{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T18:20:12Z","timestamp":1783362012984,"version":"3.54.6"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>This study integrated network pharmacology, bioinformatics, and molecular docking to explore potential immune-inflammatory pathways associated with the relationship between gut microbiota-derived metabolites and Alzheimer\u2019s disease (AD). A total of 260 gut microbiota \u2013 derived metabolites were initially retrieved, and 196 common targets were identified by intersecting predicted metabolite-associated targets with AD-related targets. Further screening identified 14 key overlapping targets, including IL6, NFKB1, IL1B, PTGS2, TLR4, and PPARG. Protein\u2013protein interaction (PPI) network analysis identified IL6, NFKB1, IL1B, CXCL8, PPARG, FOS, and JUN as central hub genes. Functional enrichment analyses indicated that these targets were mainly involved in immune-inflammatory responses, response to lipopolysaccharide, oxidative stress-related processes, and regulation of apoptosis. KEGG pathway analysis further suggested that the overlapping targets were associated with several inflammation-related signaling pathways, including the NOD-like receptor, TNF, NF-\u03baB, and MAPK signaling pathways. In silico pharmacokinetic and toxicity evaluation showed that several representative metabolites exhibited heterogeneous but informative drug-likeness and pharmacokinetic\/toxicity-related profiles relevant to gut\u2013brain-axis hypothesis generation. Molecular docking was performed as an exploratory structural assessment and suggested that selected metabolites, including Enterodiol, Coumarin, and 3,9-dihydroxy-6H-benzo[c]chromen-6-one, showed top-ranked predicted docking poses in computationally identified surface-accessible pockets of representative hub proteins such as IL6 and NFKB1, with docking scores ranging from \u2013 6.8 to \u2013 8.1 kcal\/mol. These docking scores were interpreted only as qualitative descriptors of predicted structural compatibility and were not used to infer quantitative biological activity, target inhibition, or therapeutic efficacy. Overall, this study prioritizes a potential multi-target immune-inflammatory network centered on IL6, NFKB1, and IL1B, providing a hypothesis-generating framework for understanding the possible role of gut microbiota-derived metabolites in AD-related neuroimmune regulation. Further experimental studies are required to validate the predicted metabolite\u2013target associations and clarify their biological relevance.<\/jats:p>","DOI":"10.1371\/journal.pone.0352999","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T17:57:27Z","timestamp":1783360647000},"page":"e0352999","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Key targets and mechanisms by which gut microbiota-derived metabolites regulate Alzheimer\u2019s disease through the immune - inflammatory pathway: Based on network pharmacology and molecular docking"],"prefix":"10.1371","volume":"21","author":[{"given":"Lei","family":"Miao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwei","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0399-3370","authenticated-orcid":true,"given":"Guanghong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"issue":"1","key":"pone.0352999.ref001","doi-asserted-by":"crossref","first-page":"2605768","DOI":"10.1080\/19490976.2025.2605768","article-title":"Blautia coccoides-derived metabolite trimethylamine-N-oxide exacerbates Alzheimer\u2019s disease progression via targeting HIF1\u03b1 signaling","volume":"18","author":"X Lv","year":"2026","journal-title":"Gut Microbes"},{"issue":"1","key":"pone.0352999.ref002","doi-asserted-by":"crossref","first-page":"2592413","DOI":"10.1080\/13510002.2025.2592413","article-title":"Unraveling the potential of gasotransmitters as neurogenic and neuroprotective molecules: focus on Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"31","author":"S Sim\u00e3o","year":"2026","journal-title":"Redox Rep"},{"issue":"5","key":"pone.0352999.ref003","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.4103\/NRR.NRR-D-24-01481","article-title":"Secretase inhibition in Alzheimer\u2019s disease therapeutics reveals functional roles of amyloid-beta42","volume":"21","author":"T Daly","year":"2026","journal-title":"Neural Regen Res"},{"issue":"5","key":"pone.0352999.ref004","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.4103\/NRR.NRR-D-24-01344","article-title":"Lactate and lactylation modifications in neurological disorders","volume":"21","author":"Y Gu","year":"2026","journal-title":"Neural Regen