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Original article
Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner
  1. Matthew A Ciorba1,
  2. Terrence E Riehl1,
  3. M Suprada Rao1,
  4. Clara Moon2,
  5. Xueping Ee1,
  6. Gerardo M Nava2,
  7. Monica R Walker2,
  8. Jeffrey M Marinshaw1,
  9. Thaddeus S Stappenbeck2,
  10. William F Stenson1
  1. 1Departments of Medicine, Washington University Saint Louis, School of Medicine, Saint Louis, Missouri, USA
  2. 2Departments of Pathology and Immunology, Washington University Saint Louis, School of Medicine, Saint Louis, Missouri, USA
  1. Correspondence to Professor William F Stenson, Division of Gastroenterology, Washington University Saint Louis, 660 South Euclid Avenue, Box 8124, Saint Louis, MO 63110, USA; wstenson{at}dom.wustl.edu Matthew A Ciorba, Division of Gastroenterology, Washington University, St. Louis, 660 S. Euclid Ave, Box 8124, St. Louis, MO 63110, USA; MCiorba{at}dom.wustl.edu

Abstract

Background The small intestinal epithelium is highly sensitive to radiation and is a major site of injury during radiation therapy and environmental overexposure.

Objective To examine probiotic bacteria as potential radioprotective agents in the intestine.

Methods 8-week-old C57BL/6 wild-type or knockout mice were administered probiotic by gavage for 3 days before 12 Gy whole body radiation. The intestine was evaluated for cell-positional apoptosis (6 h) and crypt survival (84 h).

Results Gavage of 5×107 Lactobacillus rhamnosus GG (LGG) improved crypt survival about twofold (p<0.01); the effect was observed when administered before, but not after, radiation. Conditioned medium (CM) from LGG improved crypt survival (1.95-fold, p<0.01), and both LGG and LGG-CM reduced epithelial apoptosis particularly at the crypt base (33% to 18%, p<0.01). LGG was detected in the distal ileal contents after the gavage cycle, but did not lead to a detectable shift in bacterial family composition. The reduction in epithelial apoptosis and improved crypt survival offered by LGG was lost in MyD88−/−, TLR-2−/− and cyclo-oxygenase-2−/− (COX-2) mice but not TLR-4−/− mice. LGG administration did not lead to increased jejunal COX-2 mRNA or prostaglandin E2 levels or a change in number of COX-2-expressing cells. However, a location shift was observed in constitutively COX-2-expressing cells of the lamina propria from the villi to a position near the crypt base (villi to crypt ratio 80:20 for control and 62:38 for LGG; p<0.001). Co-staining revealed these COX-2-expressing small intestinal lamina propria cells to be mesenchymal stem cells.

Conclusions LGG or its CM reduce radiation-induced epithelial injury and improve crypt survival. A TLR-2/MyD88 signalling mechanism leading to repositioning of constitutive COX-2-expressing mesenchymal stem cells to the crypt base is invoked.

  • Intestinal radioprotection
  • probiotic
  • cyclooxygenase-2
  • mesenchymal stem cells
  • probiotics
  • cancer immunobiology
  • colorectal neoplasia
  • crohn's disease
  • ulcerative colitis
  • IBD
  • anaerobic bacterial fermentation
  • antibacterial peptide
  • bacterial infection
  • bacterial interactions
  • gastrointestinal pathology
  • gastrointestinal immune response
  • inflammatory bowel disease
  • stem cells
  • epithelial proliferation
  • macrophages
  • inflammatory mediators
  • radiation therapy
  • inflammatory mechanisms
  • radiation enteritis

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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Footnotes

  • Funding This work was supported in part by the National Institutes of Health grants DK55753 and DK33165 (to WFS), DK089016 and L30 RR030244 (to MAC), DK071619 and DK07161-90251 (to TSS) and P30-DK52574 (to the Washington University Digestive Diseases Research Core). This work was also supported in part by the Crohn's and Colitis Foundation of America and a Global Probiotics Council Young Investigator Award (both to MAC). We thank Lynne Foster and Ellen Bettonville for additional technical assistance, and Dr Parag Parikh for useful discussions on this work.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We are happy to share our data. All the reagents used are commercially available.

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