HNF4A intestinal ablation positively influences the fate of ileal goblet cells during <i>Salmonella typhimurium</i> infection

Hepatocyte nuclear factor 4 A (HNF4A) is a transcription factor that regulates a diverse range of intestinal epithelial genes involved in tissue renewal, differentiation, and metabolism, among other functions. The HNF4A locus is associated with inflammatory bowel disease (IBD) susceptibility, and its deletion in the mouse intestine causes long-term chronic inflammation of the colon. However, it remains unclear whether HNF4A is part of the regulatory mechanisms involved in the inflammatory processes of the small intestine. Using a tamoxifen-inducible mouse intestinal knockout of <i>Hnf4a</i>, we observed a spontaneous increase in mucosal barrier permeability in the absence of HNF4A. However, when these mice were infected with the invasive-deficient <i>Salmonella typhimurium</i> SB103, this increase in permeability did not result in an increase in liver and spleen bacterial colonization compared with undeleted mice. Interestingly, ileal secretory cell lineage differentiation was favored when HNF4A was depleted during the early stages of infection. This resulted in increased production of ileal goblet cells and the expression of <i>Muc2</i>, as well as the expression of specific antimicrobial peptides such as <i>Reg3g and Rtnlb</i>. We conclude that epithelial HNF4A is sensitive to <i>Salmonella</i> in the ileum and that its reduction in expression during the early phase of infection may contribute to rapidly reinforcing the chemical barrier response to elicit mucosal threat from pathogens.<b>NEW & NOTEWORTHY</b> HNF4A is associated with inflammatory bowel disease susceptibility and protects against chronic colon inflammation. Whether HNF4A acts similarly in the small intestine remains speculative. Although its deletion led to an increase in paracellular permeability, exposure to an attenuated <i>Salmonella typhimurium</i> strain did not cause systemic infection. Ileal goblet cell lineage commitment was stimulated with increased expression of antimicrobial peptide genes. HNF4A reduction of expression may contribute to early mucosal protection against luminal pathogen burdens.