Lactobacillus reuteri (Lr)-Mediated Protection Against NEC is Associated with AHR Activation

Abstract

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease with unacceptably high morbidity and mortality that mainly affects premature infants. Despite decades of research, there is currently no known cure for the disease. One potential prophylactic strategy against NEC is the administration of probiotics, which may modulate the microbiome and prevent inflammation in the gut. Our lab has developed a novel formulation of the probiotic Lactobacillus reuteri (Lr) that leverages its ability to produce a protective biofilm, by growing it on the surface of biocompatible dextranomer microspheres (DM). In particular, DM can be loaded with beneficial substrates such as maltose that can enhance biofilm production, leading to increased efficacy. We have previously demonstrated that the delivery of Lr in its biofilm state (Lr-DM-maltose) can attenuate NEC severity in rodent (rat and mouse) and piglet models of NEC. However, the mechanisms involved remain unclear. One host signaling pathway that may be crucial to the beneficial effects of Lr-DM-maltose prophylaxis is the Aryl Hydrocarbon Receptor (AHR). AHR is a cytoplasmic ligand-binding receptor expressed in several cell types in the intestine. Interestingly, through tryptophan catabolism L. reuteri produces ligands which lead to AHR activation. Using an optimized mouse model of NEC, we now show that Lr-mediated protection against NEC is associated with AHR activation.