A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult

Abstract

Highlights d The expanding microbiota at weaning induces a vigorous immune reaction d The weaning reaction occurs during a specific time window d The weaning reaction prevents susceptibility to inflammatory pathologies in the adult d Microbiota-induced Treg cells are required for a protective weaning reaction

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…Cessation of breastfeeding was identified as a major driving factor highlighting the critical influence of breast‐milk constituents on early host–microbial homeostasis . Beside lactose, human milk oligosaccharides, lactoferrin and secretory IgA may exert direct antibacterial effects whereas epidermal growth factor has a major influence on intestinal epithelial gene expression and immune development . Notably, major differences are found between breastfed and formula‐fed babies .…”

“…This microbial stimulation may also cause the reported transient interleukin‐22‐ (IL‐22) and IL‐23‐induced signal transducer and activator of transcription 3 phosphorylation in innate lymphoid type 3 cells and epithelial cells . Notably, the time‐point of the intestinal tolerization process and Treg cell generation is critical and delayed exposure to microbiota has far reaching consequences for health and disease in later life with increased susceptibility to immune‐mediated diseases such as inflammatory bowel disease, cancer, and allergic sensitization …”

“…On the other hand, premature activation of the adaptive immune system in the intestine can also lead to enhanced disease susceptibility. It can be induced by removing maternal immunoglobulin from breast milk or enforcing a premature transport of antigen to lamina propria dendritic cells via GAPs . The consequences of premature activation are under‐studied.…”

“…, middle panel). This in turn provokes a strong immune reaction, the so‐called weaning reaction that depends on the microbiota, microbial metabolites, and dietary factors and promotes the expansion of retinoic acid receptor‐related orphan receptor γ t + Treg cells and lasting protection from inflammatory disease . At this stage, GAPs co‐transport microbiota‐derived innate immune stimuli such as lipopolysaccharide and this process might significantly strengthen a tolerogenic adaptive immune response.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…Transfer of naive transgenic T cells specific for commensal antigens into mice with a normal microbiota resulted in robust Foxp3 induction in these cells . At weaning, the intestinal microbiota induces a vigorous immune response associated with the generation of ROR γ t + Treg cells in an SCFA and retinoic acid‐dependent manner, and inhibition of this response leads to later immunopathologies including colitis …”