Author Identifier (ORCID)
Abstract
Cardiovascular–Kidney–Metabolic (CKM) syndrome represents a complex, interconnected cluster of cardiovascular disease, chronic kidney disease, and metabolic disorders such as obesity and type 2 diabetes. These conditions share overlapping metabolic, inflammatory, and vascular pathways, with the gut microbiome increasingly recognised as a key contributor and common underlying risk factor. Uremic toxins, traditionally considered waste products of host and microbial metabolism, are now recognised as active mediators of tissue damage across the CKM spectrum, particularly in the context of impaired renal function. Their production and accumulation are amplified by disrupted intestinal barrier integrity, chronic inflammation, and reduced renal clearance, collectively driving systemic toxicity throughout the CKM continuum. This review explores the origins and impact of gut-derived uremic toxins, including trimethylamine-N-oxide (TMAO), indoxyl sulfate (IS), p-cresol sulfate (PCS) and its associated metabolites, p-cresol and p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln), and imidazole propionate (ImP) within the context of CKM syndrome. These toxins originate from an imbalanced gut microbiome, often shaped by poor diets, such as low-fibre and high-meat intake. We discuss their production by the microbiome and their roles from cardiovascular, renal, and metabolic perspectives and highlight emerging microbiome-targeted strategies to mitigate their pathogenic effects.
Keywords
cardiovascular-kidney-metabolic syndrome, gut microbiome, microbiome-targeted therapy, uremic toxins
Document Type
Journal Article
Date of Publication
1-1-2026
Article Number
2685906
ISSN
19490976
Volume
18
Issue
1
PubMed ID
42296178
Publication Title
Gut Microbes
Publisher
Taylor & Francis
School
Nutrition and Health Innovation Research Institute / School of Medical and Health Sciences
RAS ID
99674
Funding Information
F.Z.M. is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation and a National Health and Medical Research Council (NHMRC) Emerging Leader Fellowship (GNT2017382). M.S. is supported by a National Heart Foundation of Australia, Postdoctoral Fellowship (106698).
Funding received from the National Health and Medical Research Council (NHMRC)
GNT2017382
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
Xu, C., Snelson, M., & Marques, F. Z. (2026). Cardiovascular–kidney–metabolic syndrome through the lens of gut‑derived uremic toxins. Gut Microbes, 18(1), Article 2685906. https://doi.org/10.1080/19490976.2026.2685906