IL-22 promotes genesis of small intestinal secretory cells that protect against cholera in mice.

The diarrhoeal disease cholera remains a global threat, but there is limited knowledge of the innate immune defences in the small intestine that protect against the causative agent, Vibrio cholerae. Here single-cell RNA sequencing of epithelial and immune cells mapped gene expression patterns in the infant mouse small intestine and revealed changes in response to V. cholerae infection and prophylactic treatment with an interleukin-22-immunoglobulin Fc region (IL-22Fc)-fusion protein. Infection increased the abundance of an enterocyte subtype with high expression of defence-associated functions and stimulated production of IL-22, a cytokine linked to epithelial integrity, from group 3 innate lymphoid cells. Administration of IL-22Fc increased production of vibriocidal Reg3β from enterocytes and the abundance of secretory lineage and Muc2-producing goblet cells, which secreted mucus into the intestinal crypts, impairing V. cholerae association with the epithelium. These IL-22-mediated responses limited V. cholerae intestinal colonization and protected mice from diarrhoea and death. Our findings suggest enterocyte specialization in mucosal defence.