{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:55:18Z","timestamp":1790603718635,"version":"4.1.0"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gut microbial metabolism is increasingly implicated in Alzheimer\u2019s disease (AD), mild cognitive impairment (MCI), preclinical amyloid accumulation, and cognitive aging. However, existing reviews often focus on microbial taxonomy rather than the metabolite mediators that connect the gut ecosystem with AD pathology, neuroinflammation, and cognition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To systematically synthesize human and translational evidence on microbiota-derived or microbiota-associated metabolite signatures across the cognitive aging continuum using structured evidence synthesis, evidence mapping, and an evidence-weighted knowledge graph.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search of PubMed, the Web of Science Core Collection, and Academic Search Premier via EBSCOhost was conducted to identify eligible studies. Citation checking and targeted full-text retrieval were used during screening and evidence verification. After de-duplication, records were screened by population, exposure or intervention, comparator, outcome layer, and study design. Human core, human bridge, human intervention, mechanistic\/translational, and resource\/background-mechanism evidence were coded separately. Module-level quantitative summaries were retained only where data were sufficiently comparable; otherwise, structured direction-of-effect synthesis and evidence mapping were used. Overlapping Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) bile-acid analyses were synthesized as complementary outcome layers rather than treated as independent replications of the same association.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The final evidence pool contains 60 records, including 32 direct, bridge, or intervention human evidence records and 28 mechanistic, translational, animal, cellular, resource, or background-mechanism records. Bile-acid profiles and short-chain fatty acid (SCFA)-related functional capacity were recurrent human evidence modules. Trimethylamine N-oxide (TMAO)\/choline-related findings were context dependent, varying by biological matrix, population, renal function, and cardiometabolic context, whereas selected tryptophan\/indole\/kynurenine pathways remained emerging. Across these metabolite modules, the evidence-weighted knowledge graph showed recurrent convergence on barrier dysfunction, inflammatory and glial signaling, and mitochondrial stress, while retaining context-dependent conflicts and gaps in human validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The current literature points to a convergent network of microbiota-related metabolic pathways rather than a single metabolite marker or causal route. The synthesis prioritizes external validation of bile-acid signatures, matched multi-compartment assessment of SCFA- and TMAO-related pathways, and direct human testing of indole\/kynurenine and lipid-like mechanisms. These priorities require longitudinal and interventional studies with harmonized metabolomics, AD biomarkers, and cognitive outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1925387","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:59:47Z","timestamp":1790600387000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbiota-derived metabolite signatures in Alzheimer\u2019s disease across the cognitive aging continuum: a human-focused systematic review and evidence-weighted knowledge graph"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoteng","family":"He","sequence":"first","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiqiu","family":"Song","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref2","doi-asserted-by":"crossref","DOI":"10.46658\/JBIMES-24-01","volume-title":"JBI Manual for Evidence Synthesis","author":"Aromataris","year":"2024"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3313","DOI":"10.3390\/nu17203313","article-title":"Efficacy and safety of Lactobacillus delbrueckii subsp. lactis CKDB001 supplementation on cognitive function in mild cognitive impairment: a randomized, double-blind, placebo-controlled clinical trial","volume":"17","author":"Baek","year":"2025","journal-title":"Nutrients"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and biomarker changes in dominantly inherited Alzheimer's disease","volume":"367","author":"Bateman","year":"2012","journal-title":"N. 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