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<p>Enterocytes mediate both nutrient absorption and antimicrobial peptide (AMP) secretion while constantly exposed to osmotic fluctuations. However, the role of volume-regulated anion channel (VRAC), a key osmo-sensitive ion channel, in enterocytes and inflammatory bowel disease (IBD) remains unclear. Here, we show that intestinal epithelial cell (IEC)-specific knockout of LRRC8A, the essential VRAC subunit, exacerbates colitis and inflammation-associated colorectal cancer. VRAC deficiency specifically disrupts enterocyte maturation and zonation, expanding AMP-producing enterocytes while reducing enterocytes responsible for nutrient absorption. Retinoic acid metabolism emerges as the most affected nutrient pathway in VRAC-deficient IECs, with reduced <i>Adh1</i>, <i>Aldh1a2</i> expression and aldehyde dehydrogenase activity. Supplementation with retinoic acid reversed inflammation caused by VRAC deficiency. Conversely, VRAC deficiency induced gut microbiota dysbiosis, while administration of <i>Lactobacillus</i> species effectively restored microbial balance and alleviated inflammation. This study delineates the role of VRAC in balancing nutrient absorption and antimicrobial defense in enterocytes to safeguard gut homeostasis.</p>

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VRAC coordinates the trade-off between nutrient absorption and antimicrobial defense in enterocytes against inflammation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月25日

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  • Xin Yi,
  • Shiqing Zhang,
  • Xinpei Gu,
  • Xiaoyan Wu,
  • Liang Ma,
  • Yudai Xu,
  • Sha Lv,
  • Jingjing Huang,
  • Yuanxing Zhi,
  • Ying Cao,
  • Xiong Cao,
  • Fengxian Li,
  • Guobing Chen,
  • Shuwen Liu,
  • Ken Kin Lam Yung,
  • Pingzheng Zhou

摘要

Enterocytes mediate both nutrient absorption and antimicrobial peptide (AMP) secretion while constantly exposed to osmotic fluctuations. However, the role of volume-regulated anion channel (VRAC), a key osmo-sensitive ion channel, in enterocytes and inflammatory bowel disease (IBD) remains unclear. Here, we show that intestinal epithelial cell (IEC)-specific knockout of LRRC8A, the essential VRAC subunit, exacerbates colitis and inflammation-associated colorectal cancer. VRAC deficiency specifically disrupts enterocyte maturation and zonation, expanding AMP-producing enterocytes while reducing enterocytes responsible for nutrient absorption. Retinoic acid metabolism emerges as the most affected nutrient pathway in VRAC-deficient IECs, with reduced Adh1, Aldh1a2 expression and aldehyde dehydrogenase activity. Supplementation with retinoic acid reversed inflammation caused by VRAC deficiency. Conversely, VRAC deficiency induced gut microbiota dysbiosis, while administration of Lactobacillus species effectively restored microbial balance and alleviated inflammation. This study delineates the role of VRAC in balancing nutrient absorption and antimicrobial defense in enterocytes to safeguard gut homeostasis.