Res"},{"issue":"5","key":"pone.0352999.ref005","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.4103\/NRR.NRR-D-24-01539","article-title":"Neuroinflammation in neurodegenerative diseases: focusing on the mediation of T lymphocytes","volume":"21","author":"K Li","year":"2026","journal-title":"Neural Regen Res"},{"key":"pone.0352999.ref006","doi-asserted-by":"crossref","first-page":"214619","DOI":"10.1016\/j.bioadv.2025.214619","article-title":"Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer\u2019s disease: modulating oxidative stress and neuroinflammation","volume":"181","author":"J Xu","year":"2026","journal-title":"Biomater Adv"},{"key":"pone.0352999.ref007","doi-asserted-by":"crossref","first-page":"121048","DOI":"10.1016\/j.jep.2025.121048","article-title":"From medicinal herb to neuroprotective candidate: a review of curculigoside\u2019s potential in central nervous system disorders","volume":"359","author":"S-G Zheng","year":"2026","journal-title":"J Ethnopharmacol"},{"issue":"3","key":"pone.0352999.ref008","doi-asserted-by":"crossref","first-page":"972","DOI":"10.4103\/NRR.NRR-D-24-01054","article-title":"Potential common pathogenesis of several neurodegenerative diseases","volume":"21","author":"T Fan","year":"2026","journal-title":"Neural Regen Res"},{"key":"pone.0352999.ref009","doi-asserted-by":"crossref","first-page":"124804","DOI":"10.1016\/j.carbpol.2025.124804","article-title":"Chitosan\/selenium nanoparticles Pickering emulsion prolong quercetin retention time to ameliorates cognitive disorder: focus on restoring the metabolic disorder and gut microbiota","volume":"375","author":"J Mei","year":"2026","journal-title":"Carbohydr Polym"},{"issue":"6","key":"pone.0352999.ref010","article-title":"A microbiome quantitative trait locus in SLC39A8 modulates disease severity in synucleinopathy-induced models of Parkinson\u2019s disease","volume":"35","author":"JC Yang","year":"2026","journal-title":"Hum Mol Genet"},{"key":"pone.0352999.ref011","article-title":"Goat milk fat globule membrane supplementation ameliorates Alzheimer disease cognitive impairment by modulating the gut microbiota","author":"H Li","year":"2026","journal-title":"J Agric Food Chem"},{"key":"pone.0352999.ref012","doi-asserted-by":"crossref","first-page":"110195","DOI":"10.1016\/j.jnutbio.2025.110195","article-title":"Fermented foods and brain health: Gut-brain axis mechanisms and clinical insights","volume":"149","author":"M Bodur","year":"2026","journal-title":"J Nutr Biochem"},{"key":"pone.0352999.ref013","doi-asserted-by":"crossref","first-page":"108082","DOI":"10.1016\/j.phrs.2025.108082","article-title":"Advance in neuroprotective effects of proanthocyanidins (PCs): structure, absorption, bioactivities, mechanism, and perspectives","volume":"223","author":"Y Zhao","year":"2026","journal-title":"Pharmacol Res"},{"key":"pone.0352999.ref014","doi-asserted-by":"crossref","first-page":"106138","DOI":"10.1016\/j.bbi.2025.106138","article-title":"Microbiota-gut-brain axis dysregulation in Alzheimer\u2019s disease and its modulation through probiotic supplementation","volume":"131","author":"M Marizzoni","year":"2026","journal-title":"Brain Behav Immun"},{"key":"pone.0352999.ref015","article-title":"Sex hormones, the gut microbiome, and neurodegenerative diseases: lifespan perspective","author":"S Stahlke","year":"2025","journal-title":"Neural Regen Res"},{"issue":"1","key":"pone.0352999.ref016","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s12035-025-05598-7","article-title":"Alterations of gut microbiota and microbial metabolites in parkinson\u2019s disease: a systematic review","volume":"63","author":"S Davoody","year":"2025","journal-title":"Mol Neurobiol"},{"key":"pone.0352999.ref017","doi-asserted-by":"crossref","first-page":"124075","DOI":"10.1016\/j.lfs.2025.124075","article-title":"Drug enteric metabolism in gut microbiota-brain crosstalk","volume":"383","author":"S Maramai","year":"2025","journal-title":"Life Sci"},{"key":"pone.0352999.ref018","doi-asserted-by":"crossref","first-page":"121073","DOI":"10.1016\/j.jep.2025.121073","article-title":"Renshen Shouwu formula alleviates Alzheimer\u2019s disease pathology by modulating tryptophan metabolism and activating the SIRT1 signaling pathway","volume":"359","author":"J Liu","year":"2026","journal-title":"J Ethnopharmacol"},{"issue":"3","key":"pone.0352999.ref019","doi-asserted-by":"crossref","first-page":"938","DOI":"10.4103\/NRR.NRR-D-24-01265","article-title":"Short-chain fatty acids mediate enteric and central nervous system homeostasis in Parkinson\u2019s disease: Innovative therapies and their translation","volume":"21","author":"S Pang","year":"2026","journal-title":"Neural