Age-Dependent Alterations in Intestinal Barrier Function: Involvement of Microbiota and TLR4 Signaling

作者：Yakun Xing, Xingyu Zhao, Xinyu Li, Jiawei Zheng, Wuyang Huang · 发表于：Biology · 年份：2026 · DOI：10.3390/biology15050441 · 被引用次数：3 · 研究领域：Gut microbiota and health、Immune Response and Inflammation、Immune cells in cancer

The intestinal barrier undergoes profound changes with age, impacting local immunity and systemic health, yet the mechanisms coordinating immune and microbial dynamics across the lifespan remain incompletely understood. Toll-like receptor 4 (TLR4) serves as a key mediator of host–microbiota interactions. This study investigated age-related changes in barrier function and the role of TLR4 using C57BL/6J and TLR4 knockout (TLR4−/−) mice across key developmental stages: pups (postnatal day 9), adults (2–4 months), middle-aged (7–9 months), and old (16–19 months). Through a multi-layered approach integrating histology, microbiome profiling, short-chain fatty acid (SCFA) analysis, cytokine quantification, ex vivo functional assays, and transcriptomics, we identified a multi-phase process of intestinal remodeling. Pup-P9 mice exhibited immature colonic structure, a simple microbiota dominated by Firmicutes and Proteobacteria, and undetectable acetic acid level. Adults reached peak diversity and SCFA concentrations, marked by a rise in Bacteroidota and the emergence of Akkermansia. In middle and old age, pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) increased, Bacteroidota declined while Firmicutes, Actinobacteria, and Turicibacter expanded, and aged colons showed blunted ex vivo responses to IL-1β. This age-associated functional decline phenotype was absent in TLR4−/− mice, supporting the involvement of TLR4 signaling. Transcriptomics further revealed biphasic PI3K/Akt activa...