{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T10:44:06Z","timestamp":1768214646379,"version":"3.49.0"},"reference-count":59,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jilin Province Science and Technology Development Plan Project","award":["YDZJ202401524ZYTS"],"award-info":[{"award-number":["YDZJ202401524ZYTS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD), a progressive brain disorder, is the most common form of dementia and necessitates the development of effective intervention strategies. Ginseng-Natto composite fermentation products (GN) have demonstrated beneficial bioactivities in mouse models of AD; however, the underlying mechanism of action through which GN ameliorates AD requires further elucidation. Methods: Mice received daily intragastric administration of low- or high-dose GN for 4 weeks, followed by intraperitoneal injection of scopolamine to induce the AD model. The pharmacological effects of GN were systematically evaluated using the Morris water maze test, ELISA, and H&amp;E staining. To further investigate the underlying mechanisms, 16S rRNA gene sequencing and metabolomics were employed to analyze the regulatory effects of GN on the gut\u2013brain axis. Additionally, Western blotting was performed to assess the impact of GN on blood\u2013brain barrier (BBB) integrity. Results: GN intervention significantly ameliorated cognitive deficits and attenuated neuropathological injury in AD mice, restoring the brain levels of acetylcholine (ACh), acetylcholinesterase (AChE), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), interleukin-6 (IL-6), and tumor necrosis factor-\u03b1 (TNF-\u03b1) to normal ranges. GN reshaped the gut microbiota by promoting beneficial bacteria and inhibiting pro-inflammatory strains. It also regulated key metabolic pathways related to amino acid and unsaturated fatty acid metabolism. This metabolic remodeling restored the compromised BBB integrity by upregulating tight junction proteins (ZO-1, Occludin and Claudin-1). Conclusions: Our findings demonstrate that GN ameliorates AD through a gut-to-brain pathway, mediated by reshaping the microbiota-metabolite axis and repairing the BBB. Thus, GN may represent a promising intervention candidate for AD.<\/jats:p>","DOI":"10.3390\/ph19010123","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T07:30:34Z","timestamp":1768203034000},"page":"123","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the Protective Mechanisms of Ginseng-Natto Composite Fermentation Products in Alzheimer\u2019s Disease: A Gut Microbiota and Metabolomic Approach"],"prefix":"10.3390","volume":"19","author":[{"given":"Zhimeng","family":"Li","sequence":"first","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiyang","family":"Yuan","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Scientific Research, Jilin Normal University, Siping 136000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoxin","family":"Ji","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuangzhuang","family":"Yao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingfang","family":"Kuang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xian","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0730-4475","authenticated-orcid":false,"given":"Shumin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China"},{"name":"Ginseng Scientific Research Institute, Changchun University of Chinese Medicine, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12929-019-0609-7","article-title":"Clinical trials of new drugs for Alzheimer disease","volume":"27","author":"Huang","year":"2020","journal-title":"J. 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