{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:28:14Z","timestamp":1785432494401,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["Grant 32570777 and Grant 32300545"],"award-info":[{"award-number":["Grant 32570777 and Grant 32300545"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Grant 32570777 and Grant 32300545"],"award-info":[{"award-number":["Grant 32570777 and Grant 32300545"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["Grant 2662025XXPY004"],"award-info":[{"award-number":["Grant 2662025XXPY004"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Growing evidence links gut microbiota dysbiosis to neurodegenerative diseases (NDs) such as Alzheimer\u2019s disease and Parkinson\u2019s disease, yet the field remains dominated by correlational observations rather than experimentally validated causal mechanisms. In this hypothesis-generating Perspective, we propose that causal inference in microbiota-associated neurodegeneration may be strengthened by combining two complementary lenses: evolutionary biomedicine and microbial metabolism. Because evolutionary information carries intrinsic temporal and causal structure, it can provide biological prior knowledge for inferring causal mechanisms of diseases. Human Accelerated Regions (HARs), genomic loci conserved across mammals but rapidly divergent in the human lineage, offer an anchor for identifying human-specific host\u2013microbe co-evolutionary units relevant to NDs. We further hypothesize that microbial metabolites represent one class of mechanistically testable intermediates linking host genetic background, gut microbial ecology, and neurodegenerative phenotypes. This integrated evolutionary-metabolic perspective offers a tractable path from correlation toward mechanism in gut microbiota\u2013ND research.<\/jats:p>","DOI":"10.3390\/metabo16050337","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration"],"prefix":"10.3390","volume":"16","author":[{"given":"Guangyan","family":"Tang","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwen","family":"Guo","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Quan","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1126\/science.abm7759","article-title":"Codiversification of gut microbiota with humans","volume":"377","author":"Suzuki","year":"2022","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1038\/s41467-022-31502-1","article-title":"An expanded reference map of the human gut microbiome reveals hundreds of previously unknown species","volume":"13","author":"Leviatan","year":"2022","journal-title":"Nat. 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