Kipp Zachary A, Badmus Olufunto O, Stec David E, Hall Brantley, Hinds Terry D
Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
Metabolism. 2025 Feb;163:156081. doi: 10.1016/j.metabol.2024.156081. Epub 2024 Nov 22.
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.
全球肥胖率的上升增加了心血管疾病（CVD）的发病率，使其成为头号死因。较高的血浆胆红素水平已被证明可预防代谢功能障碍和心血管疾病。然而，降低胆红素水平会导致有害后果，这可能是由于胆红素半衰期缩短，从而加速了其分解代谢产物尿胆原的产生，尿胆原由肠道细菌产生并自然氧化为尿胆素。最近的研究结果表明，胆红素经微生物群分解代谢为尿胆素并通过肝门静脉吸收这一过程与心血管疾病有关，提示存在肝肠轴的参与。我们讨论了一些研究，这些研究表明尿胆素在心血管疾病患者的尿液中经常升高及其在患该疾病过程中可能发挥的作用。尿胆素从肾脏排泄到尿液中，可能作为心血管 - 肾脏 - 代谢（CKM）综合征的生物标志物。我们深入探讨了新发现的产生尿胆素的细菌酶——胆红素还原酶（BilR）。我们讨论了表达BilR的细菌种类、它们如何影响心血管疾病，以及抑制尿胆素产生和增加胆红素是否可为CKM提供新的治疗策略。还讨论了实现这一目标可能的治疗机制。
