Microbiome-derived cancer: the catabolism of bilirubin to urobilin in the liver-gut axis and its consequences.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally and is associated with factors, such as obesity, inflammation, and metabolic disorders. Bilirubin, a byproduct of heme degradation, is increasingly recognized as a signaling molecule with antioxidant properties that protect against obesity by reducing oxidative stress, decreasing inflammation, and activating the nuclear receptor PPARα, which enhances fat metabolism and utilization. The gut microbiome converts bilirubin to urobilinogen via bilirubin reductase, which is then rapidly oxidized to urobilin, thereby influencing colon cancer outcomes. Urobilin may contribute to CRC by being linked to insulin resistance and inflammation in obese individuals, and it could cause DNA damage. Additionally, it may serve as a biomarker for CRC, obesity, insulin-resistant diabetes, and irritable bowel syndrome. This review covers enzymes in the heme oxygenase pathway (HMOX, BVR, UGT1A1) that regulate bilirubin production and excretion, as well as the microbiome-driven breakdown of bilirubin into urobilinogen and its subsequent oxidation to urobilin. It highlights the inverse relationships among CRC, obesity, and inflammation and suggests that urobilin pathways influence CRC risk. Restoring bilirubin's protective signaling and reducing circulating urobilin could open new avenues for prevention and treatment.