{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:02:21Z","timestamp":1785420141645,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000098","name":"National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS113337"],"award-info":[{"award-number":["R01NS113337"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01NS113337"],"award-info":[{"award-number":["R01NS113337"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alterations of gut microbiota are common in chronic kidney disease (CKD) and contribute to increased uremic toxins including indoxyl sulfate (IS), p-cresyl sulfate (pCS) and trimethylamine N-oxide (TMAO), which are linked to cerebrovascular disease risk. This study examined the kidney\u2013gut\u2013brain axis in CKD mice and in dialysis patients. Male and female mice with adenine-induced CKD were fed a high-amino-acid (HAA) diet to increase precursors of gut-derived uremic toxins. A subgroup of mice received antibiotics in drinking water to suppress gut microbiota and evaluate its role in toxin generation. Behavior tests, gut microbiome composition and brain histology for cerebral microhemorrhages were analyzed. CKD mice had higher serum levels of creatinine, cystatin C and gut-derived toxins, a 2.5-fold increase in brain microhemorrhages, and decreased locomotor activity. The HAA diet significantly increased serum TMAO but not IS and pCS, and all three toxins were reduced by antibiotic therapy. Sex differences were observed; in male animals, higher TMAO was associated with increased brain microhemorrhages, whereas in female mice, pCS was associated with brain microhemorrhage burden. The suppression of toxins with antibiotics improved working memory in male animals. Gut microbiota analysis revealed the expansion of Lactobacillus and Ileibacterium in CKD mice. The HAA diet and antibiotics altered gut microbiota composition without changing alpha diversity. The human study utilized biobanked serum samples and a retrospective review of brain imaging scans in a hemodialysis patient cohort; TMAO levels were associated with increased lobar microbleeds. Our study supports a role for bacterial-derived uremic toxins in the kidney\u2013gut\u2013brain axis and cerebral microhemorrhage formation in CKD.<\/jats:p>","DOI":"10.3390\/ijms27136020","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:43:14Z","timestamp":1783345394000},"page":"6020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the Kidney\u2013Gut\u2013Brain Axis in CKD: Uremic Toxins and Brain Microhemorrhages"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-3442","authenticated-orcid":false,"given":"Yitong","family":"Zhao","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6455-8519","authenticated-orcid":false,"given":"Su Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Irvine, CA 92697, USA"},{"name":"Department of Internal Medicine, College of Medicine, Dong-A University, Busan 49201, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8414-3003","authenticated-orcid":false,"given":"Whitney","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Floriolli","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7645-7865","authenticated-orcid":false,"given":"Peter","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2571-3803","authenticated-orcid":false,"given":"Yoko","family":"Narasaki","sequence":"additional","affiliation":[{"name":"Division of Nephrology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy S.","family":"You","sequence":"additional","affiliation":[{"name":"Division of Nephrology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90073, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4106-3334","authenticated-orcid":false,"given":"Annlia","family":"Paganini-Hill","sequence":"additional","affiliation":[{"name":"Beckman Laser Institute and Medical Clinic, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA 92697, USA"},{"name":"Department of Pathology & Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3118-1073","authenticated-orcid":false,"given":"Wei Ling","family":"Lau","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Irvine, CA 92697, USA"},{"name":"Department of Physiology & Biophysics, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1042\/CS20171107","article-title":"Altered microbiome in chronic kidney disease: Systemic effects of gut-derived uremic toxins","volume":"132","author":"Lau","year":"2018","journal-title":"Clin. 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