Combined Effects of Hydroxyurea and Penicillin on Gut Microbiota and Intestinal Health in Sickle Cell Mice

• Grant number: 25/20239-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2025
• End date: September 30, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Nicola Amanda Conran Zorzetto
• Grantee: Érica Martins Ferreira Gotardo
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/18886-1 - Pathophysiological mechanisms and treatment of red blood cell abnormalities, AP.TEM

Abstract

Sickle cell disease (SCD) is a hereditary hemoglobinopathy caused by a mutation in the hemoglobin gene, leading to the production of hemoglobin S (HbS). This alteration impairs blood flow, increases red blood cell fragility, and causes chronic hemolysis, vaso-occlusion, and endothelial dysfunction. Vaso-occlusive crises, the hallmark events of the disease, can result in severe pain, tissue ischemia, and serious complications such as stroke, pulmonary hypertension, and multiorgan dysfunction. Recent studies have demonstrated that the gut microbiota is directly involved in the pathophysiology of SCD, influencing systemic inflammation and vascular function. Dysbiosis and increased intestinal permeability favor bacterial translocation and endotoxin release, exacerbating endothelial dysfunction and immune cell activation. Moreover, microbial metabolites, such as short-chain fatty acids, can modulate inflammation and impact the severity of tissue ischemia. Hydroxyurea (HU) is the main drug used in the treatment of SCD, known to increase fetal hemoglobin levels, improve endothelial function, and reduce inflammation, thereby decreasing vaso-occlusive pain episodes. While the hematological benefits of HU are well established, its effects on gut microbiota and intestinal permeability remain poorly understood. Some studies suggest that HU may influence the composition of the gut microbiota. In addition to HU, pediatric SCD patients are often prescribed penicillin prophylaxis to prevent bacterial infections-an essential strategy to reduce childhood mortality. However, the impact of continuous antibiotic use on gut microbiota is not yet fully elucidated. Long-term antibiotic exposure may worsen gut dysbiosis, alter intestinal permeability, and increase the risk of opportunistic infections and inflammation. In this context, understanding the combined effects of HU and penicillin on gut health is crucial to optimizing the clinical management of sickle cell disease. (AU)