Journal Article

Association Between the Gut Microbiota and Alzheimer’s Disease: An Update on Signaling Pathways and Translational Therapeutics

Dhapola, Rishika, Singh, Sunil K., Medhi, Bikash, Kumari, Sneha, HariKrishnaReddy, Dibbanti, Sharma, Prajjwal, Kulkarni, Rutweek

2025

Overview

Alzheimer’s disease (AD) is a cognitive disease with high morbidity and mortality. In AD patients, the diversity of the gut microbiota is altered, which influences pathology through the gut–brain axis. Probiotic therapy alleviates pathological and psychological consequences by restoring the diversity of the gut microbial flora. This study addresses the role of altered gut microbiota in the progression of neuroinflammation, which is a major hallmark of AD. This process begins with the activation of glial cells, leading to the release of proinflammatory cytokines and the modulation of cholinergic anti-inflammatory pathways. Short-chain fatty acids, which are bacterial metabolites, provide neuroprotective effects and maintain blood‒brain barrier integrity. Furthermore, the gut microbiota stimulates oxidative stress and mitochondrial dysfunction, which promote AD progression. The signaling pathways involved in gut dysbiosis-mediated neuroinflammation-mediated promotion of AD include cGAS-STING, C/EBPβ/AEP, RAGE, TLR4 Myd88, and the NLRP3 inflammasome. Preclinical studies have shown that natural extracts such as Ganmaidazao extract, isoorentin, camelia oil, Sparassis crispa-1 , and xanthocerasides improve gut health and can delay the worsening of AD. Clinical studies using probiotics such as Bifidobacterium spp., yeast beta-glucan, and drugs such as sodium oligomannate and rifaximine have shown improvements in gut health, resulting in the amelioration of AD symptoms. This study incorporates the most current research on the pathophysiology of AD involving the gut microbiota and highlights the knowledge gaps that need to be filled to develop potent therapeutics against AD.

• Publisher: Springer US,Springer Nature B.V
• Subject: Alzheimer Disease - metabolism / Alzheimer Disease - microbiology / Alzheimer Disease - therapy / Alzheimer's disease / Animals / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Cell activation / Cell Biology / Dysbacteriosis / Gastrointestinal Microbiome - drug effects / Gastrointestinal Microbiome - physiology / Glial cells / Gut microbiota / Gut-brain axis / Humans / Inflammasomes / Inflammation / Intestinal microflora / Microbiota / Morbidity / MyD88 protein / Neurobiology / Neurodegenerative diseases / Neurology / Neuroprotection / Neurosciences / Oxidative stress / Pathophysiology / Probiotics / Probiotics - therapeutic use / Review / Signal transduction / Signal Transduction - physiology / TLR4 protein / Toll-like receptors / Translational Research, Biomedical - methods / Translational Science, Biomedical - methods