A Pilot Study of Fecal Microbiome and Neutrophil Cellular Adhesion Molecules in Patients With Sickle Cell Disease (SCD)

The clinical course of sickle cell disease (SCD) is very variable. Some patients experience vaso-occlusive disease infrequently, but other patients develop the complication recurrently. The reason for the difference remains unclear. Although erythrocyte sickling occurs due to factors such as dehydration, infections, extreme of temperatures, acidosis, and hypoxia, neutrophil adhesion and activation are crucial in eliciting the vaso-occlusive crisis in patients with SCD. Activated neutrophils upregulate the expression of various cellular adhesion molecules that increase their "stickiness" in vivo. A murine model of SCD demonstrated the importance of the intestinal microbiome in influencing the kinetics of ageing neutrophils. Depletion of the microbiota with prolonged courses of broad-spectrum systemic antibiotics resulted in a reduction of the number of these neutrophils and protection against LPS-induced fatal vaso-occlusive crisis in these mice.

Intestinal barrier is a functional barrier that separates the gut lumen from the inner host. It consists of mechanical elements (mucus, epithelial layer), humoral elements (defensins, IgA), immunologic elements (lymphocytes, innate immune cells), muscular and neurological element. Although the normal intestinal microbiota is the main source of endogenous pathogens, it also contributes to the functional integrity of the intestinal barrier through its interaction with the other components of the barrier. Failure of any of these components will result in a breakdown of the protective intestinal barrier with the consequence of recurrent intestinal-derived bacteremia/septicemia. A breakdown of the normal microbiome has been implicated in the development of various pathologic states, including Clostridium difficile infection, inflammatory bowel disease, intestinal graft-versus-host disease following allogeneic hematopoietic progenitor cell transplant, colon cancer, and metabolic disorders such as obesity and non-alcoholic steatohepatitis.

To explain the reason for the development of frequent vaso-occlusive crisis in some patients with SCD, the investigators' stepwise hypothesis is that, due to the sickling process and the consequent development of intestinal ischemia, patients with SCD, especially those with frequent vaso-occlusive crisis, are more likely to have altered microbiota than healthy individuals. If the normal microbiota is altered, the intestinal barrier will be compromised, rendering the patients more susceptible to recurrent bacteremia of intestinal origin. Since most SCD patients with vaso-occlusive crisis present without any obvious infections, it is likely that the compromised intestinal barrier facilitates an inoculum of bacteremia not high enough to cause overt infections but sufficient to activate neutrophils and elicit vaso-occlusive crisis. The first step towards testing this overall hypothesis is to test the sub-hypothesis that altered intestinal microbiomes correlate with increased number of activated neutrophils and frequent vaso-occlusive crisis in patients with SCD.