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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Midlife obesity is an established independent risk factor for age-related cognitive decline, yet direct causal experimental evidence and underlying gut microbial mechanisms remain poorly defined. Using a mouse model of high-fat diet (HFD)-induced obesity restricted to the midlife period (6\u201312 months of age) in male wild-type C57BL\/6J mice, we characterized the temporal and causal relationship between midlife weight gain and cognitive deterioration, and investigated the mediating function of Akkermansia muciniphila (Akk). Longitudinal body weight tracking across the lifespan revealed a stage-specific dynamic pattern, with sustained adipose tissue accumulation occurring during the midlife period (6\u201312 months of age). Midlife HFD exposure triggered multi-dimensional cognitive deficits accompanied by significant depletion of intestinal Akk, while oral supplementation of Akk effectively attenuated HFD-induced weight gain and ameliorated spatial, recognition and contextual memory impairments. Mechanistically, Akk suppressed hippocampal glial hyperactivation and proinflammatory factor upregulation, attenuated neuronal loss, and preserved hippocampal synaptic integrity. Serum metabolomics further identified midlife-specific metabolic remodeling characterized by dysregulated lipid metabolism and depleted microbiota-derived indole metabolites. Our findings establish a causal link between midlife obesity and accelerated cognitive aging, and identify Akk as a promising early intervention target for age-related cognitive decline.<\/jats:p>","DOI":"10.3390\/ijms27198771","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:19Z","timestamp":1790773279000},"page":"8771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Akkermansia muciniphila Ameliorates Midlife Obesity-Induced Cognitive Impairment via the Microbiota-Metabolism-Neuroinflammation Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiaomei","family":"Bian","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Laboratory for Clinical Medicine, Laboratory of Organ Synergy and Intelligent Regenerative Manufacturing, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jiaqi","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Laboratory for Clinical Medicine, Laboratory of Organ Synergy and Intelligent Regenerative Manufacturing, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Anrui","family":"He","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Weiran","family":"Jian","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Laboratory for Clinical Medicine, Laboratory of Organ Synergy and Intelligent Regenerative Manufacturing, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Xu","family":"Zha","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Laboratory for Clinical Medicine, Laboratory of Organ Synergy and Intelligent Regenerative Manufacturing, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e70021","DOI":"10.1002\/alz.70021","article-title":"Association between healthy lifestyle and cognitive decline, all-cause mortality, and mortality from cardiovascular and cerebrovascular diseases: A 10-year population-based prospective cohort study","volume":"21","author":"Li","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_2","first-page":"165","article-title":"Body mass index in midlife and dementia: Systematic review and meta-regression analysis of 589,649 men and women followed in longitudinal studies","volume":"8","author":"Albanese","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100652","DOI":"10.1016\/j.lanhl.2024.100652","article-title":"Role of age and exposure duration in the association between metabolic syndrome and risk of incident dementia: A prospective cohort study","volume":"5","author":"Qureshi","year":"2024","journal-title":"Lancet Healthy Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4434","DOI":"10.1038\/s41467-026-71141-4","article-title":"Sustained visceral fat loss is associated with attenuated brain atrophy and improved cognitive function in late midlife","volume":"17","author":"Pachter","year":"2026","journal-title":"Nat. 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