NIH Reporter #5P20GM134973-07

The macrophage/tuft cell SUCNR1 axis in neonatal intestinal inflammation

This award funds research on the role of the macrophage/tuft cell SUCNR1 axis in neonatal intestinal inflammation, specifically necrotizing enterocolitis (NEC). The study aims to understand the dysregulation of this axis in NEC and test therapeutic strategies targeting macrophage SUCNR1 signaling and tuft cell expansion to protect against NEC-like injury.

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 long-term goal is 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 both mucosal macrophages and tuft cells. While SUCNR1 activation in macrophages perpetuates inflammation, in tuft cells it induces an anti-inflammatory response, suggesting a macrophage/tuft cell SUCNR1 axis in innate immunity regulation. Increased passive diffusion and transepithelial transport of succinate across a porous preterm intestinal barrier, hypoxia-induced succinate production within macrophages, and inflammation-induced tuft cell loss likely contribute to mucosal succinate accumulation and 'runaway inflammation' in NEC. The project hypothesizes that the macrophage/tuft cell SUCNR1 axis is dysregulated during 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-specific molecular targets for NEC, improving understanding and treatment of this disease, which currently has limited therapeutic options.

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