Crohn's disease is linked to a decreased diversity in gut microbiota composition as a potential consequence of an impaired anti-microbial response and an altered polarization of T helper cells. Here, we evaluated the immunomodulatory properties of two potential probiotic strains, namely a Bifidobacterium animalis spp. lactis Bl 5764 and a Lactobacillus reuteri Lr 5454 strains. Both strains improved colitis triggered by either 2,4,6-trinitrobenzenesulfonic acid (TNBS) or Citrobacter rodentium infection in mice. Training of dendritic cells (DC) with Lr 5454 efficiently triggered IL-22 secretion and regulatory T cells induction in vitro, while IL-17A production by CD4+ T lymphocytes was stronger when cultured with DCs that were primed with Bl 5764. This strain was sufficient for significantly inducing expression of antimicrobial peptides in vivo through the Crohn's disease predisposing gene encoding for the nucleotide-binding oligomerization domain, containing protein 2 (NOD2). In contrast, NOD2 was dispensable for the impact on antimicrobial peptide expression in mice that were monocolonized with Lr 5454. In conclusion, our work highlights a differential mode of action of two potential probiotic strains that protect mice against colitis, providing the rational for a personalized supportive preventive therapy by probiotics for individuals that are genetically predisposed to Crohn's disease.

Department of Clinical Immunology BioProx Paris France

INEM UMR7355 Molecular Immunology CNRS University of Orleans Orleans France

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Infectious Diseases and Molecular Medicine Immunology Faculty of Health Sciences University of Cape Town Anzio Road Observatory 7925 Cape Town RSA

Research Group of Industrial Microbiology and Food Biotechnology Faculty of Sciences and Bioengineering Sciences Vrije Universiteit Brussel Brussels Belgium

Univ Lille CNRS Inserm CHU Lille Institut Pasteur de Lille U1019 UMR 8204 CIIL Centre d'Infection et d'Immunité de Lille F 59000 Lille France

Univ Lille Inserm U1003 PHYCEL Physiologie Cellulaire F 59000 Lille France

Zobrazit více v PubMed

Asquith M, Powrie F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J. Exp. Med. 2010;207:1573–1577. doi: 10.1084/jem.20101330. PubMed DOI PMC

Eckburg PB, Relman DA. The role of microbes in Crohn’s disease. Clin. Infect. Dis. 2007;44:256–262. doi: 10.1086/510385. PubMed DOI

Alhagamhmad MH, Day AS, Lemberg DA, Leach ST. An overview of the bacterial contribution to Crohn disease pathogenesis. J. Med. Microbiol. 2016;65:1049–1059. doi: 10.1099/jmm.0.000331. PubMed DOI

Knösel T, Schewe C, Petersen N, Dietel M, Petersen I. Prevalence of infectious pathogens in Crohn’s disease. Pathol. Res. Pract. 2009;205:223–230. doi: 10.1016/j.prp.2008.04.018. PubMed DOI

Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut. 2016;65:1906–1915. doi: 10.1136/gutjnl-2016-312297. PubMed DOI

Wehkamp J, et al. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc. Natl. Acad. Sci. USA. 2005;102:18129–18134. doi: 10.1073/pnas.0505256102. PubMed DOI PMC

Cao SS. Epithelial ER Stress in Crohn’s Disease and Ulcerative Colitis. Inflamm. Bowel Dis. 2016;22:984–993. doi: 10.1097/MIB.0000000000000660. PubMed DOI

Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517:311–320. doi: 10.1038/nature14191. PubMed DOI

Franke A, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 2010;42:1118–1125. doi: 10.1038/ng.717. PubMed DOI PMC

Kobayashi KS, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–734. doi: 10.1126/science.1104911. PubMed DOI

Chamaillard M, et al. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc. Natl. Acad. Sci. USA. 2003;100:3455–3460. doi: 10.1073/pnas.0530276100. PubMed DOI PMC

