Gut Microbiota, Insulin Resistance, and Alzheimer’s Disease: A Narrative Review of Mechanistic Links and Therapeutic Perspectives

Xiang Li,1,2 Feixiang Liu,3,4 Yonggang Zhu,5 Hao Shi5 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 2China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 3Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 4Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 5Department of Neurological Rehabilitation, The First Affiliated Hospital of Kangda College of Nanjing Medical University/The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu Province, People’s Republic of ChinaCorrespondence: Hao Shi, Department of Neurological Rehabilitation, The First Affiliated Hospital of Kangda College of Nanjing Medical University/The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu Province, People’s Republic of China, Email [email protected] Yonggang Zhu, Department of Neurological Rehabilitation, The First Affiliated Hospital of Kangda College of Nanjing Medical University/The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu Province, People’s Republic of China, Email [email protected]: Alzheimer’s disease (AD) is increasingly regarded as a “neurometabolic syndrome” wherein systemic insulin resistance exacerbates cerebral glucose hypometabolism, tau hyperphosphorylation, and neuroinflammation. We hypothesize that gut microbiota dysbiosis produces metabolites that are associated with peripheral insulin sensitivity, potentially contributing to disruptions in cerebral insulin signaling and an increased risk of AD. We conducted integrated search of PubMed, Web of Science, and Scopus to synthesize evidence showing: (i) consistent taxonomic shifts in AD, highlighting reduced Firmicutes and increased Proteobacteria and Bacteroidetes, depletion of Ruminococcaceae and enrichment of Blautia and Bilophila; (ii) functional consequences of dysbiosis, leading to lower short-chain fatty acids, altered secondary bile‑acid signaling, elevated lipopolysaccharide and trimethylamine‑N‑oxide, and perturbed tryptophan catabolism; (iii) these microbial metabolites compromising gut and blood-brain barrier integrity, thereby triggering chronic inflammation, potentially modulating the PI3K‑Akt‑GSK‑3β pathway, and linking peripheral insulin resistance to cerebral dysfunction; and (iv) a translational discussion of therapeutic strategies that target both microbiota and insulin pathways, including dietary modulation, probiotics and prebiotics, fecal microbiota transplantation, intranasal insulin, metformin, and metabolite-based agents, show promise. This review uniquely integrates taxonomic, functional, and therapeutic literature to propose a mechanistic microbiota–insulin resistance–AD axis and highlights the need for longitudinal and interventional trials.Keywords: Alzheimer’s disease, gut microbiome alterations, insulin resistance