A Product of Heme Catabolism Modulates Bacterial Function and Survival

Nobles, Christopher L.; Green, Sabrina I.; Maresso, Anthony W.

doi:10.1371/journal.ppat.1003507

Cited by 29 publications

(27 citation statements)

References 49 publications

(79 reference statements)

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“…Fecal analysis, carried out by either metabolomics or genomic techniques, will be required for better characterization of intestinal microflora and its impact on serum bilirubin levels . Interestingly, recent data suggest that bilirubin itself modulates the function of enteric bacteria, indicating that heme metabolism may play a role in modulating bacterial function and survival . Hence, an involvement of intestinal colonization in the pathogenesis of neonatal jaundice is conceivable .…”

Section: Metabolomics In Hyperbilirubinemia Research and Future Direcmentioning

confidence: 99%

“…(78) Interestingly, recent data suggest that bilirubin itself modulates the function of enteric bacteria, indicating that heme metabolism may play a role in modulating bacterial function and survival. (79) Hence, an involvement of intestinal colonization in the pathogenesis of neonatal jaundice is conceivable. (80) Furthermore, in neonatal research, metabolomics analysis of breast milk components may identify further metabolites potentially involved in modulation of UGT1A1 activity or tissue-specific expression.…”

Section: Metabolomics In Hyperbilirubinemia Research and Future Direcmentioning

confidence: 99%

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Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

et al. 2018

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Neurotoxic bilirubin is the end product of heme catabolism in mammals. Bilirubin is solely conjugated by uridine diphospho-glucuronosyltransferase 1A1, which is a membrane-bound enzyme that catalyzes the transfer of glucuronic acid. Due to low function of hepatic and intestinal uridine diphospho-glucuronosyltransferase 1A1 during the neonatal period, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage, termed kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does this most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced hyperbilirubinemia might bring certain benefits that outweigh those risks. While bilirubin is neurotoxic and cytotoxic, this compound is also a potent antioxidant. There are studies showing improved clinical conditions in patients with hyperbilirubinemia. Accumulating evidence also shows that genetic polymorphisms linked to hyperbilirubinemia are beneficial against various diseases. In this review article, we first introduce the production, metabolism, and transport of bilirubin. We then discuss the potential benefits of neonatal and adult hyperbilirubinemia. Finally, epigenetic factors as well as metabolomic information associated with hyperbilirubinemia are described. This review article advances the understanding of the physiological importance of the paradoxical compound bilirubin. (Hepatology 2018;67:1609-1619).

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Section: Metabolomics In Hyperbilirubinemia Research and Future Direcmentioning

confidence: 99%

Section: Metabolomics In Hyperbilirubinemia Research and Future Direcmentioning

confidence: 99%

Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

et al. 2018

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“…Heme is a paradoxical molecule. It is scavenged by bacterial pathogens for its elemental iron but also toxic to bacteria because of its DNA damaging and membrane disrupting properties (Anzaldi and Skaar, ; Nobles et al , ). It stands to reason that enzymes capable of breaking the heme ring might also be harnessed by blood‐borne pathogens as an important defense mechanism that assists with their survival in the blood.…”

Section: Resultsmentioning

confidence: 99%

Heme catabolism in the causative agent of anthrax

Clark

Terwilliger

Nguyen

et al. 2019

Molecular Microbiology

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A challenge common to all bacterial pathogens is to acquire nutrients from hostile host environments. Iron is an important cofactor required for essential cellular processes such as DNA repair, energy production and redox balance. Within a mammalian host, most iron is sequestered within heme, which in turn is predominantly bound by hemoglobin. While little is understood about the mechanisms by which bacterial hemophores attain heme from host-hemoglobin, even less is known about intracellular heme processing. Bacillus anthracis, the causative agent of anthrax, displays a remarkable ability to grow in mammalian hosts. Hypothesizing this pathogen harbors robust ways to catabolize heme, we characterize two new intracellular heme-binding proteins that are distinct from the previously described IsdG heme monooxygenase. The first of these, HmoA, binds and degrades heme, is necessary for heme detoxification and facilitates growth on heme iron sources. The second protein, HmoB, binds and degrades heme too, but is not necessary for heme utilization or virulence. The loss of both HmoA and IsdG renders B. anthracis incapable of causing anthrax disease. The additional loss of HmoB in this background increases clearance of bacilli in lungs, which is consistent with this protein being important for survival in alveolar macrophages.

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“…Other studies indicate that bilirubin can actually act as a protectant to E . coli strains whilst being highly toxic towards Gram-positive bacteria including Enterococcus faecalis 24 . The proposed mechanism of protection of E .…”

Section: Discussionmentioning

confidence: 99%

Adaptive response of neonatal sepsis-derived Group B Streptococcus to bilirubin

Hansen

Gibson

Alves

et al. 2018

Sci Rep

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Hyperbilirubinemia is so common in newborns as to be termed physiological. The most common bacteria involved in early-onset neonatal sepsis are Streptococcus agalactiae, commonly called Group B Streptococcus (GBS). Whilst previous studies show bilirubin has antioxidant properties and is beneficial in endotoxic shock, little thought has been given to whether bilirubin might have antibacterial properties. In this study, we performed a transcriptomic and proteomic assessment of GBS cultured in the presence/absence of bilirubin. Our analysis revealed that increasing levels of bilirubin (>100 µmol/L) negatively correlated with GBS growth (18% reduction from 0–400 µmol/L on plate model, p < 0.001; 33% reduction from 0–100 µmol/L in liquid model, p = 0.02). Transcriptome analysis demonstrated 19 differentially expressed genes, almost exclusively up-regulated in the presence of bilirubin. Proteomic analysis identified 12 differentially expressed proteins, half over-expressed in the presence of bilirubin. Functional analysis using Gene Ontology and KEGG pathways18 revealed a differential expression of genes involved in transport and carbohydrate metabolism, suggesting bilirubin may impact on substrate utilisation. The data improve our understanding of the mechanisms modulating GBS survival in neonatal hyperbilirubinemia and suggest physiological jaundice may have an evolutionary role in protection against early-onset neonatal sepsis.

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A Product of Heme Catabolism Modulates Bacterial Function and Survival

Cited by 29 publications

References 49 publications

Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

Heme catabolism in the causative agent of anthrax

Adaptive response of neonatal sepsis-derived Group B Streptococcus to bilirubin

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