Enteroendocrine cells make up 1% of the intestinal epithelium and, beyond their classical role of detecting luminal nutrients, they also detect and respond to (1) pathogens via the expression of TLRs and (2) the intestinal microbiome via the expression of specific receptors for the metabolites commensal bacteria produce. (3) In response to pathogens and microbial metabolites, enteroendocrine cells secrete peptide hormones and classical cytokines to the surrounding immune cell rich milieu. In addition to classical cytokine receptors, immune cells express a vast array of receptors for peptide hormones which have direct immunomodulatory effects. (4) Enteroendocrine-secreted hormone peptides also signal to vagal afferents triggering an anti-inflammatory vagal reflex. The resulting acetylcholine released from vagal efferents inhibits inflammatory responses from the surrounding immune cells. (5) Vagal afferent signalling also modulates classical feeding pathways resulting in altered fat deposits. This, in turn, modifies the levels of fat secreted adipokines, such as leptin, influencing immune cell function. (6) CD4+ T-cells directly influence the function of peptide hormones via increased secretion and hyperplasia of enteroendocrine cells via direct enteroendocrine and indirect stem cell signalling.