Zinc treatment is efficient against Escherichia coli α-haemolysin-induced intestinal leakage in mice

Abstract

Zinc homoeostasis exerts protective effects in inflammatory intestinal diseases and zinc supplementation has been successfully used for treating infectious diarrhoea. This study aimed at a characterisation of zinc effects on focal leak induction by α-haemolysin (HlyA)-producing Escherichia coli (E. coli) as protective mechanism for colitis. We conducted in vivo experiments by oral challenge of gnotobiotic mice colonised with HlyA-expressing E. coli-536. Mice were either fed a defined normal or high zinc diet to analyse effects of zinc as a therapeutic regimen. HlyA-deficient E. coli-536 mutants were used as controls. Mice infected with HlyA-producing E. coli showed impaired barrier integrity when receiving normal zinc. High zinc supplementation in HlyA-producing E. coli-infected mice reduced epithelial dysfunction as indicated by ameliorated macromolecule permeability. Reduced size of focal leaks with diminished bacterial translocation was observed as inherent mechanisms of this zinc action. In human colon cell monolayers application of zinc rescued the HlyA-dependent decline in transepithelial electrical resistance via reduction of the calcium entry into HlyA-exposed cells. Calcium-dependent cell exfoliation was identified as mechanism for focal leak induction. In conclusion, zinc supplementation protects from HlyA-induced barrier dysfunction in vivo and in vitro, providing an explanation for the protective efficacy of zinc in intestinal disorders.

Campylobacter fetus impairs barrier function in HT‐29/B6 cells through focal tight junction alterations and leaks

“…In severe cases, treatment with antibiotics is helpful but can also prolong the course of infection. A new therapeutic approach might be the reduction of inflammatory responses by reducing the outcome of the leaky gut during infection or shortly afterward, as was recently shown for E. coli HlyA …”

“…A new therapeutic approach might be the reduction of inflammatory responses by reducing the outcome of the leaky gut during infection or shortly afterward, as was recently shown for E. coli HlyA. 47 Thus, further efforts should also be made to discover the pathogenicity of campylobacters, the circumstances of the entry of the pathogen into the organism, the immunological background of the host, and the pathological consequences leading to diarrhea and inflammation.…”

High‐dose dietary supplementation with zinc prevents gut inflammation: Investigation of the role of metallothioneins and beyond by transcriptomic and metagenomic studies

“…14 The relationships between Zn and susceptibility to pathogenic infections is complex and we have to ensure that excess Zn will not promote the growth of over-competing microbes (such as C difficile or Salmonella). 85 However, Zn treatment also reportedly has antimicrobial properties, that is, it alleviates E coli-induced intestinal leakage and colitis 86 and inhibits Listeria monocytogenes-driven diseases. 87 We also observed a decrease in levels of Candidatus arthromitus (which became undetectable) and Lactobacillus spp.…”

Context-dependent Requirements for FimH and Other Canonical Virulence Factors in Gut Colonization by Extraintestinal PathogenicEscherichia coli

“…1E). Since the ExPEC-associated pore forming toxin α -hemolysin (HlyA) was previously shown to induce inflammation within the gut in other mouse models (33–35), we hypothesized that HlyA contributes to the transient weight loss seen in F11-colonized animals. When mice were colonized with F11Δ hlyA , fecal titers of the mutant were notably lower at 1 and 3 days post-inoculation, relative to wild type (WT) F11 (Fig.…”