Retinoid Levels Influence Enterohemorrhagic Escherichia coli Infection and Shiga Toxin 2 Susceptibility in Mice

Abstract

e Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that produces Shiga toxin (Stx) and causes hemorrhagic colitis. Under some circumstances, Stx produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome. Although retinoids like vitamin A (VA) and retinoic acid (RA) are beneficial to gut integrity and the immune system, the effect of VA supplementation on gastrointestinal infections of different etiologies has been controversial. Thus, the aim of this work was to study the influence of different VA status on the outcome of an EHEC intestinal infection in mice. We report that VA deficiency worsened the intestinal damage during EHEC infection but simultaneously improved survival. Since death is associated mainly with Stx toxicity, Stx was intravenously inoculated to analyze whether retinoid levels affect Stx susceptibility. Interestingly, while VA-deficient (VA-D) mice were resistant to a lethal dose of Stx2, RA-supplemented mice were more susceptible to it. Given that peripheral blood polymorphonuclear cells (PMNs) are known to potentiate Stx2 toxicity, we studied the influence of retinoid levels on the absolute number and function of PMNs. We found that VA-D mice had decreased PMN numbers and a diminished capacity to produce reactive oxygen species, while RA supplementation had the opposite effect. These results are in line with the well-known function of retinoids in maintaining the homeostasis of the gut but support the idea that they have a proinflammatory effect by acting, in part, on the PMN population.

Role of Dietary Micronutrients on Gut Microbial Dysbiosis and Modulation in Inflammatory Bowel Disease

“…The safety of supplementing high micronutrient doses to microbiota should be definitely explored because high doses of certain micronutrients can favor enteropathogen growth or enhance their virulence as shown in high Proteobacteria microbiota for Fe [ 130,235–237 ] and vitamin A. [ 238 ]…”

“…The safety of supplementing high micronutrient doses to microbiota should be definitely explored because high doses of certain micronutrients can favor enteropathogen growth or enhance their virulence as shown in high Proteobacteria microbiota for Fe [130,[235][236][237] and vitamin A. [238] Figure 1. Overview of the detected dietary micronutrient and microbiome shifts in IBD and impact of micronutrients in maintaining gut homeostasis through host and microbial cellular processes (top).…”

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

“…Ligand binding results in recruitment of molecular machinery that modifies local chromatin and promotes active transcription. RA and vitamin A availability can modulate C. rodentium and E.coli infection in mice and humans, respectively (Cabrera et al, 2014;McDaniel et al, 2015), provoking the hypothesis that RA may mediate the SFB-induced decrease in C. rodentium. Therefore, to first test whether RA is protective against C. rodentium in an SFB-deficient context, GF mice were treated with exogenous RA prior to and throughout the duration of infection.…”

Vitamin A at the interface of host–commensal–pathogen interactions

“…Vitamin A deficiency, although detrimental in the intestine, results in less recruitment of PMNs and reduced ROS. The increased survival in VAD mice is attributed to ineffective activation of the Shiga toxin [19].…”