How Hydroxyurea Alters the Gut Microbiome: A Longitudinal Study Involving Angolan Children with Sickle Cell Anemia

Delgadinho, Mariana; Ginete, Catarina; Santos, Branca Maria de Oliveira; Fernandes, Carlos A. F.; Silva, Carina; Miranda, Armandina; Vasconcelos, Jocelyne Neto de; Brito, Miguel

doi:10.3390/ijms23169061

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…In previous papers from our research group, we have proved the existence of notable microbial differences between SCA patients and healthy controls [ 39 ] and have also reported that SCA children before HU treatment had a higher abundance of the pathogenic Clostridium_g24 , whereas after HU, it was observed higher proportions of several beneficial bacteria, mostly short-chain fatty acids (SCFAs) producing species [ 40 ]. This last study was the first evidence of hydroxyurea’s positive effect on the gut microbiome.…”

Section: Discussionmentioning

confidence: 90%

Differential expression of adhesion molecules in sickle cell anemia and gut microbiome effect

Delgadinho,

Veiga,

Ginete

et al. 2023

Ann Hematol

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Sickle cell anemia (SCA) causes a long-standing vascular inflammation state, leading to endothelial dysfunction and chronic overexpression of several adhesion molecules, which contributes to acute and constant vaso-occlusive (VOC) episodes. It has been demonstrated that hydroxyurea (HU) can reduce VOC events, organ damage, blood transfusions, and even the adhesion properties to endothelial cells of SCA subjects. Due to VOC episodes, these patients are also more susceptible to recurrent bacterial translocation and dysbiosis. Given this, our study aimed to uncover the interplay between adhesion molecules, gut microbiome, and hydroxyurea in a population of Angolan SCA children. Serum and fecal samples were obtained before and after HU treatment in 35 children. After HU, four of these adhesion molecules were significantly reduced: sE-selectin (p = 0.002), ADAMTS13 (p = 0.023), sICAM-1 (p = 0.003), and sVCAM-1 (p = 0.018). A positive correlation was observed between the number of neutrophils and sICAM-1, platelets, and sP-selectin, and also between leukocytes, sICAM-1, and sVCAM-1. Most taxa showing a significant correlation mainly belonged to the Clostridiales order. Specifically, from the Clostridium genera, the groups g19, g21, and g34 were all negatively correlated with HbF levels; g19, g21, and g24 positively correlated with leukocytes; g19 positively with neutrophils and sVCAM-1; and g34 positively with E- and P-selectin. Serratia, an opportunistic pathogen, was positively correlated with sE-selectin and sICAM-1 levels. Additionally, a negative correlation was observed between sP-selectin and Bifidobacterium. Research studies in this area could improve our understanding and contribute to finding new prognostic biomarkers to guarantee precise SCA patient stratification and predict severe complications.

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Section: Discussionmentioning

confidence: 90%

Differential expression of adhesion molecules in sickle cell anemia and gut microbiome effect

Delgadinho,

Veiga,

Ginete

et al. 2023

Ann Hematol

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“…First, due to small sample sizes, we were unable to reconcile our microbiota findings with the different treatment modalities in ET. We have previously shown that patients with PV treated with interferon-alpha have a gut microbiota more similar to HCs compared with patients with PV not treated with interferon-alpha ( 25 ), and treatment with hydroxyurea has recently been reported to be associated with an increase in the abundance of beneficial bacteria, such as Faecalibacterium in children with sickle cell anemia ( 39 ). Furthermore, the number of JAK2V617F- negative patients with ET was small (limiting the statistical power) and heterogeneous with other mutations ( CALR and MPL ) or triple negative.…”

Section: Discussionmentioning

confidence: 99%

Pronounced gut microbiota signatures in patients with JAK2V617F- positive essential thrombocythemia

