At 400 mg/kg oral dosing in naturally aged mice, Polygonatum sibiricum polysaccharide (PSP) — a glucose-mannose-galactose polymer — significantly restored intestinal barrier integrity, reduced permeability, reshaped gut microbiota composition, and suppressed inflammatory cytokine production. In D-galactose-induced senescent Caco-2 cells, PSP dose-dependently (100–400 μg/mL) reversed cellular senescence markers, recovered tight junction protein expression, and attenuated pro-inflammatory signaling. Network pharmacology and experimental validation converged on TLR4/NF-κB pathway inhibition as the central mechanism.
Intestinal barrier deterioration — often called "leaky gut" — is increasingly recognized as a driver of systemic inflammaging, the chronic low-grade inflammation that accelerates virtually every age-related disease. PSP joins a growing class of prebiotic-adjacent polysaccharides, including beta-glucans and inulin-type fructans, shown to modulate the gut-immune axis, but its dual action on both the microbiome architecture and the TLR4 innate immune checkpoint is mechanistically distinctive. TLR4 is the canonical receptor for lipopolysaccharide (LPS) translocated from a leaky gut, making PSP's inhibition of this pathway biologically coherent and clinically suggestive. Key limitations: mouse-to-human translation remains unproven, the 400 mg/kg murine dose extrapolates to impractical human equivalents, and the abstract truncates before reporting full pathway validation data. This is solid confirmatory-plus work — incremental in concept but methodologically rigorous — that strengthens the case for botanical polysaccharides as targeted anti-inflammaging interventions worthy of human pilot trials.