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Summary: There is a large therapeutic gap in the treatment of sickle cell disease (SCD). Recent studies demonstrated the presence of pathophysiological and microbial changes in the intestine of patients with SCD. The intestinal microbes have also been found to regulate neutrophil ageing and possible basal activation of circulating neutrophils. Both aged and activated neutrophils are pivotal for the pathogenesis of vaso‐occlusive crisis in SCD. In this paper, we will provide an overview of the intestinal pathophysiological and microbial changes in SCD. Based on these changes, we will propose therapeutic approaches that could be investigated for treating SCD. [ABSTRACT FROM AUTHOR]