Bilirubin Metabolism and Associated Health Implications

Bilirubin arises from the stepwise catabolism of haem: haem oxygenase cleaves the porphyrin ring of haem to biliverdin, which is subsequently reduced by biliverdin reductase to yield the unconjugated pigment. Transported in the bloodstream bound to albumin, unconjugated bilirubin is taken up by hepatocytes and conjugated by UDP-glucuronosyltransferase (UGT1A1) before excretion into bile. In the gut, resident bacteria further convert bilirubin to urobilinogen, linking microbial activity to systemic bilirubin homeostasis. Clinically, impaired uptake or conjugation leads to hyperbilirubinaemia and jaundice, with potential neurotoxicity in neonates, whereas mildly raised bilirubin levels confer antioxidant, anti-inflammatory and cytoprotective effects. Emerging evidence highlights the dual nature of bilirubin as both a cytotoxin at high concentrations and an endogenous defence molecule at modest levels, with implications for cardiovascular health, metabolic regulation and neuroprotection. Understanding the balance of hepatic processing, enterohepatic circulation and microbial transformation is therefore critical to harness bilirubin’s therapeutic potential and mitigate its pathological consequences.

Research from Nature Portfolio

Recent work has identified BilR, a gut-microbiota-derived bilirubin reductase, elucidating the enzymatic step that converts bilirubin to urobilinogen. Comparative genomics and biochemical assays showed that BilR is widespread among Firmicutes in healthy adults but diminished in neonates and in inflammatory bowel disease, underscoring the gut–liver axis in maintaining pigment equilibrium and suggesting microbiome-targeted interventions to modulate systemic bilirubin levels.

In foundational studies of vascular endothelium, high-precision chromatography and mass spectrometry revealed that endothelial cells contain picomolar concentrations of IXα-bilirubin and exhibit potent intracellular antioxidant activity at physiologically relevant levels. These findings demonstrate that endothelial bilirubin oscillates in response to haem oxygenase induction and external uptake, positioning the pigment as a dynamic regulator of vascular redox homeostasis.

Bilirubin Metabolism and Associated Health Implications publication trend

The graph below shows the total number of articles in bilirubin metabolism and associated health implications across all publications each year (not limited to Nature Index journals).

Technical terms

Unconjugated bilirubin: Lipid-soluble pigment resulting from biliverdin reduction, transported bound to albumin.

Conjugated bilirubin: Water-soluble form produced by UGT1A1-mediated glucuronidation in hepatocytes for biliary excretion.

Urobilinogen: Colourless product of intestinal bacterial reduction of bilirubin, partly reabsorbed and excreted in urine or converted to stercobilin.

TRPM2 channel: A calcium-permeable cation channel activated by oxidative stress and certain ligands, implicated in ischaemic brain injury.

Gut–liver axis: Bidirectional communication network between the gastrointestinal microbiota and hepatic metabolism regulating bile pigment homeostasis.

References

1. BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen. Nature Microbiology (2024).
2. A Platform for the Synthesis of Oxidation Products of Bilirubin. Journal of the American Chemical Society (2024).
3. Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage. Neuron (2023).
4. Sex differences in the relationship between serum total bilirubin and risk of incident metabolic syndrome in community-dwelling adults: Propensity score analysis using longitudinal cohort data over 16 years. Cardiovascular Diabetology (2024).
5. Bilirubin is an Endogenous Antioxidant in Human Vascular Endothelial Cells. Scientific Reports (2016).