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

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• The intestinal barrier's age-related changes affect local immunity and systemic health.
• Mechanisms coordinating immune and microbial dynamics throughout life are not fully understood.
• Toll-like receptor 4 (TLR4) is a key mediator in host-microbiota interactions.

Purpose of the Study:

• To investigate age-related changes in intestinal barrier function.
• To elucidate the role of Toll-like receptor 4 (TLR4) in these age-related changes.
• To understand the dynamics of host-microbiota interactions across the lifespan.

Main Methods:

• Utilized C57BL/6J and TLR4 knockout mice across developmental stages (pups, adults, middle-aged, old).
• Employed histology, microbiome profiling, SCFA analysis, cytokine quantification, ex vivo assays, and transcriptomics.
• Analyzed colonic structure, microbial composition, immune responses, and signaling pathways.

Main Results:

• Identified distinct phases of intestinal remodeling across the lifespan.
• Observed age-dependent shifts in microbiota composition and short-chain fatty acid (SCFA) production.
• Demonstrated increased pro-inflammatory cytokines and blunted immune responses in aged mice, which were absent in TLR4 knockout mice.
• Revealed biphasic PI3K/Akt pathway activation in young and old mice.

Conclusions:

• Aging induces systemic rewiring of host metabolic and immune pathways in response to the aging microbiota.
• Toll-like receptor 4 (TLR4) signaling plays a critical role in age-associated intestinal functional decline.
• The lifespan-wide microbiota-host signaling axis represents a potential therapeutic target for age-related intestinal dysfunction.