Gilbert's Syndrome and the Gut Microbiota - Insights From the Case-Control BILIHEALTH Study.

Patrick A Zöhrer,David Berry,Anela Tosevska,Craig W Herbold,Nazlisadat Seyed Khoei,Karl-Heinz Wagner,Andrew C Bulmer,Claudia A Hana,Rodrig Marculescu,Marlies Hörmann-Wallner,Daniel Doberer,Christine Mölzer

doi:10.3389/fcimb.2021.701109

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.

Highlights

Mild hyperbilirubinemia, a benign condition known as Gilberts Syndrome (GS), is usually defined by an unconjugated bilirubin (UCB) blood concentration of above 17.1 μmol/L
We have recently reported on associations between UCB and colorectal cancer (CRC) risk in the European Prospective Investigation into Cancer and nutrition (EPIC) study, whereby serum UCB concentrations were positively associated with CRC risk in men and inversely associated in women (Seyed Khoei et al, 2020)
Mild hyperbilirubinaemia (GS) with normal circulating liver transaminases, biliary markers, and red blood cell counts, is a benign condition that is highly prevalent among the general population

Summary

Introduction

A benign condition known as Gilberts Syndrome (GS), is usually defined by an unconjugated bilirubin (UCB) blood concentration of above 17.1 μmol/L. The prevalence of GS is remarkably common, affecting 5-10% (depending on ethnicity and sex) of the adult population (Wagner et al, 2018). This condition is influenced by a combination of increased haem catabolism and various underlying promoter polymorphisms in the uridine diphosphoglucuronyltransferase (UGT1A1) gene, leading to reduced conjugating activity of this enzyme and elevated UCB levels. One common link between reduced disease risk and increased UCB concentration is reduced body weight, with consistent reports in the literature demonstrating significantly reduced BMI and occasionally reduced fat mass in GS when compared to age- and sex-matched controls (Bulmer et al, 2013; Wallner et al, 2013c; Seyed Khoei et al, 2018) A compelling body of evidence has demonstrated that serum bilirubin, a byproduct of hemoglobin breakdown, has substantial anti-inflammatory, anti-oxidative and antimutagenic properties (Stocker, 2004; Bulmer et al, 2008; Vitek and Tiribelli, 2020) and that mildly elevated serum bilirubin levels are strongly associated with a reduced prevalence of chronic diseases, such as CVD, Type-2 diabetes and some cancers (Zucker et al, 2004; Wagner et al, 2015; Bulmer et al, 2018; Kwon et al, 2018).

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