title: 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: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee 37232-0696, USA. fang.yan@vanderbilt.edu
authors: Fang
authors: F
authors: Yan
authors: Hanwei
authors: H
authors: Cao
authors: Timothy L
authors: TL
authors: Cover
authors: M Kay
authors: MK
authors: Washington
authors: Yan
authors: Y
authors: Shi
authors: LinShu
authors: L
authors: Liu
authors: Rupesh
authors: R
authors: Chaturvedi
authors: Richard M
authors: RM
authors: Peek
authors: Keith T
authors: KT
authors: Wilson
authors: D Brent
authors: DB
authors: Polk
references: Oncogene. 2001 Mar 26;20(13):1594-600
references: 11313906
references: Curr Opin Gastroenterol. 2010 Mar;26(2):95-101
references: 19952741
references: Immunity. 2002 Nov;17(5):629-38
references: 12433369
references: Inflamm Bowel Dis. 2008 Nov;14(11):1585-96
references: 18623173
references: Gastroenterology. 2007 Feb;132(2):562-75
references: 17258729
references: Drug Deliv. 2006 Nov-Dec;13(6):417-23
references: 17002969
references: Am J Physiol Cell Physiol. 2006 Apr;290(4):C1018-30
references: 16306130
references: Mamm Genome. 2004 Jul;15(7):525-36
references: 15366372
references: Nat Rev Immunol. 2009 May;9(5):313-23
references: 19343057
references: Biochem Soc Trans. 2003 Dec;31(Pt 6):1203-8
references: 14641026
references: FEMS Immunol Med Microbiol. 2001 Jul;31(1):35-9
references: 11476979
references: Cell. 2004 Aug 6;118(3):285-96
references: 15294155
references: Growth Factors. 2006 Jun;24(2):121-36
references: 16801132
references: J Clin Invest. 2007 Mar;117(3):514-21
references: 17332878
references: Nature. 1999 Dec 23-30;402(6764):884-8
references: 10622253
references: J Immunol. 1996 Aug 1;157(3):1261-70
references: 8757634
references: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):587-91
references: 7678459
references: Science. 1965 Feb 12;147(3659):747-8
references: 14242024
references: Br J Nutr. 2006 Jun;95(6):1177-84
references: 16768842
references: Inflamm Bowel Dis. 2005 Sep;11(9):833-9
references: 16116318
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references: 11252954
references: Gastroenterol Clin North Am. 2005 Sep;34(3):483-98, ix
references: 16084309
references: BMC Gastroenterol. 2004 Mar 15;4:5
references: 15113451
references: Gastroenterology. 2001 Jul;121(1):68-78
references: 11438495
references: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11772-7
references: 18701712
references: Semin Cell Dev Biol. 2004 Apr;15(2):177-82
references: 15209377
references: J Biol Chem. 2002 Dec 27;277(52):50959-65
references: 12393915
references: Curr Top Dev Biol. 2003;54:125-44
references: 12696748
references: Nat Biotechnol. 2005 Dec;23(12):1527-33
references: 16273110
references: Aliment Pharmacol Ther. 2004 Nov 15;20(10):1133-41
references: 15569116
references: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1415-20
references: 9990038
references: Gastroenterology. 1990 Mar;98(3):694-702
references: 1688816
references: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2512-7
references: 14983040
references: Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19967-72
references: 21041656
references: N Engl J Med. 2003 Jul 24;349(4):350-7
references: 12878742
references: Biomaterials. 2003 Aug;24(19):3333-43
references: 12763460
references: Immunol Lett. 2008 Aug 15;119(1-2):22-31
references: 18601952
references: Pediatrics. 2005 Jan;115(1):178-81
references: 15629999
references: Eur J Cancer. 2001 Sep;37 Suppl 4:S3-8
references: 11597398
references: Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G1060-9
references: 18292183
references: Cell Microbiol. 2003 Apr;5(4):277-85
references: 12675685
references: Curr Opin Clin Nutr Metab Care. 2006 Nov;9(6):717-21
references: 17053425
references: Gastroenterology. 2003 May;124(5):1202-9
references: 12730861
references: J Exp Med. 1998 Nov 16;188(10):1929-39
references: 9815270
references: Gastroenterology. 1999 Oct;117(4):858-65
references: 10500068
references: Am J Gastroenterol. 2005 Jul;100(7):1539-46
references: 15984978
references: Gut. 1998 Jul;43(1):64-70
references: 9771407
references: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G276-85
references: 17991704
references: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15611-6
references: 17030793
references: J Biol Chem. 2001 Dec 21;276(51):48510-7
references: 11600492
references: Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1465-9
references: 7533293
references: Scand J Gastroenterol. 2000 Nov;35(11):1181-7
references: 11145290
references: Gastroenterology. 1994 Jul;107(1):109-16
references: 8020653
references: Dig Dis. 2009;27(4):455-64
references: 19897960