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Emerging evidence suggests that infection-driven intestinal dysbiosis may function as an upstream contributor to systemic inflammation through disruption of gut barrier integrity. Increased permeability can facilitate the translocation of microbial components and metabolites into circulation, potentially influencing host immune programming via epigenetic mechanisms. Among CNS immune cells, microglia appear particularly susceptible to such peripheral cues due to their longevity and capacity for stimulus-dependent transcriptional adaptation. Experimental studies indicate that transient systemic immune challenges may induce persistent chromatin-level alterations within microglial regulatory regions, thereby reshaping their responsiveness to subsequent inflammatory stimuli or age-related stressors, including oxidative stress, chronic low-grade inflammation (inflammaging), and age-associated decline in cellular homeostatic and repair mechanisms. This phenomenon, often described as innate immune memory, may contribute to sustained neuroinflammatory activity and impaired synaptic function across the lifespan. Microbiota-derived metabolites, including short-chain fatty acids and tryptophan catabolites, have been implicated in modulating host transcriptional pathways through histone deacetylase inhibition and receptor-mediated signaling.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1815265","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:23:22Z","timestamp":1784867002000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Infection-driven gut dysbiosis and epigenetic programming of microglia: toward a systems level framework linking microbial metabolites, neuroinflammation, synaptic dysfunction, and probiotic modulation"],"prefix":"10.3389","volume":"16","author":[{"given":"Delin","family":"Han","sequence":"first","affiliation":[{"name":"School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences)","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences)","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/nu16040538","article-title":"Potential therapeutic effects of bifidobacterium breve MCC1274 on Alzheimer\u2019s disease pathologies in AppNL-GF mice","volume":"16","author":"Abdelhamid","year":"2024","journal-title":"Nutrients"},{"key":"B2","first-page":"1","article-title":"BACTERIAL AMYLOID CURLI INFLUENCES AGGREGATION OF AMYLOID BETA PEPTIDES ASSOCIATED WITH ALZHEIMER \u0301S DISEASE: University of Saskatchewan","volume":"2023","author":"Aboytes Flores","year":"2023"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00662","article-title":"Does severity of Alzheimer's disease contribute to its responsiveness to modifying gut microbiota? 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