Hydroxyurea and Gut Microbiome Interactions in Sickle Cell Disease: Toward Adjunctive Microbiome-based Therapy

Sickle cell disease (SCD) is a monogenic disorder marked by hemoglobin S polymerization, resulting in chronic hemolysis, vaso-occlusion, systemic inflammation, and progressive multiorgan damage. Despite major therapeutic advances, SCD remains a complex inflammatory condition with significant morbidity. Hydroxyurea is the cornerstone of treatment, primarily by inducing fetal hemoglobin and reducing vaso-occlusive crises and hemolysis. It also exerts anti-inflammatory effects by decreasing leukocyte activation and endothelial adhesion. However, hydroxyurea does not fully reverse microvascular injury, persistent immune activation, or organ dysfunction, particularly renal and endothelial damage. This review aims to synthesize current evidence on the interactions between hydroxyurea and the gut microbiome in SCD and to evaluate the potential role of microbiome-directed therapies as adjunctive strategies to control inflammation and organ damage. Recent evidence highlights the gut microbiome as a critical regulator of immune homeostasis and inflammation in SCD. Dysbiosis, marked by reduced microbial diversity and diminished short-chain fatty acid (SCFA) production, drives cytokine activation, endothelial dysfunction, and pain sensitization. Emerging studies suggest that hydroxyurea may partially restore microbial balance, yet residual dysbiosis persists. Microbiome-directed therapies, including probiotics and microbial metabolites, show promise for reducing pro-inflammatory cytokines, strengthening gut barrier integrity, and modulating immune responses. Probiotic strains such as Lactobacillus and Bifidobacterium, together with SCFA-mediated pathways, may enhance anti-inflammatory effects and address therapeutic gaps left by hydroxyurea. A combined strategy targeting both hematologic and microbiome pathways may offer superior control of inflammation and organ damage. Integrating microbiome-based interventions with conventional therapy represents a promising, patient-centered approach to improving long-term outcomes and quality of life in SCD.