axis