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

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.