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Lactobacillus GG-fermented milk prevents DSS-induced colitis and regulates intestinal epithelial homeostasis through activation of epidermal growth factor receptor

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Abstract

Background

Fermented milk is considered one of the best sources for efficient consumption of probiotic strains by hosts to promote good health. The purpose of this study was to investigate the effects of orally administering LGG-fermented milk (LGG milk) on intestinal inflammation and injury and to study the mechanisms of LGG milk’s action.

Methods

LGG milk and non-LGG-fermented milk (non-LGG milk) were administered through gavage to mice before and during dextran sodium sulfate (DSS)-induced intestinal injury and colitis. Inflammatory/injury score and colon length were assessed. Intestinal epithelial cells were treated with the soluble fraction of LGG milk to detect its effects on the epidermal growth factor receptor (EGFR) and its downstream target, Akt activation, cytokine-induced apoptosis, and hydrogen peroxide (H2O2)-induced disruption of tight junctions.

Results

LGG milk treatment significantly reduced DSS-induced colonic inflammation and injury, and colon shortening in mice, compared to that in non-LGG milk-treated and -untreated mice. The soluble fraction of LGG milk, but not non-LGG milk, stimulated the activation of EGFR and Akt in a concentration-dependent manner, suppressed cytokine-induced apoptosis, and attenuated H2O2-induced disruption of tight junction complex in the intestinal epithelial cells. These effects of LGG milk were blocked by the EGFR kinase inhibitor. LGG milk, but not non-LGG milk, contained two soluble proteins, p40 and p75, that have been reported to promote survival and growth of intestinal epithelial cells through the activation of EGFR. Depletion of p40 and p75 from LGG milk abolished the effects of LGG milk on prevention of cytokine-induced apoptosis and H2O2-induced disruption of tight junctions.

Conclusions

These results suggest that LGG milk may regulate intestinal epithelial homeostasis and potentially prevent intestinal inflammatory diseases through activation of EGFR by LGG-derived proteins.

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References

  1. Gilliland SE, Morelli L, Reid G (2001) Report of a joint FAO/WHO expert consultation on evaluation of health and nutritional properties of probiotics in food: health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria report. Córdoba, Argentina

  2. Szajewska H, Mrukowicz JZ (2001) Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr 33(Suppl 2):S17–S25

    Article  CAS  Google Scholar 

  3. Kawase M, He F, Kubota A, Harata G, Hiramatsu M (2010) Oral administration of lactobacilli from human intestinal tract protects mice against influenza virus infection. Lett Appl Microbiol 51:6–10

    CAS  Google Scholar 

  4. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E (2001) Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357:1076–1079

    Article  CAS  Google Scholar 

  5. Kawase M, He F, Kubota A, Hiramatsu M, Saito H, Ishii T et al (2009) Effect of fermented milk prepared with two probiotic strains on Japanese cedar pollinosis in a double-blind placebo-controlled clinical study. Int J Food Microbiol 128:429–434

    Article  CAS  Google Scholar 

  6. Kawase M, He F, Kubota A, Harata G, Hiramatsu M (2009) Clinical effects of cell preparation of Lactobacillus GG and L. gasseri TMC0356 on perennial allergic rhinitis: a double-blind placebo-controlled trial. Int J Probio Prebio 4:241–248

    Google Scholar 

  7. Schultz M (2008) Clinical use of E. coli Nissle 1917 in inflammatory bowel disease. Inflamm Bowel Dis 2008(14):1012–1018

    Article  Google Scholar 

  8. Fedorak RN, Madsen KL (2004) Probiotics and the management of inflammatory bowel disease. Inflamm Bowel Dis 10:286–299

    Article  Google Scholar 

  9. Saxelin M (2008) Probiotic formulations and applications, the current probiotics market, and changes in the marketplace: a European perspective. Clin Infect Dis 46(Suppl 2):S76–S79; discussion S144–S51

    Google Scholar 

  10. Blayney D, Gehlhar M, Hilda CH, Jones K, Langley S, Normile HA, et al (2006) Appendix A. In: World production and trade by country and product USDA economic research report number 28. USDA, Washington pp 30–44

  11. Hu D (2009) China: dairy product quality as the new industry driver. In: Animal Production and Health Commission for Asia and The Pacific. FAO Regional Office for Asia and The Pacific, Bangkok, pp 22–43

  12. Gorbach SL (1996) The discovery of lactobacillus GG. Nutr Today 31:2S–4S

    Article  Google Scholar 

  13. Yan F, Polk DB (2006) Probiotics as functional food in the treatment of diarrhea. Curr Opin Clin Nutr Metab Care 9:717–721

    Article  Google Scholar 

  14. Goldin BR, Gorbach SL (2008) Clinical indications for probiotics: an overview. Clin Infect Dis 46(Suppl 2):S96–100; discussion S144–S151

    Google Scholar 

  15. Yan F, Polk DB (2002) Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem 277:50959–50965

    Article  CAS  Google Scholar 

  16. Yan F, Cao H, Cover TL, Whitehead R, Washington MK, Polk DB (2007) Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132:562–575

