The gut–kidney–brain axis
The gut–kidney–brain axis is a bidirectional communication network linking the gastrointestinal tract, kidneys and central nervous system, and a central concept in the CKC Working Group's research.
What is the gut–kidney–brain axis?
It connects the gut, kidneys and central nervous system through metabolic, immune, endocrine and neural pathways. Gut microbes produce metabolites such as short-chain fatty acids that support epithelial barrier integrity and exert renoprotective and neuroprotective effects, while uremic toxins produced when kidney function declines can damage both the gut barrier and the brain.
How kidney disease affects the brain
When kidney function declines, protein-bound uremic toxins such as indoxyl sulphate and p-cresyl sulphate accumulate in the circulation. These toxins are both nephrotoxic and neurotoxic: indoxyl sulphate can loosen endothelial tight junctions, contributing to blood–brain barrier leakage in chronic and end-stage kidney disease, while other toxins disrupt the brain's excitatory–inhibitory balance and reduce neuronal energy. This contributes to cognitive impairment and dementia risk in people with chronic kidney disease. The axis is bidirectional: the brain's autonomic and circadian regulation also controls renal blood flow, sodium excretion and blood pressure.
Barrier integrity as a convergence point
Our framework, published in The Lancet Planetary Health, positions the intestinal barrier and the blood–brain barrier as convergence and amplification points through which climatic and environmental stressors — heat, air pollution, food insecurity, infection and psychosocial stress — might drive multi-organ vulnerability.
Evidence status. The gut–kidney–brain framework is a mechanistic synthesis. These proposed mechanisms require validation in longitudinal human studies, and much of the supporting evidence is currently pre-clinical or associative rather than causal.
Key references
- Adalat S, Giannakou K, Valderrama B, et al. Global environmental change and the gut–kidney–brain axis: a review and framework of vulnerability and resilience. The Lancet Planetary Health (2026). doi:10.1016/j.lanplh.2026.101453
- Giordano L, Ahmed S, van der Made TK, Masereeuw R, Mihăilă SM. Gut microbial-derived short chain fatty acids enhance kidney proximal tubule cell secretory function. Biomed Pharmacother (2025). doi:10.1016/j.biopha.2025.118214
- Wagner CA, Frey-Wagner I, Ortiz A, et al. The role of the intestinal microbiome in cognitive decline in patients with kidney disease. Nephrol Dial Transplant (2025). doi:10.1093/ndt/gfae253