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 8

EGFR kinase activity mediates p40 amelioration of oxazolone-induced colitis in mice.

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EGFR kinase activity mediates p40 amelioration of oxazolone-induced coli...
(A) Mice were presensitized with oxazolone. Then oxazolone (Oxa) was administered rectally in the presence or absence of gavage with p40-containing beads at 10 μg/mouse/d, beginning on the day of rectal oxazolone administration until the end of the experiment. Mice were sacrificed 5 days after intrarectal challenge with oxazolone. Control mice received ethanol only. Body weight changes after intrarectal challenge with ethanol or oxazolone are shown. *P < 0.05 compared with WT mice on the same day of oxazolone treatment. (B) Paraffin-embedded colon sections were stained with H&E for light microscopic assessment of epithelial damage. Original magnification, ×10. (C) Colon injury scores are shown. (D) Paraffin-embedded tissue sections were analyzed using ISOL staining to detect apoptosis, as described in Figure 5. The number of apoptotic nuclei per 100 crypts is shown. In C and D, *P < 0.01 compared with ethanol groups in WT or Egfrwa5 mice; #P < 0.05 compared with oxazolone group in WT mice.