Hypobaric hypoxia exposure impairs colonic goblet cell subpopulation via the HIF-1α signaling pathway

Exposure to hypobaric hypoxia during rapid ascent to high altitudes significantly impacts intestinal barrier function. Goblet cells, as one of the primary cell types in the intestinal mucosa, play a crucial role in maintaining this barrier. However, the effects of hypobaric hypoxia on goblet cell function and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of hypobaric hypoxia exposure (simulating an altitude of 6,000 m) and studied its effects on colonic goblet cells by transcriptomic analysis. In addition, the hypoxia-treated (1% O₂) goblet cell line Ls174t was used to investigate potential mechanisms underlying hypoxia-induced changes in goblet cells. In the present study, we discovered that hypobaric hypoxia exposure not only reduced the number of colonic goblet cells in mice by 27.6% but also impaired their mucus secretion. Transcriptome sequencing analysis of sorted goblet cells from the mice colon revealed significant changes in gene expression profiles, particularly in the expression of canonical goblet cell markers such as calcium-activated chloride channel regulator 1 (<i>Clca1</i>) and Fcγ-binding protein (<i>Fcgbp</i>). We confirmed the effects of hypobaric hypoxia/hypoxia exposure on CLCA1 and FCGBP expression at both mRNA and protein levels in mouse colonic tissues and in Ls174t cells. The expression of these canonical goblet cell marker genes was dependent upon hypoxia-inducible factor-1α (HIF-1α) activity; their expression decreased upon hypoxia-induced activation of HIF-1α and increased when HIF-1α was knocked down using siRNA. Thus, hypobaric hypoxia exposure regulates the distribution and function of colonic goblet cell subsets through the HIF-1α signaling pathway.<b>NEW & NOTEWORTHY</b> We investigated the role of hypoxia-inducible factor-1α (HIF-1α) in colonic goblet cell injury under hypobaric hypoxia exposure. Our results indicate that the elevation of HIF-1α caused by hypobaric hypoxia exposure can significantly reduce canonical goblet cells and disrupt intestinal mucosal barrier function. It provides a potential intervention strategy for restoring goblet cell function under hypobaric hypoxic conditions.