T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota

How the gut microbiota and immune system maintain intestinal homeostasis in concert with the enteric nervous system (ENS) remains incompletely understood. To address this gap, we assessed small intestinal transit, enteric neuronal density, enteric neurogenesis, intestinal microbiota, immune cell populations and cytokines in wildtype and T-cell deficient germ-free mice colonized with specific pathogen-free (SPF) microbiota, conventionally raised SPF and segmented filamentous bacteria (SFB)-monocolonized mice. SPF microbiota increased small intestinal transit in a T cell-dependent manner. SPF microbiota increased neuronal density in the myenteric and submucosal plexuses of the ileum and colon, similar to conventionally raised SPF mice, independently of T cells. SFB increased neuronal density in the ileum in a T cell-dependent manner, but independently of T cells in the colon. SPF microbiota stimulated enteric neurogenesis (Sox2 expression in enteric neurons) in the ileum in a T cell-dependent manner, but in the colon this effect was T cell-independent. T cells regulated nestin expression in the ENS. SPF colonization increased Th17 cells, RORγT⁺ Treg cells, and IL-1β and IL-17A levels in the ileum and colon. By neutralizing IL-1β and IL-17A, we observed that they control microbiota-mediated enteric neurogenesis but were not involved in the regulation of motility. Together, these findings provide new insights into the microbiota-neuroimmune dialog that regulates intestinal physiology.