Direct therapeutic effect of sulfadoxine-pyrimethamine on nutritional deficiency-induced enteric dysfunction in a human intestine chip

ABSTRACT Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to improve the birth weight of infants in pregnant women in sub-Saharan Africa independently of malarial infection. Here, we investigated whether SP could have a direct impact on improving intestinal function, thereby enhancing the absorption of essential fats and nutrients crucial for fetal growth. Using a human organ-on-a-chip model, we replicated the adult female intestine with patient organoid-derived duodenal epithelial cells interfaced with human intestinal endothelial cells. Nutrient-deficient (ND) medium was perfused to simulate malnutrition, resulting in the appearance of enteric dysfunction indicators such as villus blunting, reduced mucus production, impaired nutrient absorption, and increased inflammatory cytokine secretion. SP was administered to these chips in the presence or absence of human peripheral blood mononuclear cells (PBMCs). Treatment with SP successfully reversed many abnormalities observed in malnourished chips, as confirmed by transcriptomic and proteomic analysis. Notably, SP significantly enhanced intestinal absorptive functions. Furthermore, SP suppressed the recruitment of PBMCs in the nutrient deficient chips. SP may improve the birth weight of children born to malnourished mothers by countering the effects of enteric dysfunction and suppressing inflammation. These findings highlight the possibility of using SP as a direct intervention to improve maternal absorption and subsequently contribute to healthier fetal growth.