Abstract

The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies that demonstrate that urobilin is frequently raised in the urine of persons with CVD and its probable role in acquiring the disease. Urobilin is excreted from the kidneys into the urine and may serve as a biomarker for Cardiovascular-Kidney-Metabolic (CKM) Syndrome. We deliberate on the newly discovered bilirubin reductase (BilR) bacterial enzyme that produces urobilin. We discuss the bacterial species expressing BilR, how they impact CVD, and whether suppressing urobilin production and increasing bilirubin may provide new therapeutic strategies for CKM. Possible therapeutic mechanisms for achieving this goal are discussed.

Document Type

Article

Publication Date

2-2025

Notes/Citation Information

0026-0495/© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.metabol.2024.156081

Funding Information

The authors thank the University of Kentucky Center for Clinical and Translational Sciences (CCTS) Biomedical Informatics team for the retrospective chart review of patient data, supported by the NIH National Center for Advancing Translational Sciences through grant number UL1TR001998. This work was supported by grants from the National Institutes of Health (NIH) F31Hl170972 (Z.A.K.), R01DK121748 (D.E.S.), R01DK121797 (T.D.H.J.), and R01DA058933 (T.D.H.J.). This publication was supported by the National Institute on Minority Health and Health Disparities grant L32MD009154 (T.D.H.J.) and the UNited In True Racial Equity Research Priority Area at the University of Kentucky and the National Cancer Institute through the Cancer Center Support Grant P30CA177558 (T.D.H.J.). The National Institute of General Medical Sciences Grant P20GM104357, P30GM149404 and P20GM144041 (D.E.S.). American Heart Association Postdoctoral Award (23POST1020493, O.O.B.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS or NIH. B.H. was supported by startup funding from the University of Maryland.

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