Eickhardt-Dalbøge,

Ingham,

Nielsen

et al. 2023

Microbiol Spectr

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Essential thrombocythemia (ET) is part of the Philadelphia chromosome-negative myeloproliferative neoplasms. It is characterized by an increased risk of thromboembolic events and also to a certain degree hypermetabolic symptoms. The gut microbiota is an important initiator of hematopoiesis and regulation of the immune system, but in patients with ET, where inflammation is a hallmark of the disease, it is vastly unexplored. In this study, we compared the gut microbiota via amplicon-based 16S rRNA gene sequencing of the V3–V4 region in 54 patients with ET according to mutation status Janus-kinase 2 ( JAK2V617F )-positive vs JAK2V617F -negative patients with ET, and in 42 healthy controls (HCs). Gut microbiota richness was higher in patients with ET (median-observed richness, 283.5; range, 75–535) compared with HCs (median-observed richness, 191.5; range, 111–300; P < 0.001). Patients with ET had a different overall bacterial composition (beta diversity) than HCs (analysis of similarities [ANOSIM]; R = 0.063, P = 0.004). Patients with ET had a significantly lower relative abundance of taxa within the Firmicutes phylum compared with HCs (51% vs 59%, P = 0.03), and within that phylum, patients with ET also had a lower relative abundance of the genus Faecalibacterium (8% vs 15%, P < 0.001), an important immunoregulative bacterium. The microbiota signatures were more pronounced in patients harboring the JAK2V617F mutation, and highly similar to patients with polycythemia vera as previously described. These findings suggest that patients with ET may have an altered immune regulation; however, whether this dysregulation is induced in part by, or is itself inducing, an altered gut microbiota remains to be investigated. IMPORTANCE Essential thrombocythemia (ET) is a cancer characterized by thrombocyte overproduction. Inflammation has been shown to be vital in both the initiation and progression of other myeloproliferative neoplasms, and it is well known that the gut microbiota is important in the regulation of our immune system. However, the gut microbiota of patients with ET remains uninvestigated. In this study, we characterized the gut microbiota of patients with ET compared with healthy controls and thereby provide new insights into the field. We show that the gut microbiota of patients with ET differs significantly from that of healthy controls and the patients with ET have a lower relative abundance of important immunoregulative bacteria. Furthermore, we demonstrate that patients with JAK2V617F -positive ET have pronounced gut microbiota signatures compared with JAK2V617F -negative patients. Thereby confirming the importance of the underlying mutation, the immune response as well as the composition of the microbiota.

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“…Our ndings are consistent with a study on the use of hydroxyurea in sickle cell disease and its impact on the gut microbiota, which also showed a higher abundance of bene cial bacteria belonging to phyla Firmicutes. (12) The highly abundant genera in the responder's group are mostly butyrate producers from phylum Firmicutes that are bene cial to the host gut. Butyrate, a Short-chain fatty acid (SCFA) is the main source of energy for colonocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the participants were Balochi (20%), Sindhi (20%), and Urdu-speaking (17%). The median of transfusion per year six months after hydroxyurea therapy in responders group was zero with IQR (0-5), and in nonresponder group was 12 per year with IQR (12)(13)(14)(15)(16)(17)(18)(19)(20). Most participants were using Deferasirox as an Ironchelator (53.3%), out of which the majority were HNR (73.3%) and HNU (73.3%).…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…It has been suggested in limited studies that hydroxyurea metabolism is responsible for differential drug response, and the gut has a minor role related to hydroxyurea metabolism (9)(10)(11). In previous studies, hydroxyurea is shown to increase the phylum Firmicute and its bene cial butyrateproducing species (12)(13)(14). Hydroxyurea is also known to be toxic to bacteria such as E.coli and certain parasites (15,16).…”

Section: Introductionmentioning

confidence: 99%

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

Khan

Ansari

et al. 2023

Preprint

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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.

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How Hydroxyurea Alters the Gut Microbiome: A Longitudinal Study Involving Angolan Children with Sickle Cell Anemia

Cited by 7 publications

References 43 publications

Differential expression of adhesion molecules in sickle cell anemia and gut microbiome effect

Differential expression of adhesion molecules in sickle cell anemia and gut microbiome effect

Pronounced gut microbiota signatures in patients with JAK2V617F- positive essential thrombocythemia

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

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