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Increased Bacterial Translocation in Gluten-Sensitive Mice Is Independent of Small Intestinal Paracellular Permeability Defect

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Abstract

Aim

We investigated whether treatment with gliadin induces a paracellular permeability defect that enhances bacterial translocation to mesenteric lymph nodes (MLN) via resident dendritic cells (DC) expressing TLR-2 or 4 in HCD4/HLA-DQ8 transgenic mice.

Methods

HLA-DQ8 transgenic mice were sensitized and subsequently gavaged with gliadin, in the presence or absence of AT1001 (paracellular permeability inhibitor). Non-sensitized mice were gavaged with indomethacin (permeability inducer) or rice cereal. CD11c and CD103 (DC markers) and TLR-2 and 4 were investigated by immunostaining. Intestinal permeability was assessed by paracellular flux of 51Cr-EDTA in Ussing chambers. Bacterial translocation to MLN was performed by plate counting on aerobic and anaerobic conditions.

Results

In gliadin-treated mice, both 51Cr-EDTA flux in jejunal mucosa and aerobic and anaerobic bacterial counts in MLN were increased (p < 0.05) compared to indomethacin-treated mice and controls. The inhibitor AT1001 normalized 51Cr-EDTA flux, but had no effect on bacterial translocation in gliadin-treated mice. In addition, changes in mucosal DC marker distribution such as increased (p < 0.05) trans-epithelial CD103+ cells and reduction (p < 0.05) of CD11c immunostaining were detected in gliadin-treated mice. Moreover, changes in DC markers and TLR-2 or 4 immunophenotypes were not associated.

Conclusions

Pharmacological restoration of paracellular permeability was not sufficient to prevent bacterial translocation in gluten-sensitive mice. We hypothesize that transcellular mechanisms involving CD103+DC and CD11c+DC may explain in gluten-sensitive HCD4/HLA-DQ8 transgenic mice the sustained increased bacterial translocation observed in the absence of a significant inflammatory response.

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Acknowledgments

This work was supported by grants from the Canadian Association of Gastroenterology (CAG)/Canadian Institute of Health Research (CIHR) (GN2-114709), the Canadian Celiac Association New Investigator Award, ALBA Therapeutics (E. Verdú), the National Institute of Health grant R01 DK048373-13 (A. Fasano), and AGL2008-01440/ALI and Consolider Fun-C-Food CSD2007-00063 from Ministry of Science and Innovation (Spain, Y. Sanz). E. Verdú holds a McMaster University Department of Medicine Internal Career Research Award. Drs. David and Murray were supported in part by R01 DK71003.

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Authors and Affiliations

  1. Department of Medicine, Health Sciences Centre, Farncombe Family Digestive Health Research Institute, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada

    Manuel A. Silva, Jennifer Jury, Michelle Wiepjes, Xianxi Huang & Elena F. Verdú

  2. Division of Gastroenterology, Mayo Clinic, Rochester, MN, USA

    Joseph A. Murray

  3. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Chella S. David

  4. Institute of Agrochemistry and Food Technology (IATA), Spanish National Research Council (CSIC), Valencia, Spain

    Yolanda Sanz

  5. Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Alessio Fasano

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  1. Manuel A. Silva
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  2. Jennifer Jury
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  3. Yolanda Sanz
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  9. Elena F. Verdú
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Corresponding authors

Correspondence to Manuel A. Silva or Elena F. Verdú.

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Silva, M.A., Jury, J., Sanz, Y. et al. Increased Bacterial Translocation in Gluten-Sensitive Mice Is Independent of Small Intestinal Paracellular Permeability Defect. Dig Dis Sci 57, 38–47 (2012). https://doi.org/10.1007/s10620-011-1847-z

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  • DOI: https://doi.org/10.1007/s10620-011-1847-z

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