Age-related loss of intestinal barrier integrity plays an integral role in Thymic involution and T cell ageing

The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age-related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we identify several strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Most importantly, we confirm a direct effect of mucosal permeability on the regulation of thymic ageing and hyperactivation of the immune system by demonstrating that aged germ-free mice are protected from age-related intestinal membrane permeability. Together, these findings establish a mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing, via causing thymic involution, extending our understanding of the consequences of intestinal membrane permeability and opening up the possibility for the use of microbiome-based interventions to restore immune homeostasis in older adults.