IL-26 produced by innate lymphoid cells regulates early-life gut epithelial homeostasis through modulating microbiot

Multicellular organisms host numerous symbiotic microbial communities which are established early in life and are most diverse in the gut. Dysregulation in the composition or function of gut microbial communities, namely the gut microbiota, can lead to various host disorders, including inflammatory bowel disease (IBD) and colorectal cancer . The mechanisms that establish and maintain a balanced and healthy gut microbiota remain poorly understood, especially during first exposure to these microorganisms in early life. Interleukin-26 (IL-26) has been identified as a risk factor for IBD and shown to have intrinsic antibacterial properties in vitro. The in vivo functions of IL-26 in the intestine as well as whether and how it regulates the gut microbiota are not well understood, primarily due to its absence in rodents. To examine the role of IL-26, we utilized zebrafish and found that the absence of this cytokine during early life leads to increased proliferation and DNA damage in gut epithelial cells. Microbiota profiling, coupled with germ-free and microbiota transfer experiments, revealed that epithelial deregulation results from dysbiosis in il26-/- larvae. Moreover, our analysis identified innate lymphoid cells (ILCs) as the primary source of IL-26 at this early developmental stage. These findings highlight IL-26 as a central player in a regulatory circuit involving the microbiota, ILCs, and intestinal epithelial cells during early life. Our data underscore the importance of IL-26 in gut health and disease, highlighting its crucial role in shaping the microbiota landscape and controlling gut bacterial infection, which are key factors in maintaining epithelial homeostasis and influencing the onset and progression of IBD. These insights could inform the development of novel therapeutic strategies for this and other microbiota-driven disorders.