Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease

BMC Gastroenterology

Reetta Satokari³  Jarkko Salojärvi³  Willem M de Vos⁴  Hannu Lähteenoja²  Airi Palva³  Hans GHJ Heilig⁵  Marko Kalliomäki¹  Jing Cheng³ 

[1] Functional Foods Forum, 20014 University of Turku, Turku, Finland;Department of Internal Medicine, Turku University Central Hospital, P.O. Box 52, Turku 20521, Finland;Department of Veterinary Biosciences, University of Helsinki, P.O. Box 66, Helsinki FI-00014, Finland;Haartman Institute, University of Helsinki, P.O. Box 21, Helsinki FI-00014, Finland;Laboratory of Microbiology, Wageningen University, Dreijenplein 10, Wageningen 6703 HB, The Netherlands

关键词: Host-microbe cross-talk;    Duodenum;    Gene expression;    Microbiota;    Celiac disease;   

Others  :  857813
DOI  :  10.1186/1471-230X-13-113

 received in 2013-04-19, accepted in 2013-07-08,  发布年份 2013

【 摘 要 】

Background

Celiac disease (CD) is an autoimmune disorder of the small intestine which is triggered by dietary gluten in genetically predisposed (HLA-DQ2/DQ8 positive) individuals. Only a fraction of HLA-DQ2/DQ8 positive individuals develop CD indicating that other factors have a role in the disorder. Several studies have addressed intestinal microbiota aberrancies in pediatric CD, but the results are inconsistent. Previously, we demonstrated that pediatric CD patients have lower duodenal expression of TLR2 and higher expression of TLR9 as compared to healthy controls (HC) indicating that microbiota may have a role in CD.

Methods

We used bacterial phylogenetic microarray to comprehensively profile the microbiota in duodenal biopsies of CD (n = 10) and HC (n = 9) children. The expression of selected mucosa-associated genes was assessed by qRT-PCR in CD and HC children and in treated CD adults (T-CD, n = 6) on gluten free diet.

Results

The overall composition, diversity and the estimated microbe associated molecular pattern (MAMP) content of microbiota were comparable between CD and HC, but a sub-population profile comprising eight genus-like bacterial groups was found to differ significantly between HC and CD. In HC, increased TLR2 expression was positively correlated with the expression of tight junction protein ZO-1. In CD and T-CD, the expression of IL-10, IFN-g and CXCR6 were higher as co5mpared to HC.

Conclusions

The results suggest that microbiota and altered expression of mucosal receptors have a role in CD. In CD subjects, the increased expression of IL-10 and IFN-g may have partly resulted from the increased TLR9 expression and signaling.

