Retinoid Signaling in Intestinal Epithelial Cells Is Essential for Early Survival From Gastrointestinal Infection

Abstract

Vitamin A deficiency (A-) increases morbidity and mortality to gastrointestinal (GI) infection. Blocking retinoid signaling (dominant negative retinoic acid receptor, dnRAR) in intestinal epithelial cells (IEC, IEC dnRAR) had no effect on vitamin A absorption, the expression of tight junction proteins or the integrity of the barrier. Immune cells in the gut were present in normal frequencies in the IEC dnRAR mice, with the exception of the T cell receptor (TCR)αβ+/CD8αα cells, which were significantly lower than in wildtype littermates. Challenging the IEC dnRAR mice with dextran sodium sulfate to induce colitis or Citrobacter rodentium infection resulted in similar disease to wildtype littermates. Feeding mice vitamin A deficient diets reduced vitamin A status and the A-IEC dnRAR mice developed more severe colitis and C. rodentium infection. In particular, retinoid signaling in the IEC was crucial for the A-host to survive early infection following C. rodentium. Treating A-mice with retinoic acid (RA) beginning on the day of infection protects most mice from early lethality. However, RA treatment of the A-IEC dnRAR mice was ineffective for preventing lethality following C. rodentium infection. Retionid signaling in IEC is critical, especially when there are reduced levels of dietary vitamin A. IEC are direct targets of vitamin A for mounting early defense against infection.

Retinoic Acid Signaling Modulates Recipient Gut Barrier Integrity and Microbiota After Allogeneic Hematopoietic Stem Cell Transplantation in Mice

“…We are interested in how micronutrients, in particular vitamin A, regulates this process given the well-established beneficial effects of this molecule in maintaining mucosal barrier function. Indeed, recent studies have shown the crucial role of intestinal epithelial retinoid signaling in regulating the survival of mice in the context of GI infection ( 37 ). In this paper, we provide novel insights into how retinoic acid signaling influences intestinal tight junctions and microbiota in the setting of allogeneic HSCT.…”

Gut Health and Influencing Factors in Pigs

“…Moreover, it is essential for developing adaptive immunity to intestinal microorganisms and is an anti-inflammation vitamin because it is critical in enhancing immune function. Hence, its deficiency can be detrimental to the animals’ intestinal health [ 118 , 119 , 120 ]. Vitamin A supplementation in piglets (14 days post-weaning) improved their intestinal morphology and activity of digestive enzymes, positively affecting the piglets’ intestinal function [ 88 ].…”

Gut commensals expand vitamin A metabolic capacity of the mammalian host

“…Postnatal local RA synthesis and signaling is essential for maintenance of epithelial homeostasis (Wolbach and Howe, 1925), immune function (Hall et al, 2011), and stem cell populations (Strickland and Mahdavi, 1978). Role of RA in maintaining a robust intestinal epithelium barrier is especially important in regulating host microbe interactions (Gattu et al, 2019;Snyder et al, 2020). Loss of intestinal epithelial cell (IEC) intrinsic RA signaling in mice results in defective goblet cell lineage commitment and reduced epithelial cell shedding upon infection (Iyer et al, 2020;Jijon et al, 2018).…”