Innate Lymphoid Cells: A Link between the Nervous System and Microbiota in Intestinal Networks

Figure 2

The main relationships between ILCs and the gut microbiota and between ILCs and the ENS in IBD. The gut microbiota can stimulate macrophagocytes to secrete IL-β, which can induce RORγt⁺ ILCs to produce IL-22. This process is also observed for IL-7, which is secreted by intestinal epithelial cells (IECs). IL-25, which is produced by IECs and stimulated by the gut microbiota, decreases the production of IL-22 by ILC3s. IL-22 can also induce fucosylation, which is required for host protection against enteric pathogens, in IECs. Microbial sensing and production of IL-1β by intestinal macrophages drive CSF2 secretion by ILC3s. Toll-like receptor 2 (TLR2) expressed on the surface of ILC3s can identify bacterial signals. ILC3 subsets express the neuroregulatory receptor tyrosine kinase (RET), which is activated by glial-derived neurotrophic factor family ligands (GFL) derived from enteric glial cells (EGCs), in response to IL-22 secretion. Neuronal messenger neuromedin U (NMU), produced by neurons, binds to NMUR1 on ILC2s, and ILC2s are activated to secrete innate type 2 cytokines. Activation of ILCs via the ENS or induction of cytokines via the gut microbiota can modulate the development or progression of IBD, as detailed in Figure 1. The gut microbiota is also associated with the ENS. Cytokines regulated by gut microbiota could modulate ENS activity directly or indirectly, e.g., IL-1β, which has its receptors on ENS neurons.