Kübler I, et al. Influence of standard treatment on ileal and colonic antimicrobial defensin expression in active Crohn’s disease. Aliment. Pharmacol. Ther. 2009;30:621–633. doi: 10.1111/j.1365-2036.2009.04070.x. PubMed DOI

Saez-Lara MJ, Gomez-Llorente C, Plaza-Diaz J, Gil A. The role of probiotic lactic acid bacteria and bifidobacteria in the prevention and treatment of inflammatory bowel disease and other related diseases: a systematic review of randomized human clinical trials. Biomed Res. Int. 2015;2015:505878. doi: 10.1155/2015/505878. PubMed DOI PMC

Ghouri YA, et al. Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clin. Exp. Gastroenterol. 2014;7:473–487. PubMed PMC

Macho Fernandez E, et al. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut. 2011;60:1050–1059. doi: 10.1136/gut.2010.232918. PubMed DOI

Alard J, et al. New probiotic strains for inflammatory bowel disease management identified by combining in vitro and in vivo approaches. Benef. Microbes. 2018;9:317–331. doi: 10.3920/BM2017.0097. PubMed DOI

Zaylaa M, et al. Probiotics in IBD: Combining in vitro and in vivo models for selecting strains with both anti-inflammatory potential as well as a capacity to restore the gut epithelial barrier. Journal of Functional Foods. 2018;47:304–315. doi: 10.1016/j.jff.2018.05.029. DOI

Zelante T, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–385. doi: 10.1016/j.immuni.2013.08.003. PubMed DOI

Foligne B, et al. Correlation between in vitro and in vivo immunomodulatory properties of lactic acid bacteria. World J. Gastroenterol. 2007;13:236–243. doi: 10.3748/wjg.v13.i2.236. PubMed DOI PMC

Karimi K, Inman MD, Bienenstock J, Forsythe P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 2009;179:186–193. doi: 10.1164/rccm.200806-951OC. PubMed DOI

Silberger DJ, Zindl CL, Weaver CT. Citrobacter rodentium: a model enteropathogen for understanding the interplay of innate and adaptive components of type 3 immunity. Mucosal. Immunol. 2017;10:1108–1117. doi: 10.1038/mi.2017.47. PubMed DOI PMC

Johnson-Henry KC, et al. Amelioration of the effects of Citrobacter rodentium infection in mice by pretreatment with probiotics. J. Infect. Dis. 2005;191:2106–2117. doi: 10.1086/430318. PubMed DOI

Kumar A, et al. Lactobacillus acidophilus counteracts inhibition of NHE3 and DRA expression and alleviates diarrheal phenotype in mice infected with Citrobacter rodentium. Am. J. Physiol. Gastrointest. Liver Physiol. 2016;311:G817–G826. doi: 10.1152/ajpgi.00173.2016. PubMed DOI PMC

O’Connor W, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 2009;10:603–609. doi: 10.1038/ni.1736. PubMed DOI PMC

Kleinschek MA, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 2009;206:525–534. doi: 10.1084/jem.20081712. PubMed DOI PMC

Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 2004;110:55–62. doi: 10.1016/j.clim.2003.09.013. PubMed DOI

Yang XO, et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 2008;205:1063–1075. doi: 10.1084/jem.20071978. PubMed DOI PMC

Möndel M, et al. Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans. Mucosal. Immunol. 2009;2:166–172. doi: 10.1038/mi.2008.77. PubMed DOI PMC

Becker HM, Apladas A, Scharl M, Fried M, Rogler G. Probiotic Escherichia coli Nissle 1917 and commensal E. coli K12 differentially affect the inflammasome in intestinal epithelial cells. Digestion. 2014;89:110–118. doi: 10.1159/000357521. PubMed DOI

Schlee M, et al. Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2. Clin. Exp. Immunol. 2008;151:528–535. doi: 10.1111/j.1365-2249.2007.03587.x. PubMed DOI PMC

