The Microbiome–Sickle Cell Disease Axis: Emerging Mechanisms Linking Dysbiosis, Inflammation, VasoOcclusion and End-Organ Injury

Abstract

Sickle cell disease (SCD) is a genetic haemoglobin illness characterised by persistent haemolytic anaemia, recurrent vaso-occlusion, inflammation and gradual end-organ damage. While polymerisation of deoxygenated haemoglobin S is the fundamental molecular event in SCD, the clinical expression of the disease is increasingly understood to be the product of interactions among erythrocytes, leukocytes, endothelial cells, platelets, inflammatory mediators, metabolic pathways and environmental factors. Recently, the gut microbiome has been identified as a potentially essential element of this complicated pathophysiologic network. Intestinal hypoxia reperfusion damage, compromised epithelial integrity, repeated antibiotic exposure, diet, drugs and systemic inflammation could be responsible for dysbiosis in SCD. Conversely, microbial composition and microbial metabolites may alter intestinal permeability, immunological activation, neutrophil ageing, endothelial dysfunction and vaso-occlusion. Human and experimental investigations of patients and animal models with SCD have shown considerable modifications in gut microbiota including bacterial diversity and abundance of possibly pro-inflammatory and short-chain-fatty-acid-producing organisms. The gut microbiome has also been involved with chronic SCD pain through microbial metabolites and gut–brain signalling, based on experimental studies. Our results imply that dysbiosis may be part of a microbiome-SCD axis linking gut injury to systemic inflammation, vaso-occlusive crises and end-organ damage. However, for many postulated pathways, the existing data is insufficient to prove causation. Indeed, much of the mechanistic evidence stems from animal models or rather small human research. However, the knowledge of this axis could help to discover new indicators and treatment targets such as dietary interventions, probiotics, prebiotics, microbial metabolites and other microbiome-targeted strategies. Thus, the microbiome–SCD axis provides a nascent paradigm for understanding disease heterogeneity and devising complimentary approaches to mitigate inflammation, vaso-occlusion and organ damage.