Thermophiles, Thick‐Walled Bacteria, and Pseudomonads in High‐Altitude Gut Microbiota

BACKGROUND AND AIM: High-altitude environments are characterized by low oxygen and reduced low pressure, which impose significant physiological challenges on organisms. Among various adaptive systems, the intestinal flora plays a crucial role in maintaining gut health and barrier integrity function under such conditions. This study aimed to elucidate the regulatory mechanisms of intestinal flora in high-altitude environments, focusing on downregulating intracellular Bone Morphogenetic Protein 4 (BMP4) to influence glycolysis metabolism, thereby affecting intercellular communication of the intestinal mucosal barrier and matrix remodeling. METHODS: High-altitude mouse intestinal flora composition and function were analyzed using 16S rRNA and metagenomic sequencing. Additionally, single-cell sequencing was employed to examine cell population communication and gene expression differences between normal and high-altitude mouse intestinal tissues. RESULTS: Single-cell sequencing showed significantly reduced interactions between intestinal fibroblasts and epithelial cells in high-altitude mice, accompanied by a marked increase in BMP4 expression. Overexpression of BMP4 was found to activate the glycolysis pathway. Gut microbiota metabolites, including secondary bile acids, lactic acid, and butyrate, exhibited protective effects on hypoxia-induced intestinal mucosal barrier injury, with butyrate showing the most prominent effect. Under hypoxic conditions, butyrate suppressed the BMP4/glycolysis pathway, thereby alleviating hypoxia-induced intestinal mucosal barrier damage. CONCLUSION: This study uncovered a novel mechanism by which the gut microbiota in high-altitude environments modulate glycolysis metabolism through BMP4 downregulation, thereby affecting intercellular communication and matrix remodeling within the intestinal mucosal barrier.