Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism
Fang Yan, … , Keith T. Wilson, D. Brent Polk
Fang Yan, … , Keith T. Wilson, D. Brent Polk
Published May 23, 2011
Citation Information: J Clin Invest. 2011;121(6):2242-2253. https://doi.org/10.1172/JCI44031.
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Research Article

Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism

Abstract

Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria–derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40’s effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation.

Authors

Fang Yan, Hanwei Cao, Timothy L. Cover, M. Kay Washington, Yan Shi, LinShu Liu, Rupesh Chaturvedi, Richard M. Peek Jr., Keith T. Wilson, D. Brent Polk

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Figure 7

EGFR kinase activity is required for p40 to prevent DSS-induced disruption of intestinal barrier function.

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EGFR kinase activity is required for p40 to prevent DSS-induced disrupti...
(A) Mice were treated with DSS for 7 days with or without p40-containing pectin/zein bead cotreatment, as described in Figure 5. Intestinal permeability was determined by rectal administration of FITC-dextran on the sixth day of DSS treatment. FITC-dextran level in sera is shown. (B) Paraffin-embedded colon tissues were used to determine ZO-1 distribution by immunohistochemistry using an anti–ZO-1 antibody and FITC-labeled secondary antibody and visualized using fluorescence microcopy (green staining). Nuclei were stained with DAPI (blue staining). *P < 0.01 compared with water groups in WT or Egfrwa2 mice; #P < 0.01 compared with either WT mice treated with DSS or WT mice treated with DSS and control beads. Original magnification, ×20; ×60 (insets).