Salloum, Y.; Gros, G.; Quintero-Castillo, K.; Garcia Baudino, C.; Rabahi, S.; Janardhana Kurup, A.; Diabangouaya, P.; Perez-Pascual, D.; Morales, R. A.; Boekhorst, J.; Villablanca, E.; Ghigo, J.-M.; Feijoo, C. G.; Brugman, S.; Hernandez Cerda, P. P.

Animals host symbiotic microbial communities that shape gut health. However, how the host immune system and microbiota interact to regulate epithelial homeostasis, particularly during early development, remains unclear. Human interleukin-26 (IL-26) is associated with gut inflammation and has intrinsic bactericidal activity in vitro, yet its in vivo functions are largely unknown, primarily due to its absence in rodents. To examine the role of IL-26 in early life, we used zebrafish and found that gut epithelial cells in il26-/- larvae exhibited increased proliferation and DNA damage, faster turnover, and an altered abundance of cell populations. This epithelial dysregulation occurred independently of the IL-26 canonical receptor and resulted from dysbiosis in il26-/-. Moreover, IL-26 bactericidal activity was conserved in zebrafish. Our findings suggest that IL-26 directly regulates microbiota composition through this property. We further identified innate lymphoid cells (ILCs) as the primary source of IL-26 at this developmental stage. These findings establish IL-26 as a central player in a regulatory circuit linking the microbiota, ILCs, and intestinal epithelial cells to maintain gut homeostasis during early life.