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The gut microbiome may mediate diet effects, and specific microbes may be particularly significant contributors to these processes. Oscillospira, a genus of gut-dwelling bacteria, has been implicated as a key microbial target. Other peripheral contributors may include short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), insulin resistance, and microbial translocation. Methods: We determined the effects of long-term (31 months, ~9 human years) consumption of a Mediterranean or Western-type diet on Oscillospira abundance, fecal SCFAs, plasma BCAAs, soluble CD14 (sCD14), and insulin responses in a randomized trial of 38 middle-aged female cynomolgus macaques (Macaca fascicularis). We determined diet effects and associations between dependent variables. For variables that were affected by diet composition and significantly associated with Oscillospira, we tested whether Oscillospira abundance mediated the effects of diet. Results: The Mediterranean diet resulted in higher Oscillospira (p = 0.004) and SCFAs (acetate p = 0.002; propionate p = 0.049) and lower BCAAs (isoleucine p = 0.035; leucine p = 0.007; valine p &lt; 0.001). The Western diet increased insulin resistance (p = 0.040) and WM loss (p = 0.011). Oscillospira abundance was negatively associated with BCAAs (leucine p = 0.007; valine p = 0.005) and insulin resistance (insulin AUC: p = 0.024; increase in insulin AUC from pretreatment: p = 0.020), with trends for isoleucine (p = 0.066) and sCD14 (p = 0.103). Oscillospira abundance was positively associated with acetate (p = 0.032) and WM volume changes (p = 0.012). Oscillospira abundance significantly mediated the effects of diet on white matter volume changes (p = 0.020) and on insulin resistance (insulin AUC: p = 0.012 at study end; increase in insulin AUC during study: p = 0.020), presenting potential pathways through which diet may influence the brain. Conclusions: These findings suggest that diet-driven differences in Oscillospira are linked to metabolic regulation and white matter integrity, and Oscillospira may mediate the relationships. The results highlight a potential role for diet\u2013microbiome interactions in shaping metabolic and brain aging trajectories.<\/jats:p>","DOI":"10.3390\/nu18071124","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:23:17Z","timestamp":1774963397000},"page":"1124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dietary Pattern-Induced Gut Microbiota Differences Are Associated with White Matter Volume Changes in Middle-Aged Female Macaques"],"prefix":"10.3390","volume":"18","author":[{"given":"Brett M.","family":"Frye","sequence":"first","affiliation":[{"name":"Department of Pathology\/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Biology and Biochemistry, Emory and Henry University, 30461 Garnand Drive, Emory, VA 24327-9001, USA"},{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haleigh","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Biology and Biochemistry, Emory and Henry University, 30461 Garnand Drive, Emory, VA 24327-9001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob D.","family":"Negrey","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"School of Anthropology, The University of Arizona, 1009 E South Campus Dr, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Sutphen","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4250-1749","authenticated-orcid":false,"given":"Ravinder","family":"Nagpal","sequence":"additional","affiliation":[{"name":"Department of Health, Nutrition, and Food Sciences, Florida State University, 120 Convocation Way, Tallahassee, FL 32304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongchul","family":"Kim","sequence":"additional","affiliation":[{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Radiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Barcus","sequence":"additional","affiliation":[{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Radiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel N.","family":"Lockhart","sequence":"additional","affiliation":[{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Internal Medicine\/Gerontology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher T.","family":"Whitlow","sequence":"additional","affiliation":[{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Radiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet A.","family":"Tooze","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4504-1597","authenticated-orcid":false,"given":"Hariom","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Brain Repair, University of South Florida, 3000 Medical Park Dr #340, Tampa, FL 33613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Craft","sequence":"additional","affiliation":[{"name":"Wake Forest Alzheimer\u2019s Disease Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"},{"name":"Department of Internal Medicine\/Gerontology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Register","sequence":"additional","affiliation":[{"name":"Department of Pathology\/Comparative Medicine, Wake Forest 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