Kobayashi R, et al. Oral administration of Lactobacillus gasseri SBT2055 is effective in preventing Porphyromonas gingivalis-accelerated periodontal disease. Sci. Rep. 2017;7:545. doi: 10.1038/s41598-017-00623-9. PubMed DOI PMC

Liu, H. et al. Lactobacillus reuteri I5007 Modulates Intestinal Host Defense Peptide Expression in the Model of IPEC-J2 Cells and Neonatal Piglets. Nutrients9 (2017). PubMed PMC

Simms LA, et al. Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease. Gut. 2008;57:903–910. doi: 10.1136/gut.2007.142588. PubMed DOI

Elphick D, Liddell S, Mahida YR. Impaired luminal processing of human defensin-5 in Crohn’s disease: persistence in a complex with chymotrypsinogen and trypsin. Am. J. Pathol. 2008;172:702–713. doi: 10.2353/ajpath.2008.070755. PubMed DOI PMC

Selber-Hnatiw S, et al. Human Gut Microbiota: Toward an Ecology of Disease. Front. Microbiol. 2017;8:1265. doi: 10.3389/fmicb.2017.01265. PubMed DOI PMC

Seth EC, Taga ME. Nutrient cross-feeding in the microbial world. Front. Microbiol. 2014;5:350. doi: 10.3389/fmicb.2014.00350. PubMed DOI PMC

Hibbing ME, Fuqua C, Parsek MR, Peterson SB. Bacterial competition: surviving and thriving in the microbial jungle. Nat. Rev. Microbiol. 2010;8:15–25. doi: 10.1038/nrmicro2259. PubMed DOI PMC

Yamamoto S, Ma X. Role of Nod2 in the development of Crohn’s disease. Microbes Infect. 2009;11:912–918. doi: 10.1016/j.micinf.2009.06.005. PubMed DOI PMC

Kreymborg K, et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 2007;179:8098–8104. doi: 10.4049/jimmunol.179.12.8098. PubMed DOI

Ye P, et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 2001;194:519–527. doi: 10.1084/jem.194.4.519. PubMed DOI PMC

Foligne B, et al. A key role of dendritic cells in probiotic functionality. PLoS ONE. 2007;2:e313. doi: 10.1371/journal.pone.0000313. PubMed DOI PMC

Foligné B, et al. Recommendations for improved use of the murine TNBS-induced colitis model in evaluating anti-inflammatory properties of lactic acid bacteria: technical and microbiological aspects. Dig. Dis. Sci. 2006;51:390–400. doi: 10.1007/s10620-006-3143-x. PubMed DOI

Wallace, J. L., MacNaughton, W. K., Morris, G. P. & Beck, P. L. Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology96(1), 29–36 (1989). PubMed

Chassaing B, et al. Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS ONE. 2012;7:e44328. doi: 10.1371/journal.pone.0044328. PubMed DOI PMC

Hrdý J, et al. Cytokine expression in cord blood cells of children of healthy and allergic mothers. Folia Microbiol. (Praha) 2010;55:515–519. doi: 10.1007/s12223-010-0085-7. PubMed DOI

Oral supplementation with selected Lactobacillus acidophilus triggers IL-17-dependent innate defense response, activation of innate lymphoid cells type 3 and improves colitis

The Impact of Escherichia coli Probiotic Strain O83:K24:H31 on the Maturation of Dendritic Cells and Immunoregulatory Functions In Vitro and In Vivo

Effect of early postnatal supplementation of newborns with probiotic strain E. coli O83:K24:H31 on allergy incidence, dendritic cells, and microbiota

Ecological Adaptations of Gut Microbiota Members and Their Consequences for Use as a New Generation of Probiotics

In Vitro Characterization of Gut Microbiota-Derived Commensal Strains: Selection of Parabacteroides distasonis Strains Alleviating TNBS-Induced Colitis in Mice