The effect of hydroxyurea response on gut microbiota of beta-thalassemia major patients

Background: Hydroxyurea (HU), a fetal hemoglobin inducer is effective in alleviating the symptoms of beta-thalassemia patients; however, its efficacy is not the same in all patients. Hydroxyurea metabolism in the gut might be responsible, which, as several studies suggest, impacts the metabolism of drugs and diseases including sickle cell diseasea and thalassemia. Hydroxyurea also influences the composition of the gut microbiota as evidenced by literature. In this study, we attempted to find a relationship between the gut microbiota and the response difference of hydroxyurea in beta-thalassemia major patients. Methods: A total of 45 Beta-thalasssemia patients stool samples were collected. They were divided into 3 groups; responders, non-responders, and non-users of hydroxyurea. The samples of each group were pooled into 6 samples after DNA extraction. The V3-V4 hyper-variable region of the 16SrRNA gene was sequenced. Results: The three groups did not differ in alpha diversity. Our study revealed significant differences in the gut microbiota of hydroxyurea responders, non-responders and non-users at genus and species level. Hydroxyurea response was found to be associated with butyrate producers belonging to phlyum Firmicutes. The responders were enriched in genera belonging to phylum Firmicutes especially Butyrate-producing bacteria such as Faecalibacterium, Butyrivibrio, Oscillobacter, Gemmiger, and Eubacterium. The non-responders were abundant in Prevotella, Mitsuokella, and Treponema. The non-users were abundant in Succinivibrio, followed by Bacteroides, and Megasphaera. Conclusion: Our results suggest that the altered gut microbiota might be the reason for inter-individual variation of hydroxyurea and reveals various microbes that may serve as potential biomarkers for thalassemia or hydroxyurea efficacy.