Regen Res"},{"key":"pone.0352999.ref020","doi-asserted-by":"crossref","first-page":"124610","DOI":"10.1016\/j.carbpol.2025.124610","article-title":"Demonstration of the effective intestinal immunity activity of a high branched rhamnogalacturonan-I type pectin from wolfberry via exploration its interaction with colon biological and mechanical barrier","volume":"373","author":"J Gu","year":"2026","journal-title":"Carbohydr Polym"},{"key":"pone.0352999.ref021","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.ijbiomac.2020.05.180","article-title":"Yeast beta-glucan alleviates cognitive deficit by regulating gut microbiota and metabolites in Abeta(1)(-)(42)-induced AD-like mice","volume":"161","author":"M Xu","year":"2020","journal-title":"Int J Biol Macromol"},{"key":"pone.0352999.ref022","doi-asserted-by":"crossref","first-page":"128391","DOI":"10.1016\/j.micres.2025.128391","article-title":"The gut microbiota in post-stroke depression: a systematic review of microbial mechanisms and therapeutic targeting of neuroinflammation","volume":"303","author":"Q Zhang","year":"2026","journal-title":"Microbiol Res"},{"key":"pone.0352999.ref023","doi-asserted-by":"crossref","first-page":"1729708","DOI":"10.3389\/fmicb.2025.1729708","article-title":"Microbiome-targeted Alzheimer\u2019s interventions via gut-brain axis","volume":"16","author":"R Qin","year":"2025","journal-title":"Front Microbiol"},{"key":"pone.0352999.ref024","doi-asserted-by":"crossref","first-page":"118861","DOI":"10.1016\/j.biopha.2025.118861","article-title":"Microbiota-brain interaction: The role of gut-derived proteins in addressing various neurological disorders including Parkinson\u2019s (PD) and Alzheimer\u2019s diseases (AD)","volume":"193","author":"T Taj","year":"2025","journal-title":"Biomed Pharmacother"},{"issue":"1","key":"pone.0352999.ref025","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11064-025-04613-6","article-title":"Progress and perspectives on the estrogen-microbiota-brain axis in Alzheimer\u2019s Disease","volume":"51","author":"M Wang","year":"2025","journal-title":"Neurochem Res"},{"issue":"1","key":"pone.0352999.ref026","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s43556-026-00443-2","article-title":"Alzheimer\u2019s disease: from molecular pathways to therapies","volume":"7","author":"J-Q Feng","year":"2026","journal-title":"Mol Biomed"},{"issue":"6","key":"pone.0352999.ref027","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.3390\/ijms27062791","article-title":"Fecal microbiota transplantation from APP\/PS1 mice induces Th17-related inflammatory parameters and pathological changes in the gut-brain axis of healthy C57BL\/6J mice","volume":"27","author":"D Lei","year":"2026","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0352999.ref028","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12974-024-03195-4","article-title":"Secoisolariciresinol diglucoside attenuates neuroinflammation and cognitive impairment in female Alzheimer\u2019s disease mice via modulating gut microbiota metabolism and GPER\/CREB\/BDNF pathway","volume":"21","author":"M Jia","year":"2024","journal-title":"J Neuroinflammation"},{"issue":"4","key":"pone.0352999.ref029","doi-asserted-by":"crossref","first-page":"101220","DOI":"10.1016\/j.ajcnut.2026.101220","article-title":"Plasma n6 polyunsaturated fatty acid levels and risk for dementia: a prospective observational study from the United Kingdom Biobank","volume":"123","author":"A Sala-Vila","year":"2026","journal-title":"Am J Clin Nutr"},{"issue":"4","key":"pone.0352999.ref030","doi-asserted-by":"crossref","first-page":"101891","DOI":"10.1016\/j.gendis.2025.101891","article-title":"Receptor-mediated endocytosis by Megalin: exploring its role in ligand interaction and disease mechanisms","volume":"13","author":"X Zhang","year":"2025","journal-title":"Genes Dis"},{"key":"pone.0352999.ref031","article-title":"Current advances in 7-hydroxycoumarin derivatives as potential therapeutic agents for Alzheimer\u2019s disease","author":"H Sharmah","year":"2026","journal-title":"Mol Divers"},{"issue":"1","key":"pone.0352999.ref032","doi-asserted-by":"crossref","DOI":"10.3390\/molecules31010195","article-title":"Antioxidant, anti-inflammatory, and chemical composition analysis of in vitro Huperzia serrata thallus and wild Huperzia serrata","volume":"31","author":"Y Huang","year":"2026","journal-title":"Molecules"},{"issue":"1","key":"pone.0352999.ref033","doi-asserted-by":"crossref","first-page":"2374608","DOI":"10.1080\/19490976.2024.2374608","article-title":"Quinic acid alleviates high-fat diet-induced neuroinflammation by inhibiting DR3\/IKK\/NF-\u03baB