The Gut-Immune-Brain Axis in Aging: Integrating Immunosenescence, Inflammaging, and Neuroinflammation for Precision Medicine.

Abstract

Background: Population aging is accompanied by progressive immune remodeling, chronic low-grade inflammation, and increased susceptibility to neurodegenerative diseases. Although the microbiota-gut-brain axis is increasingly recognized as a regulator of neuroimmune homeostasis, mechanisms linking age-associated dysbiosis with immunosenescence, barrier dysfunction, and brain aging remain incompletely understood. This review integrates current evidence into the proposed Gut-Immune-Brain Resilience Axis (GIBRA), a systems-level model describing how microbial signaling shapes neuroimmune resilience during aging. Methods: A structured narrative review was conducted using PubMed and the Web of Science Core Collection from database inception up to July 2026. Evidence from systematic reviews, meta-analyses, consensus statements, mechanistic and translational studies, longitudinal cohorts, randomized clinical trials, and observational studies was synthesized. Results: Current evidence supports an important role for the disruption of microbial functional signaling in neuroimmune aging, while microbial taxonomy and functional profiles provide complementary levels of biological information. Reduced short-chain fatty acid production, dysregulated tryptophan metabolism, microbial translocation, endotoxin-mediated innate immune activation, and gut-conditioned adaptive immune responses promote immunosenescence, inflammaging, barrier dysfunction, and microglial priming. The proposed Double-Barrier Hypothesis links intestinal and blood-brain barrier dysfunction as complementary mechanisms underlying chronic neuroinflammation. GIBRA highlights functional microbiome endotypes, biomarkers, multi-omics, and artificial intelligence as emerging tools for precision medicine. Conclusions: GIBRA provides an integrated systems biology perspective connecting microbial signaling, immune resilience, barrier integrity, and brain resilience during aging. Prioritizing functional resilience over microbial taxonomy may improve biomarker discovery, patient stratification, and microbiome-targeted interventions for neurodegenerative disease prevention. Prospective longitudinal studies integrating multi-omics are needed to support clinical translation.