Lactobacillus GG-fermented milk prevents DSS-induced colitis and regulates intestinal epithelial homeostasis through activation of epidermal growth factor receptor
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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.
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.
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.
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.
KeywordsLactobacillus GG Fermented milk Colitis Epidermal growth factor receptor Apoptosis Tight junction Intestinal epithelial cells
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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