signaling via gut microbial tryptophan metabolites","volume":"16","author":"S Li","year":"2024","journal-title":"Gut Microbes"},{"issue":"2","key":"pone.0352999.ref034","article-title":"Divergent CNS-peripheral signaling reflects astrocyte dysfunction and contributes to insulin resistance in early A\u03b2 pathology","volume":"74","author":"K-Y Liao","year":"2026","journal-title":"Glia"},{"key":"pone.0352999.ref035","doi-asserted-by":"crossref","first-page":"120785","DOI":"10.1016\/j.jep.2025.120785","article-title":"ShengHui Decoction mitigates oxidative stress and neuroinflammation in AlCl3-induced AD zebrafish via activating Nrf2\/HO-1 and inhibiting NF-\u03baB signaling pathway","volume":"356","author":"M Kong","year":"2026","journal-title":"J Ethnopharmacol"},{"issue":"1","key":"pone.0352999.ref036","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3390\/ijms27010511","article-title":"Propyl gallate attenuates methylglyoxal-induced Alzheimer-like cognitive deficits and neuroinflammation in mice","volume":"27","author":"H-Y Tsai","year":"2026","journal-title":"Int J Mol Sci"},{"key":"pone.0352999.ref037","doi-asserted-by":"crossref","first-page":"115585","DOI":"10.1016\/j.expneurol.2025.115585","article-title":"Calcaratarin D exerts neuroprotective effects in Alzheimer\u2019s disease mouse model by inhibiting CERT-mediated NF-\u03baB pathway","volume":"397","author":"J-Z Pan","year":"2026","journal-title":"Exp Neurol"},{"issue":"9","key":"pone.0352999.ref038","doi-asserted-by":"crossref","first-page":"4122","DOI":"10.4103\/NRR.NRR-D-25-00927","article-title":"Microbiota-gut-brain axis and bile acids-driven neuromodulation","volume":"21","author":"T Dong","year":"2026","journal-title":"Neural Regen Res"},{"issue":"1","key":"pone.0352999.ref039","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3390\/ijms27010369","article-title":"More than dysbiosis: imbalance in humoral and neuronal bidirectional crosstalk between gut and brain in Alzheimer\u2019s disease","volume":"27","author":"G Tassibekova","year":"2025","journal-title":"Int J Mol Sci"},{"key":"pone.0352999.ref040","doi-asserted-by":"crossref","first-page":"121035","DOI":"10.1016\/j.jep.2025.121035","article-title":"Shenqi funeng xingnao prescription regulated the TNF\/NOD\u2012like receptor signaling pathway and brain-gut axis dysfunction caused by exercise-induced fatigue","volume":"358","author":"D Xu","year":"2026","journal-title":"J Ethnopharmacol"},{"key":"pone.0352999.ref041","doi-asserted-by":"crossref","first-page":"154371","DOI":"10.1016\/j.tox.2025.154371","article-title":"Food-borne polystyrene microplastic exposure exacerbates cognitive deficiency via enhanced neuronal synaptic damage and neuroinflammation in Alzheimer\u2019s disease","volume":"520","author":"C Liu","year":"2026","journal-title":"Toxicology"},{"key":"pone.0352999.ref042","doi-asserted-by":"crossref","first-page":"117251","DOI":"10.1016\/j.jpba.2025.117251","article-title":"Integrated analysis strategies reveal the pharmacodynamic substances and action mechanisms of Huangqi San in the treatment of Alzheimer\u2019s disease","volume":"270","author":"Y Xu","year":"2026","journal-title":"J Pharm Biomed Anal"},{"issue":"2","key":"pone.0352999.ref043","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s10787-025-02090-5","article-title":"From nutrition to therapeutics: the diverse inflammopharmacological and biomedical roles of astaxanthin","volume":"34","author":"HR Ghaiad","year":"2026","journal-title":"Inflammopharmacology"},{"issue":"2","key":"pone.0352999.ref044","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1007\/s11357-025-02062-1","article-title":"The aging gut-glia-immune axis in alzheimer\u2019s disease: microbiome-derived mediators of neuroinflammation and therapeutic innovation","volume":"48","author":"PA Mir","year":"2026","journal-title":"Geroscience"},{"key":"pone.0352999.ref045","doi-asserted-by":"crossref","first-page":"120586","DOI":"10.1016\/j.jep.2025.120586","article-title":"Bazi Bushen improves cognitive dysfunction in 5\u00d7FAD mice by targeting amyloid pathology, neuroinflammation and cellular senescence","volume":"355","author":"H Huang","year":"2026","journal-title":"J Ethnopharmacol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0352999","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T17:57:34Z","timestamp":1783360654000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0352999"}},"subtitle":[],"editor":[{"given":"Shailza","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,6]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0352999","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,6]]}}}