Chicory polysaccharide alleviates hypoxia-induced gut dysbiosis and cognitive deficits in mice via IL-6/IL-6R/STAT3-mediated anti-inflammatory mechanisms.

Abstract

BACKGROUND: Hypoxia-induced intestinal injury and cognitive deficits have become significant health issues in high-altitude regions. This study aims to investigate the protective effects and mechanisms of chicory polysaccharide (CP) against intestinal injury and cognitive deficits in mice exposed to hypoxia. METHODS: C57BL/6 mice were randomly divided into control, model, and three CP dose groups (150 mg/kg, 300 mg/kg, 600 mg/kg). The model and CP groups were exposed to a hypobaric hypoxia environment for 7 days that simulated an altitude of 7000 m. The intestinal permeability of the mice was assessed to evaluate gut function, and behavioral tests were conducted to assess cognitive performance. Histopathological staining was performed to evaluate morphological changes in the colon and hippocampus. ELISA was used to measure levels of inflammatory cytokines and lipopolysaccharides (LPS), and western blotting was used to analyze tight junction (TJ) and IL-6/IL-6R/STAT3 signaling pathway proteins. 16S rRNA sequencing and metabolomics were performed to evaluate gut microbiota composition and short-chain fatty acid (SCFAs) metabolism. RESULTS: CP significantly upregulated the expression of TJ proteins, which provide intestinal protection by enhancing intestinal barrier function and reducing inflammatory cytokine levels in the colon. The mechanism underlying these effects may be related to IL-6/IL-6R/STAT3 signaling pathway inhibition. Furthermore, CP reduced serum levels of LPS and inflammatory cytokines. CP provided neuroprotection by effectively alleviating cognitive deficits in model mice, as evidenced by significant improvements in short-term memory and spatial exploration. Specifically, CP markedly attenuated microglial cell overactivation and neuroinflammatory responses, restored synaptic plasticity, and strengthened the integrity of the blood-brain barrier. mo, CP significantly altered the gut microbiota composition, characterized by an increase in the beneficial bacteria Lactobacillus and a decrease in the potentially pathogenic bacteria Escherichia-Shigella. Additionally, CP markedly enhanced SCFA biosynthesis. CONCLUSION: CP effectively mitigates hypoxia-induced intestinal injury and cognitive deficits, possibly through IL-6/IL-6R/STAT3 signaling pathway inhibition and gut microbiota remodeling. Our study suggests that CP supplementation may be a potential means of preventing altitude sickness.