{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:35:28Z","timestamp":1792604128069,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1AG062480"],"award-info":[{"award-number":["RF1AG062480"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late\u2010onset Alzheimer's disease (AD), associated with early brain metabolic dysfunction and gut microbiome alterations. Targeting these early changes through dietary interventions may reduce AD risk in asymptomatic carriers. This study evaluated whether a ketogenic diet (KD) could reshape the gut microbiome and enhance key brain metabolite levels in young APOE4 mice, using APOE3 mice as a neutral\u2010risk comparison. Male and female APOE3 and APOE4 mice were fed either a control diet or KD for 16\u2009weeks, starting at 12\u2009weeks of age. We used shotgun metagenomics and targeted brain metabolomics to identify microbe\u2013metabolite signatures linked to neuroprotection. KD increased beneficial species such as\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Lactobacillus johnsonii<\/jats:italic>\n                    <\/jats:styled-content>\n                    and\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Lactobacillus reuteri<\/jats:italic>\n                    <\/jats:styled-content>\n                    while reducing pathogenic\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Bacteroides intestinalis<\/jats:italic>\n                    <\/jats:styled-content>\n                    . These microbial shifts correlated with improved brain metabolites related to mitochondrial function, neurotransmitter balance, redox homeostasis, and lipid metabolism. Notably,\n                    <jats:italic>Lactobacillus<\/jats:italic>\n                    species and\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>B.\u2009intestinalis<\/jats:italic>\n                    <\/jats:styled-content>\n                    exhibited inverse correlations with key brain metabolite levels, suggesting their roles as both modulators and biomarkers of brain health. APOE4 females showed the greatest benefits, including restored microbiome diversity and normalization of brain metabolite levels. In contrast, APOE3 mice showed microbiome changes but limited brain metabolic responses. These findings highlight KD's potential to reprogram the gut\u2013brain axis in a genotype\u2010 and sex\u2010dependent manner, supporting its use as a precision nutrition strategy to reduce AD risk, particularly in asymptomatic female APOE4 carriers.\n                  <\/jats:p>","DOI":"10.1111\/jnc.70216","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T03:20:06Z","timestamp":1756783206000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ketogenic Diet Modulates Gut Microbiota\u2013Brain Metabolite Axis in a Sex\u2010 and Genotype\u2010Specific Manner in\u00a0\n                    <scp>APOE4<\/scp>\n                    Mice"],"prefix":"10.1111","volume":"169","author":[{"given":"Kira","family":"Ivanich","sequence":"first","affiliation":[{"name":"Department of Radiology University of Missouri  Columbia Missouri USA"},{"name":"Roy Blunt NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Interdisciplinary Neuroscience Program University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Yackzan","sequence":"additional","affiliation":[{"name":"Sanders\u2010Brown Center on Aging University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeoseh","family":"Flemister","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Hsuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Missouri  Columbia Missouri USA"},{"name":"Roy Blunt NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Nebraska \u2013 Omaha  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chen","sequence":"additional","affiliation":[{"name":"Sanders\u2010Brown Center on Aging University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucille M.","family":"Yanckello","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenna","family":"Sun","sequence":"additional","affiliation":[{"name":"Sanders\u2010Brown Center on Aging University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chetan","family":"Aware","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Missouri  Columbia Missouri USA"},{"name":"Roy Blunt NextGen Precision Health University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maalavika","family":"Govindarajan","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Missouri  Columbia Missouri USA"},{"name":"Roy Blunt NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Interdisciplinary Neuroscience Program University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler","family":"Kramer","sequence":"additional","affiliation":[{"name":"Institute of Data Science &amp; Informatics University of Missouri  Columbia Missouri USA"},{"name":"Bioinformatics and Analytics Core University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Ericsson","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology University of Missouri  Columbia Missouri USA"},{"name":"Metagenomics Center University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5197-2219","authenticated-orcid":false,"given":"Ai\u2010Ling","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Missouri  Columbia Missouri USA"},{"name":"Roy Blunt NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Interdisciplinary Neuroscience Program University of Missouri  Columbia Missouri USA"},{"name":"Sanders\u2010Brown Center on Aging University of Kentucky  Lexington Kentucky USA"},{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24135"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2019.02.023"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2021.106793"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11940-008-0043-8"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-42381-x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-326269"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0694-180"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-9-S2-S16"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54187-x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/ac901536h"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R048975"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.732120"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2020.10.005"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1227203"},{"key":"e_1_2_9_16_1","first-page":"15","article-title":"Glucose Metabolism Is a Better Marker for Predicting Clinical Alzheimer's Disease Than Amyloid or Tau","volume":"4","author":"Hammond T. 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