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Investigating the Kidney-Gut-Brain Axis in CKD: Uremic Toxins and Brain Microhemorrhages.

Overview

Authors: Yitong Zhao1, Su Mi Lee1,2, Whitney Li1, David Floriolli3, Peter Chang3, Yoko Narasaki4, Amy S You4, Kamyar Kalantar-Zadeh5, Connie M Rhee4, Han Liu1, Tiffany Tran1, Annlia Paganini-Hill6, Mark Fisher7,8, Wei Ling Lau1,9
ORCID iDs: Yitong Zhao, Su Mi Lee, Whitney Li, Peter Chang, Yoko Narasaki, Kamyar Kalantar-Zadeh, Connie M Rhee, Annlia Paganini-Hill, Wei Ling Lau
  1. Division of Nephrology, Department of Medicine, University of California, Irvine, CA 92697, USA
  2. Department of Internal Medicine, College of Medicine, Dong-A University, Busan 49201, Republic of Korea
  3. Department of Radiology, University of California, Irvine, CA 92697, USA
  4. Division of Nephrology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA
  5. The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
  6. Beckman Laser Institute and Medical Clinic, University of California, Irvine, CA 92697, USA
  7. Department of Neurology, University of California, Irvine, CA 92697, USA
  8. Department of Pathology & Laboratory Medicine, University of California, Irvine, CA 92697, USA
  9. Department of Physiology & Biophysics, University of California, Irvine, CA 92697, USA
Institutions: University of California, Irvine (United States); Dong-A University (South Korea); University of California, Los Angeles (United States); The Lundquist Institute (United States); Harbor–UCLA Medical Center (United States); Beckman Laser Institute and Medical Clinic (United States)
Journal: International journal of molecular sciences, volume 27, issue 13, article 6020
Dates: received 3 April 2026; accepted 30 June 2026; published online 4 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3390/ijms27136020 · PMID 42450287 · PMCID PMC13361717 · OpenAlex W7167473383
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism)
Methods: Statistics, Machine learning, Connectivity
Keywords: chronic kidney disease, gut microbiome, uremic toxins, behavior testing, brain microbleeds
MeSH: Brain*, Cerebral Hemorrhage*, Gastrointestinal Microbiome*, Kidney*, Renal Insufficiency, Chronic*, Uremic Toxins*, Aged, Animals, Cresols, Female, Humans, Indican, Male, Methylamines, Mice, Middle Aged, Sulfuric Acid Esters (* major topic)
Topic: Gut microbiota and health (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Institutes of Health Clinical Center (R01NS113337); NINDS NIH HHS (R01 NS113337)
Citations: not cited yet (Europe PMC); 64 references in the paper

Abstract

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–gut–brain 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–gut–brain axis and cerebral microhemorrhage formation in CKD.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

4.4. Data Availability

All raw data from this study are available in Dryad datasets (https://10.5061/dryad.hx3ffbgr4, accessed on 29 June 2026). All microbial sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive under BioProject ID PRJNA954040. A complete list of individual accession numbers is provided in the Dryad link.

Reproduced under the paper's license (CC BY), from the paper cited above.

Data Availability Statement

The data presented in this study are openly available in Dryad datasets at https://doi.org/10.5061/dryad.hx3ffbgr4, accessed on 29 June 2026.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 5 keywords, 17 MeSH terms, 2 funders, 63 references.

Cite

This paper

Zhao, Y., Lee, S. M., Li, W., Floriolli, D., Chang, P., Narasaki, Y., You, A. S., Kalantar-Zadeh, K., Rhee, C. M., Liu, H., Tran, T., Paganini-Hill, A., Fisher, M., & Lau, W. L. (2026). Investigating the Kidney-Gut-Brain Axis in CKD: Uremic Toxins and Brain Microhemorrhages. International journal of molecular sciences, 27(13), 6020. https://doi.org/10.3390/ijms27136020

BibTeX

@article{zhao2026investigating,
author = {Zhao, Yitong and Lee, Su Mi and Li, Whitney and Floriolli, David and Chang, Peter and Narasaki, Yoko and You, Amy S and Kalantar-Zadeh, Kamyar and Rhee, Connie M and Liu, Han and Tran, Tiffany and Paganini-Hill, Annlia and Fisher, Mark and Lau, Wei Ling},
title = {{Investigating the Kidney-Gut-Brain Axis in CKD: Uremic Toxins and Brain Microhemorrhages}},
journal = {International journal of molecular sciences},
year = {2026},
month = jul,
volume = {27},
number = {13},
pages = {6020},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {1422-0067},
doi = {10.3390/ijms27136020},
url = {https://doi.org/10.3390/ijms27136020},
pmid = {42450287},
pmcid = {PMC13361717}
}

RIS

TY - JOUR
AU - Zhao, Yitong
AU - Lee, Su Mi
AU - Li, Whitney
AU - Floriolli, David
AU - Chang, Peter
AU - Narasaki, Yoko
AU - You, Amy S
AU - Kalantar-Zadeh, Kamyar
AU - Rhee, Connie M
AU - Liu, Han
AU - Tran, Tiffany
AU - Paganini-Hill, Annlia
AU - Fisher, Mark
AU - Lau, Wei Ling
TI - Investigating the Kidney-Gut-Brain Axis in CKD: Uremic Toxins and Brain Microhemorrhages
T2 - International journal of molecular sciences
J2 - Int J Mol Sci
PY - 2026
DA - 2026/07/04
VL - 27
IS - 13
SP - 6020
SN - 1422-0067
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/ijms27136020
UR - https://doi.org/10.3390/ijms27136020
LA - en
ER -

CSL-JSON

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