title: Oral tolerance failure upon neonatal gut colonization with Escherichia coli producing the genotoxin colibactin.
abstract: The intestinal barrier controls the balance between tolerance and immunity to luminal antigens. When this finely tuned equilibrium is deregulated, inflammatory disorders can occur. There is a concomitant increase, in urban populations of developed countries, of immune-mediated diseases along with a shift in Escherichia coli population from the declining phylogenetic group A to the newly dominant group B2, including commensal strains producing a genotoxin called colibactin that massively colonized the gut of neonates. Here, we showed that mother-to-offspring early gut colonization by colibactin-producing E. coli impairs intestinal permeability and enhances the transepithelial passage of luminal antigen, leading to an increased immune activation. Functionally, this was accompanied by a dramatic increase in local and systemic immune responses against a fed antigen, decreased regulatory T cell population, tolerogenic dendritic cells, and enhanced mucosal delayed-type hypersensitivity response. Conversely, the abolition of colibactin expression by mutagenesis abrogates the alteration of oral tolerance induced by neonatal colonization by E. coli. In conclusion, the vertical colonization by E. coli producing the genotoxin colibactin enhances intestinal translocation and subsequently alters oral tolerance. Thus, early colonization by E. coli from the newly dominant phylogenetic group B2, which produces colibactin, may represent a risk factor for the development of immune-mediated diseases.
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Secher
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Payros
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Brehin
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Boury
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Watrin
authors.affiliation: INRA/INPT/UPS, UMR1331, Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gillet
authors.affiliation: INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard-Cadenat
authors.affiliation: INRA/INPT/UPS, UMR1331, Toulouse, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Menard
authors.affiliation: INRA/INPT/UPS, UMR1331, Toulouse, France.
authors.forename: Vassilia
authors.initials: V
authors.lastname: Theodorou
authors.affiliation: INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France.
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France INRA/INPT/UPS, UMR1331, Toulouse, France.
authors.forename: Maiwenn
authors.initials: M
authors.lastname: Olier
authors.affiliation: INRA, USC 1360, Toulouse, France INSERM, UMR 1043, Toulouse, France CNRS, UMR 5282, Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie Toulouse Purpan, Toulouse, France CHU Toulouse, Hôpital Purpan, Service de Bactériologie-Hygiène, Toulouse, France eric.oswald@inserm.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002353:Carrier State; D004926:Escherichia coli / Q000378:metabolism*; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology*; D010455:Peptides / Q000378:metabolism*; D061065:Polyketides / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010455:Peptides; D061065:Polyketides; C569566:colibactin
references.citation: Int J Inflam. 2010 Sep 19;2010:823710
references.pmid: 21188221
references.citation: Blood. 2003 Nov 1;102(9):3295-301
references.pmid: 12855551
references.citation: Pediatrics. 2006 Aug;118(2):511-21
references.pmid: 16882802
references.citation: Environ Microbiol Rep. 2013 Feb;5(1):58-65
references.pmid: 23757131
references.citation: PLoS Biol. 2007 Jul;5(7):e177
references.pmid: 17594176
references.citation: Immunobiology. 2007;212(6):433-9
references.pmid: 17544828
references.citation: J Immunol. 2010 Feb 15;184(4):2026-37
references.pmid: 20089703
references.citation: N Engl J Med. 2011 Feb 24;364(8):701-9
references.pmid: 21345099
references.citation: Infect Immun. 1979 Feb;23(2):403-11
references.pmid: 154474
references.citation: PLoS One. 2013;8(10):e77157
references.pmid: 24116215
references.citation: Gut. 2009 Aug;58(8):1091-103
references.pmid: 19240062
references.citation: Cell. 2010 Mar 19;140(6):859-70
references.pmid: 20303876
references.citation: Microbes Infect. 2006 Mar;8(3):834-40
references.pmid: 16483819
references.citation: Curr Opin Gastroenterol. 2008 Nov;24(6):720-4
references.pmid: 19122522
references.citation: Pediatr Res. 1996 Mar;39(3):415-20
references.pmid: 8929860
references.citation: J Reprod Immunol. 1983 Jul;5(4):203-13
references.pmid: 6620251
references.citation: Nat Rev Microbiol. 2009 Dec;7(12):887-94
references.pmid: 19898491
references.citation: Microb Pathog. 2012 Sep;53(3-4):180-2
references.pmid: 22709536
references.citation: Clin Exp Immunol. 1981 Mar;43(3):574-82
references.pmid: 7285393
references.citation: J Med Microbiol. 2013 Nov;62(Pt 11):1680-7
references.pmid: 23861296
references.citation: Environ Microbiol. 2008 Apr;10(4):1000-6
references.pmid: 18177373
references.citation: Nat Rev Immunol. 2009 May;9(5):313-23
references.pmid: 19343057
references.citation: Gut Microbes. 2014 May-Jun;5(3):313-25
references.pmid: 24971581
references.citation: Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9):416-22
references.pmid: 16265432
references.citation: Nat Immunol. 2010 Aug;11(8):647-55
references.pmid: 20644570
references.citation: Cell. 2009 Oct 30;139(3):485-98
references.pmid: 19836068
references.citation: Mol Biol Evol. 2004 Jun;21(6):1085-94
references.pmid: 15014151
references.citation: Science. 2011 Jan 21;331(6015):337-41
references.pmid: 21205640
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11537-42
references.pmid: 20534522
references.citation: Immunol Rev. 2003 Apr;192:161-80
references.pmid: 12670403
references.citation: Clin Immunol. 2000 Jan;94(1):1-8
references.pmid: 10607484
references.citation: Immunity. 2007 Feb;26(2):149-61
references.pmid: 17307704
references.citation: J Invest Dermatol. 1982 Mar;78(3):206-9
references.pmid: 6276474
references.citation: Science. 2006 Aug 11;313(5788):848-51
references.pmid: 16902142
references.citation: Dig Dis Sci. 2001 May;46(5):1120-6
references.pmid: 11341658
references.citation: N Engl J Med. 2002 Sep 19;347(12):911-20
references.pmid: 12239261
references.citation: Trends Immunol. 2008 Nov;29(11):532-40
references.pmid: 18835746
references.citation: Nature. 2010 Mar 4;464(7285):59-65
references.pmid: 20203603
references.citation: Eur J Clin Microbiol Infect Dis. 2005 Jan;24(1):31-40
references.pmid: 15599646
references.citation: Nestle Nutr Workshop Ser Pediatr Program. 2008;62:13-29; discussion 29-33
references.pmid: 18626190
references.citation: Allergol Int. 2013 Sep;62(3):279-89
references.pmid: 23974874
references.citation: Lab Invest. 1993 Aug;69(2):238-49
references.pmid: 8350599
references.citation: Pediatr Res. 2003 Jul;54(1):8-14
references.pmid: 12700366
references.citation: Cell Immunol. 2000 Jun 15;202(2):71-8
references.pmid: 10896766
references.citation: Nature. 2011 Jun 16;474(7351):298-306
references.pmid: 21677746
references.citation: Cell. 2005 Jul 15;122(1):107-18
references.pmid: 16009137
references.citation: Lab Invest. 2006 May;86(5):504-16
references.pmid: 16482102
references.citation: Allergy. 2001;56 Suppl 67:16-20
references.pmid: 11298000
references.citation: Ann N Y Acad Sci. 2004 Dec;1029:36-43
references.pmid: 15681741
references.citation: Nat Rev Microbiol. 2010 Mar;8(3):207-17
references.pmid: 20157339
references.citation: Nat Rev Immunol. 2012 Jan;12(1):9-23
references.pmid: 22158411