Low-grade mucosal inflammation in aged senescence-accelerated mouse-prone 8 mice blunts epithelial barrier recovery after dextran sodium sulphate-induced chronic colitis.

Abstract

The gastrointestinal (GI) barrier maintains gut homeostasis by regulating nutrient absorption and preventing the entry of harmful agents. While its disruption has been linked to chronic disease, stress and dietary lifestyle, the role of aging in intestinal permeability remains subject of debate. Understanding how aging and age-associated inflammation affect barrier integrity is crucial for promoting GI health in the elderly. In this study, we used the Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice and their normally aging Senescence-Accelerated Mouse-Resistant 1 (SAMR1) counterparts to investigate GI homeostasis at 2, 5, 9 and 11 months of age under basal conditions and during chronic colitis induced by repetitive dextran sodium sulphate (DSS) treatment. Until 9 months of age, no histological deviations were observed in either strain. At 11 months, SAMP8 mice exhibited low-grade colon inflammation marked by immune cell infiltration, including neutrophils and macrophages, and elevated expression levels of pro-inflammatory genes (Il1b, ccl5, cxcl1, cxcl10, Tnf and Saa3), while GI barrier function remained intact. However, after DSS-induced chronic colitis, aged SAMP8 mice showed a heightened disease activity index and intestinal hyperpermeability, unlike age-matched SAMR1 mice. Mechanistically, this impaired GI barrier recovery correlates with aberrant STAT3 signaling. Notably, SAMP8 mice exhibited increased epithelial proliferation and macrophage abundance at baseline, which did not further increase after DSS treatment. In conclusion, our findings support the notion that aging alone does not compromise GI barrier function but rather predisposes the gut to barrier dysfunction upon inflammatory challenge due to impaired resolution mechanisms.