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Diet may modulate immune responses in health and disease. We hypothesised a role for nutrient sensing pathways. Nutrient sensing enteroendocrine cells (EEC) within intestinal epithelium release local neuroendocrine peptides.1 We examined their effects on immune responses in intestinal mucosa.Three studies were conducted with proximal colon biopsies, comparing whole or de-epithelialised biopsies and dispersed lamina propria to determine contribution of epithelial populations. 1. Expression of genes for nutrient receptors (GPR92, GPR84) and neuroendocrine peptide receptors (GLP1R, GLP2R, NPY1R, NPY2R) was measured using Taqman microfluidic cards (n=5–7). 2. Whole biopsies and de-epithelialised lamina propria (n=12–20) incubated with macronutrients protein hydrolysate (whey protein derivative) or lauric acid (medium chain fatty acid), agonists for GPR92 and GPR84 respectively. IL-8, IL-6, TNFα, IL-10 and IL-1β profiles were measured in supernatant using a MAGPIX (magnetic bead) multiplex assay. 3. Dispersed lamina propria cells incubated with neuroendocrine peptides GLP1 and NPY (n=3–5) and IL-8 release measured by ELISA.1. GPR92 and GPR84 mRNA was detected in both mucosal epithelium and lamina propria. GPR92 expression did not differ but GPR84 expression was significantly greater in epithelium compared with lamina propria (p=0.03). Expression of neuroendocrine peptide receptors GLP2R, NPY1R and NPY2R was also detected. 2. GPR92 agonist protein hydrolysate significantly reduced IL-8, IL-6 and IL-10 release p<0.05. Removal of epithelium negated this inhibitory effect (figure 1). The GPR84 agonist lauric acid significantly reduced IL-8, IL-6 and IL-10 release within whole biopsies, this inhibitor effect remained after removal of the epithelium, p<0.05 (figure 1). 3. IL-8 release from lamina propria was reduced by 56% (±8.5%) in presence of PY2R agonist NPY compared with medium only (data not shown).Nutrient sensing receptors GPR92, GPR84 and neuroendocrine peptide receptors GLP2R, NPY1R and NPY2R are expressed by colonic epithelium and lamina propria. Dietary nutrients can modulate mucosal immune responses, certain nutrients via epithelial EEC signalling pathways and others via direct effects on lamina propria.. Symonds EL, Peiris M, Page AJ, et al. Mechanisms of activation of mouse and human enteroendocrine cells by nutrients. Gut2015;64(4):618–626.