National Institute of General Medical Sciences 5P20GM134973-07

The macrophage/tuft cell SUCNR1 axis in neonatal intestinal inflammation

This NIH-funded project investigates the role of the macrophage/tuft cell SUCNR1 axis in neonatal intestinal inflammation, specifically necrotizing enterocolitis (NEC). It aims to understand the molecular mechanisms and identify therapeutic targets to improve treatment for NEC in preterm infants.

Description

Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease of the neonatal period with an unclear, and likely multifactorial, pathogenesis. It most often affects preterm, very low birthweight (VLBW, < 1500 g) infants, with risk factors including dysbiosis, formula feeding, and prematurity. The project aims to identify interventions promoting healthy development of the intestine and gut microbiome during early life. Proinflammatory M1 macrophages infiltrate the preterm intestine during NEC, accelerating mucosal inflammation. Conversely, intestinal tuft cells, which induce an anti-inflammatory, type 2 immune response, are depleted during murine ileitis. Experimental expansion of tuft cells has been shown to protect against ileal inflammation. Succinate accumulates in the NEC intestine, binding to succinate receptor 1 (SUCNR1) in mucosal macrophages and tuft cells. While macrophage SUCNR1 perpetuates inflammation, tuft cell SUCNR1 induces an anti-inflammatory response, suggesting a macrophage/tuft cell SUCNR1 axis in mucosal innate immunity regulation. The project hypothesizes that this axis is dysregulated during NEC, with preliminary data indicating tuft cell depletion during preterm NEC. The study will test whether inhibition of macrophage SUCNR1 signaling and expansion of tuft cells can protect against NEC-like injury, and whether NEC is associated with increased macrophage SUCNR1 expression, increased epithelial succinate transporters, and decreased tuft cell numbers and SUCNR1 expression. The goal is to identify cell-type-specific molecular targets for NEC, improving understanding and treatment of this disease, which currently has limited therapeutic options beyond surgery and supportive care.

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