Aged Gut Microbiota Induces Mucosal Transcriptional Dysregulation, Impairing Immune Surveillance

Aging is associated with systemic immune remodeling and disease susceptibility, but its impact on intestinal mucosal immunity, particularly changes in M cells, remains largely unknown. This study aimed to investigate how aging alters intestinal mucosal immune phenotypes, specifically follicle-associated epithelial cells (FAE) and the gut microbiota, and to identify interconnected pathways that may be exploited to maintain intestinal immune function in the elderly. Using intestinal tissue from young and aged mice, this study assessed manifestations of intestinal epithelial aging, changes in immune cells in the lamina propria, and microbial composition. Aging was associated with increased expression of senescence-associated secretory phenotype (SASP) markers (IL-1β, TNF-α, p16) and decreased levels of tight junction proteins (Occludin, Tricellulin), suggesting epithelial barrier dysfunction. Aged mice exhibited decreased Naïve Th cells, increased Effector Th and Th17 subsets, and decreased fecal IgA. Microbiome analysis revealed enrichment of inflammatory bacteria, such as Desulfovibrio and Candidatus_Saccharimonas, and elevated dysbiosis indices. RNA sequencing of FAEs revealed 578 differentially expressed genes, including downregulation of Gp2 and Ccl28, indicating impaired M cell function. Association analysis between microbiome changes and mucosal immune aging revealed that enrichment of key inflammatory bacteria may contribute to impaired M cell function and dysregulated intestinal mucosal immunity. These findings reveal a multi-layered disruption of intestinal homeostasis during aging-comprising barrier function, immune imbalance, FAEs dysfunction, and shifts in specific microbial taxa -leading to increased susceptibility to pathogens. Targeting these age-related pathways may provide strategies for maintaining intestinal immunity in the elderly.