Genes modulating intestinal permeability and microbial community are dysregulated in sickle cell disease

Intestinal barrier dysfunction in murine sickle cell disease is associated with small intestine neutrophilic inflammation, oxidative stress, and dysbiosis

“… 41 Our results add to the current data supporting potential for SCD as a candidate for such therapies. We demonstrate intestinal barrier dysfunction and changes in microbiome composition in 3 to 4‐month‐old SCD model mice and find that, unlike older mice that show dysfunction throughout the intestine, 11 , 13 inflammation and tight junction loss is specific to the small intestine at this time point. We, therefore, suggest that intestinal dysfunction first emerges in this region and later extends to the large intestine.…”

“… 13 Loss of ZO‐1 gene expression is also consistent with the recent report from Poplawska et al, who additionally show decreased JAM‐A (JAM‐1), Occludin, E‐cadherin and Mucin‐2, and increased CL‐2 in the small intestine and colon of 6‐month‐old SCD mice. 11 Given our mice were younger, it is likely that our trends for decreased mucin‐2 and JAM‐1 expression would become more robust with age. At odds with their data; however, we did not see any decreases in colon expression of these genes (Figure 1 ), suggesting that dysregulation of small intestine barrier function precedes any dysfunction in the colon.…”

“…This decrease in intestinal barrier integrity can ultimately lead to the translocation of bacterial products into circulation that may exacerbate chronic inflammation in SCD, contributing to worsened disease outcomes. Recent studies in SCD patients and mouse models have demonstrated gut dysbiosis, 7 , 10 elevated markers of intestinal barrier dysfunction 8 , 11 , 12 and protective effects of intestinal microbiome depletion. 9 , 13 , 14 , 15 , 16 In this study, we add to the growing body of evidence for a “leaky gut” phenotype in SCD.…”

“… 9 Since then, additional studies have shown similar protective effects of gut microbiome depletion in SCD‐induced bone loss 13 and demonstrated intestinal dysbiosis in stool samples from SCD patients and mice. 7 , 10 Lim and colleagues 11 , 12 , 16 have built on their initial observation of genus‐level differences in gut microbial communities 10 to suggest that dysbiosis coincides with intestinal barrier impairment in SCD patients, demonstrating increased serum lipopolysaccharide (LPS) and intestinal fatty acid binding protein (iFABP), potential markers of intestinal barrier dysfunction. 8 They also demonstrated a reduction in CANs in SCD patients receiving the minimally absorbed oral antibiotic rifaximin 15 and, most recently, intestinal barrier dysfunction in SCD mice following VOC or in 6‐month‐old mice.…”

“… 8 They also demonstrated a reduction in CANs in SCD patients receiving the minimally absorbed oral antibiotic rifaximin 15 and, most recently, intestinal barrier dysfunction in SCD mice following VOC or in 6‐month‐old mice. 11 , 12 …”