Global environmental change and the gut-kidney-brain axis: a review and framework of vulnerability and resilience

Climate-health research often examines organ systems in isolation, which limits our understanding of how environmental stressors shape multiorgan disease patterns. We propose an integrative framework that explores how perturbations in the gut-kidney-brain axis might contribute to differential climate and environmental vulnerability. Climatic and environmental stressors might influence intestinal and blood-brain barrier integrity alongside established haemodynamic, toxicological, endocrine, and neurovascular pathways. Experimental and mechanistic evidence indicates that some environmental exposures can alter epithelial tight junction function and promote translocation of microbial products. Such translocation can drive systemic inflammation, altered metabolic signalling, and neural dysfunction implicated in chronic kidney disease progression and neurological impairment. In the proposed framework, barrier integrity is positioned as a biologically plausible interface within a multipathway model linking the gut, kidney, and brain. The framework highlights how climate and environmental exposures interact with pre-existing physiological and social vulnerabilities, adaptive capacity, and cumulative exposure burden to shape susceptibility to adverse health outcomes across the life course. Because current evidence relies heavily on experimental models and associative data, these mechanisms require validation under real-world, multifactorial climatic and environmental conditions. We also identify crucial research priorities, including prospective studies in climate-exposed populations, biomarker validation of barrier integrity, and targeted interventions to help preserve gut-kidney-brain axis function alongside exposure-reducing efforts. If empirical evidence supports this framework, the suggested systems-based approach could inform prevention, surveillance, and equity-centred resilience strategies.