Gilbert’s Syndrome and the Gut Microbiota – Insights From the Case-Control BILIHEALTH Study

Abstract

The heme catabolite bilirubin has anti-inflammatory, anti-oxidative and anti-mutagenic effects and its relation to colorectal cancer (CRC) risk is currently under evaluation. Although the main metabolic steps of bilirubin metabolism, including the formation of stercobilin and urobilin, take place in the human gastrointestinal tract, potential interactions with the human gut microbiota are unexplored. This study investigated, whether gut microbiota composition is altered in Gilbert’s Syndrome (GS), a mild form of chronically elevated serum unconjugated bilirubin (UCB) compared to matched controls. Potential differences in the incidence of CRC-associated bacterial species in GS were also assessed. To this end, a secondary investigation of the BILIHEALTH study was performed, assessing 45 adults with elevated UCB levels (GS) against 45 age- and sex-matched controls (C). Fecal microbiota analysis was performed using 16S rRNA gene sequencing. No association between mildly increased UCB and the composition of the gut microbiota in this healthy cohort was found. The alpha and beta diversity did not differ between C and GS and both groups showed a typical representation of the known dominant phyla. Furthermore, no difference in abundance of Firmicutes and Proteobacteria, which have been associated with the mucosa of CRC patients were observed between the groups. A sequence related to the Christensenella minuta strain YIT 12065 was identified with a weak association value of 0.521 as an indicator species in the GS group. This strain has been previously associated with a lower body mass index, which is typical for the GS phenotype. Overall, sex was the only driver for an identifiable difference in the study groups, as demonstrated by a greater bacterial diversity in women. After adjusting for confounding factors and multiple testing, we can conclude that the GS phenotype does not affect the composition of the human gut microbiota in this generally healthy study group.

Serum metabolomics analysis reveals increased lipid catabolism in mildly hyperbilirubinemic Gilbert's syndrome individuals

“…Increased TMA serum concentrations as identified in GS can be the result of a diet rich in red meat as well as an increased gut microbial metabolism of carnitine and choline [33]. In our study, both the red meat consumption and the composition of fecal microbiota were similar between GS and control individuals (in press) [63]. However, increased TMA in hand with similar TMAO levels between groups can also be attributable to a lower activity of Flavin-containing monooxygenase 3 (FMO3), the enzyme that catalyzes the TMA to TMAO conversion.…”

Gilbert’s syndrome - bright and dark sides of the disease - literature review

“…(10) In addition, patients have a lower BMI and less tendency to gain weight later in life. (7,16,29,30) With elevated blood bilirubin levels, the body's sensitivity to insulin increases, which is associated with a reduced risk of type 2 diabetes and metabolic syndrome. ( 16) Clinical studies have also highlighted the immunosuppressive effect of bilirubin, which has an inhibitory effect on the development of immune diseases.…”

“…Research is currently underway toward the use of bilirubin administration as a new drug. (1,(5)(6)(7) This review paper aims to show Gilbert's syndrome as a disease with which it is possible to live a completely normal life, and to reap the health benefits that result from the described mutation.…”

Effects of vitamin E on neonatal hyperbilirubinemia in preterm newborns

“…[ 8 ] Bilirubin excretion in preterm infants is also reduced due to decreased ligand and decreased uridine 5’-diphospho-glucuronosyltransferase activity in hepatocytes. [ 9 ] Increases in bilirubin enterohepatic cycle might also contribute to this mechanisms due to delayed feeding in premature infants. [ 10 ] As a result, bilirubin levels are higher in preterm infants due to increased production and decreased excretion.…”