Invasive non-typhoidal Salmonella in sickle cell disease in Africa: is increased gut permeability the missing link?

Abstract

Non-typhoidal Salmonella usually induces self-limiting gastroenteritis. However, in many parts of Africa, especially in individuals who are malnourished, infected with malaria, or have sickle cell disease, the organism causes serious and potentially fatal systemic infections. Since the portal of entry of non-typhoidal Salmonella into the systemic circulation is by way of the intestine, we argue that an increased gut permeability plays a vital role in the initiation of invasive non-typhoidal Salmonella in these patients. Here, we will appraise the evidence supporting a breach in the intestinal barrier and propose the mechanisms for the increased risks for invasive non-typhoidal Salmonella infections in these individuals.

Keywords: Gut permeability; Intestinal dysbiosis; Invasive non-typhoidal Salmonella; Sickle cell disease.

Fig. 1

Intestinal homeostasis provided by a balanced intestinal microbiota community. A balanced intestinal microbiota community helps maintain microbial homeostasis and immunologic tolerance, and modulate the metabolic processes that influence the intestinal permeability. An intact intestinal barrier is provided by an anatomical barrier of the intestinal wall and a physiological barrier linked to the intestinal microbiota and elements of the mucosal immune system. The space between enterocytes is sealed by TJs that regulate the flow of water ions and small molecules across the barrier. TJ development is maintained by SCFAs and indole metabolites produced by some intestinal microbes. However, TJ development can also be disrupted by the relative abundance of certain intestinal microbes. An intact intestinal barrier prevents the translocation of intestinal microbes, including NTS, across the barrier into the systemic circulation, thereby reduce the risks for systemic infections by the enteric microbes

Fig. 2

Intestinal dysbiosis leads to a breakdown of the normal gut barrier. Due most likely to the intermittent hypoxia induced by recurrent vaso-occlusive crises of the splanchnic vasculature, patients with SCD often experience intestinal dysbiosis. However, frequent diarrheal illnesses, malnutrition, and malaria further worsen the intestinal dysbiosis that may result in changes in the compositions of the intestinal microbes disrupt TJ formation and reductions in the production of SCFAs that enhance TJ formation and enterocyte health, while reduce enterocyte apoptosis. Deficiencies of the indole metabolites produced by microbial metabolism of tryptophan, enterocyte health is further compromised. A breach in the intestinal barrier results in an increased in gut permeability, enhancing translocation of enteric NTS and other microbes to cause systemic infections