BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen, playing a crucial role in bilirubin metabolism and maintaining bilirubin homeostasis. The study identifies BilR as the key enzyme responsible for this reduction, which is predominantly encoded by Firmicutes species. Analysis of human gut metagenomes reveals that BilR is nearly ubiquitous in healthy adults but is less prevalent in neonates and individuals with inflammatory bowel disease (IBD). This discovery highlights the importance of the gut–liver axis in bilirubin metabolism and underscores the role of the gut microbiome in regulating bilirubin levels. Bilirubin, a byproduct of hemoglobin degradation, is metabolized in the gut by microbial enzymes, which reduce it to urobilinogen, a more excreted metabolite. Dysregulation of this process can lead to elevated serum bilirubin levels, causing jaundice and neurological damage. The study also shows that BilR is essential for the complete reduction of bilirubin to urobilinogen and is involved in the enterohepatic circulation of bilirubin. The presence of BilR is significantly lower in IBD patients, suggesting a disruption in the gut microbiome's ability to metabolize bilirubin. The research provides a deeper understanding of the bilirubin degradation pathway and its implications for health, emphasizing the need for further studies to explore the role of gut microbiota in bilirubin homeostasis and related diseases.BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen, playing a crucial role in bilirubin metabolism and maintaining bilirubin homeostasis. The study identifies BilR as the key enzyme responsible for this reduction, which is predominantly encoded by Firmicutes species. Analysis of human gut metagenomes reveals that BilR is nearly ubiquitous in healthy adults but is less prevalent in neonates and individuals with inflammatory bowel disease (IBD). This discovery highlights the importance of the gut–liver axis in bilirubin metabolism and underscores the role of the gut microbiome in regulating bilirubin levels. Bilirubin, a byproduct of hemoglobin degradation, is metabolized in the gut by microbial enzymes, which reduce it to urobilinogen, a more excreted metabolite. Dysregulation of this process can lead to elevated serum bilirubin levels, causing jaundice and neurological damage. The study also shows that BilR is essential for the complete reduction of bilirubin to urobilinogen and is involved in the enterohepatic circulation of bilirubin. The presence of BilR is significantly lower in IBD patients, suggesting a disruption in the gut microbiome's ability to metabolize bilirubin. The research provides a deeper understanding of the bilirubin degradation pathway and its implications for health, emphasizing the need for further studies to explore the role of gut microbiota in bilirubin homeostasis and related diseases.