The gut microbiome in sickle cell disease: Characterization and potential implications

Abstract

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

Plasma Levels of Acyl-Carnitines and Carboxylic Acids Correlate With Cardiovascular and Kidney Function in Subjects With Sickle Cell Trait

“…On the other hand, other tryptophan metabolites-indoles-were found to increase in the plasma of individuals with SCT. Though the clinical relevance of this observation is unclear, these metabolites are of bacterial origin and indicate a potential role of microbiome dysbiosis in the etiology of some metabolic alterations in individuals with SCT (Brim et al, 2021). Markers of hemolysis (biliverdin, bilirubin) were noted to increase in plasma from individuals with SCT, suggestive of basally higher levels of stress to the erythrocyte in these subjects.…”

“…On the other hand, other tryptophan metabolites—indoles—were found to increase in the plasma of individuals with SCT. Though the clinical relevance of this observation is unclear, these metabolites are of bacterial origin and indicate a potential role of microbiome dysbiosis in the etiology of some metabolic alterations in individuals with SCT ( Brim et al, 2021 ).…”

A Microbiota-Dependent Response to Anticancer Treatment in an In Vitro Human Microbiota Model: A Pilot Study With Hydroxycarbamide and Daunorubicin

“…Among the many perspectives in oncology, the MBRA system could be an interesting tool to evaluate the impact of more drugs and combinations of drugs on the gut microbiota. Here, relying on previous works ( Flores et al., 2014 ; Montassier et al., 2014 ; Brim et al., 2021 ), we measured the Firmicutes/Bacteroidetes ratio biomarker, allowing us to confirm the dysbiosis evidenced by the diversity metrics. This biomarker is easy to measure ( Guo et al., 2008 ; Magne et al., 2020 ) and enables rapid screening for dysbiosis in a high-throughput manner.…”

Recent advances in “sickle and niche” research - Tribute to Dr. Paul S Frenette -

“…Regulation of the immune system by the gut microbiota is crucial for host immunity, and perturbation of the microbiome can lead to immune pathologies ( Postler and Ghosh, 2017 ). The gut microbiome in SCD has altered density, diversity, and composition ( Brim et al., 2021 ; Lim et al., 2018 ; Stewart et al., 2021 ). The mechanisms involved in this dysbiosis, however, remain unclear.…”

“…Intrinsic SCD pathologies, including vaso-occlusion injury to the gastrointestinal microvasculature, may cause increased gut permeability that alters the microbiome ( Stewart et al., 2021 ). Environmental factors might also be involved, particularly the long-term use of prophylactic antibiotics that are administered to prevent potentially fatal bacterial sepsis in children with SCD ( Brim et al., 2021 ; Stewart et al., 2021 ). Accumulating evidence suggests that psychological stress can affect the composition of the microbiota ( Bailey et al., 2011 ; Mayer et al., 2014 ; Moloney et al., 2014 ).…”