    Article  CAS  Google Scholar 

  17. Seth A, Yan F, Polk DB, Rao RK (2008) Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 294:G1060–G1069

    Article  CAS  Google Scholar 

  18. Yan F, Cao H, Cover TL, Washington MK, Shi Y, Liu L et al (2011) Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J Clin Invest 121:2242–2253

    Article  CAS  Google Scholar 

  19. Dieleman LA, Palmen MJ, Akol H, Bloemena E, Pena AS, Meuwissen SG et al (1998) Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol 114:385–391

    Article  CAS  Google Scholar 

  20. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694–702

    CAS  Google Scholar 

  21. Bauerl C, Perez-Martinez G, Yan F, Polk DB, Monedero V (2010) Functional analysis of the p40 and p75 proteins from Lactobacillus casei BL23. J Mol Microbiol Biotechnol 19:231–241

    Article  Google Scholar 

  22. Shibolet O, Karmeli F, Eliakim R, Swennen E, Brigidi P, Gionchetti P et al (2002) Variable response to probiotics in two models of experimental colitis in rats. Inflamm Bowel Dis 8:399–406

    Article  Google Scholar 

  23. Mileti E, Matteoli G, Iliev ID, Rescigno M (2009) Comparison of the immunomodulatory properties of three probiotic strains of Lactobacilli using complex culture systems: prediction for in vivo efficacy. PLoS One 4:e7056

    Article  Google Scholar 

  24. Lin PW, Myers LE, Ray L, Song SC, Nasr TR, Berardinelli AJ et al (2009) Lactobacillus rhamnosus blocks inflammatory signaling in vivo via reactive oxygen species generation. Free Radic Biol Med 47:1205–1211

    Article  CAS  Google Scholar 

  25. Claes IJ, Lebeer S, Shen C, Verhoeven TL, Dilissen E, De Hertogh G et al (2010) Impact of lipoteichoic acid modification on the performance of the probiotic Lactobacillus rhamnosus GG in experimental colitis. Clin Exp Immunol 162:306–314

    Article  CAS  Google Scholar 

  26. Jiang H, Przybyszewski J, Mitra D, Becker C, Brehm-Stecher B, Tentinger A et al (2011) Soy protein diet, but not Lactobacillus rhamnosus GG, decreases mucin-1, trefoil factor-3, and tumor necrosis factor-alpha in colon of dextran sodium sulfate-treated C57BL/6 mice. J Nutr 141:1239–1246

    Article  CAS  Google Scholar 

  27. Saxelin M, Elo S, Salminen S, Vapaatalo H (1991) Dose response colonisation of faeces after oral administration of Lactobacillus casei strain GG. Microb Ecol Health Dis 4:209–214

    Article  Google Scholar 

  28. Saxelin M, Ahokas M, Salminen S (1993) Dose response on the faecal colonisation of Lactobacillus strain GG administered in two different formulations. Microb Ecol Health Dis 6:119–122

    Article  Google Scholar 

  29. Segawa S, Fujiya M, Konishi H, Ueno N, Kobayashi N, Shigyo T et al (2011) Probiotic-derived polyphosphate enhances the epithelial barrier function and maintains intestinal homeostasis through integrin-p38 MAPK pathway. PLoS One 6:e23278

    Article  CAS  Google Scholar 

  30. Tao Y, Drabik KA, Waypa TS, Musch MW, Alverdy JC, Schneewind O et al (2006) Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells. Am J Physiol Cell Physiol 290:C1018–C1030

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Ms. Ayako Kusanagi (Product Development Department at Takanashi Milk Products) for kindly providing non-LGG milk and Dr. M. Kay Washington (Department of Pathology, Microbiology, and Immunology at Vanderbilt University Medical Center) for the analysis of colon inflammation and injury. This work was supported by Takanashi Milk Products Co., Ltd. and NIH grants R01DK081134 (F.Y.) and P30DK058404 (Vanderbilt University Digestive Disease Research Center).

Conflict of interest

K. Yoda, K. Miyazawa, M. Hosoda, M. Hiramatsu, and F. He are employees of Takanashi Milk Products Co., Ltd.; F. Yan declares no conflicts of interest.

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Authors and Affiliations

  1. Technical Research Laboratory, Takanashi Milk Products Co., Ltd., Yokohama, Kanagawa, 241-0023, Japan

    Kazutoyo Yoda, Kenji Miyazawa, Masataka Hosoda, Masaru Hiramatsu & Fang He

  2. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Fang Yan

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  1. Kazutoyo Yoda
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  2. Kenji Miyazawa
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  3. Masataka Hosoda
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  4. Masaru Hiramatsu
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  5. Fang Yan
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  6. Fang He
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Correspondence to Fang Yan or Fang He.

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Yoda, K., Miyazawa, K., Hosoda, M. et al. Lactobacillus GG-fermented milk prevents DSS-induced colitis and regulates intestinal epithelial homeostasis through activation of epidermal growth factor receptor. Eur J Nutr 53, 105–115 (2014). https://doi.org/10.1007/s00394-013-0506-x

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  • DOI: https://doi.org/10.1007/s00394-013-0506-x

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