【 授权许可】

   
2013 Cheng et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Green P, Jabri B: Celiac disease. Annu Rev Med 2006, 57:207-221.
• [2]Papista C, Gerakopoulos V, Kourelis A, Sounidaki M, Kontana A, Berthelot L, Moura IC, Monteiro RC, Yiangou M: Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics. Lab Invest 2012, 92:625-635.
• [3]Soni S, Badawy SZA: Celiac disease and its effect on human reproduction a review. J Reprod Med 2010, 55:3-8.
• [4]Sellitto M, Bai G, Serena G, Fricke WF, Sturgeon C, Gajer P, White JR, Koenig SSK, Sakamoto J, Boothe D, Gicquelais R, Kryszak D, Puppa E, Catassi C, Ravel J, Fasano A: Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS One 2012, 7:e33387.
• [5]Trynka G, Wijmenga C, van Heel DA: A genetic perspective on coeliac disease. Trends Mol Med 2010, 16:537-550.
• [6]Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, Bakker SF, Bardella MT, Bhaw-Rosun L, Castillejo G, de la Concha EG, de Almeida RC, Dias KRM, van Diemen CC, Dubois PCA, Duerr RH, Edkins S, Franke L, Fransen K, Gutierrez J, Heap GAR, Hrdlickova B, Hunt S, PlazaIzurieta L, Izzo V, Joosten LAB, Langford C, Mazzilli MC, Mein CA, Midah V, et al.: Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 2011, 43:1193-1201.
• [7]Sperandeo MP, Tosco A, Izzo V, Tucci F, Troncone R, Auricchio R, Romanos J, Trynka F, Auricchio S, Jabri B, Greco L: Potential celiac patients: a model of celiac disease pathogenesis. PLoS One 2011, 6:e21281.
• [8]Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO: Development of the human infant intestinal microbiota. PLoS Biol 2007, 5:e177.
• [9]Nylund L, Satokari R, Nikkilä J, Rajilic-Stojanovic M, Kalliomäki M, Isolauri E, Salminen S, de Vos WM: Microarray analysis reveals marked intestinal microbiota aberrancy in infants having eczema compared to healthy children in at-risk for atopic disease. BMC Microbiol 2013, 13:12. BioMed Central Full Text
• [10]Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Gordon JI: Human gut microbiome viewed across age and geography. Nature 2012, 486:222-227.
• [11]De Palma G, Capilla A, Nova E, Castillejo G, Varea V, Pozo T, Antonio GJ, Polanco I, Lopez A, Ribes-Koninckx C, Marcos A, Dolores GNM, Calvo C, Ortigosa L, Pena-Quintana L, Palau F, Sanz Y: Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study. PLoS One 2012, 7:e30791.
• [12]Nadal I, Donant E, Ribes-Koninckx C, Calabuig M, Sanz Y: Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J Med Microbiol 2007, 56:1669-1674.
• [13]Sanz Y, Sanchez E, Marzotto M, Calabuig M, Torriani S, Dellaglio F: Differences in faecal bacterial communities in coeliac and healthy children as detected by PCR and denaturing gradient gel electrophoresis. FEMS Immunol Med Microbiol 2007, 51:562-568.
• [14]Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y: Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol 2009, 62:264-269.
• [15]De Palma G, Nadal I, Medina M, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y: Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol 2010, 10:63. BioMed Central Full Text
• [16]Schippa S, Iebba V, Barbato M, Di Nardo G, Totino V, Checchi MP, Longhi C, Maiella G, Cucchiara S, Conte MP: A distinctive 'microbial signature' in celiac pediatric patients. BMC Microbiol 2010, 10:175. BioMed Central Full Text
• [17]Ou G, Hedberg M, Hörstedt P, Baranov V, Forsberg G, Drobni M, Sandström O, Wai SN, Johansson I, Hammarström ML, Hernell O, Hammarström S: Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am J Gastroenterol 2009, 104:3058-3067.
• [18]Kalliomäki M, Satokari R, Lähteenoja H, Vähämiko S, Grönlund J, Routi T, Salminen S: Expression of microbiota, Toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease. J Pediatr Gastroenterol Nutr 2012, 54:727-732.
• [19]Nistal E, Caminero A, Herran AR, Arias L, Vivas S, Ruiz de Morales JM, Jose M, Calleja S, Saenz De M, Luis E, Arroyo P, Casqueiro J: Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflamm Bowel Dis 2012, 18:649-656.
• [20]Maynard CL, Elson CO, Hatton RD, Weaver CT: Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012, 489:231-241.
• [21]Abreu MT: Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 2010, 10:131-144.
• [22]Rajilic-Stojanovic M, Heilig HGHJ, Molenaar D, Kajander K, Surakka A, Smidt H, de Vos WM: Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ Microbiol 2009, 11:1736-1751.
• [23]Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, Nikk J, Monti D, Satokari R, Franceschi C, Brigidi P, De Vos W: Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 2010, 5:e10667.
• [24]Jalanka-Tuovinen J, Salonen A, Nikkilä J, Immonen O, Kekkonen R, Lahti L, Palva A, de Vos WM: Intestinal Microbiota in Healthy Adults: Temporal Analysis Reveals Individual and Common Core and Relation to Intestinal Symptoms. PLoS One 2011, 6:e23035.
• [25]Iwamoto T, Tani K, Nakamura K, Suzuki Y, Kitaqawa M, Equchi M, Nasu M: Monitoring impact of in situ biostimulation treatment on groundwater bacterial community by DGGE. FEMS Microbiol Ecol 2000, 32:129-141.
• [26]Salonen A, Nikk J, Jalanka-Tuovinen J, Immonen O, Rajilic-Stojanovic M, Kekkonen RA, Palva A, de Vos WM: Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. J Microbiol Methods 2010, 81:127-134.
• [27]Bolstad B, Irizarry R, Astrand M, Speed T: A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 2003, 19:185-193.
• [28]Han JKM: Data mining: concepts and techniques. San Francisco, CA: Morgan Kaufmann Publishers; 2006.
• [29]Menard O, Gafa V, Kapel N, Rodriguez B, Butel M, Waligora-Dupriet A: Characterization of immunostimulatory CpG-rich sequences from different Bifidobacterium species. Appl Environ Microbiol 2010, 76:2846-2855.
• [30]Lee KW, Jung JW, Lee Y, Kim TY, Choi SY, Park J, Kim DS, Kwon HJ: Immunostimulatory oligodeoxynucleotide isolated from genome wide screening of Mycobacterium bovis chromosomal DNA. Mol Immunol 2006, 43:2107-2118.
• [31]Simpson E: Measurement of diversity. Nature 1949, 163:688-688.
• [32]Hill MO: Diversity and evenness - a unifying notation and its consequences. Ecology 1973, 54:427-432.
• [33]Legendre PLL: Numerical Ecology. Amsterdam, NL: Elservier Science BV; 1998.
• [34]Venables WNRB: Modern applied statistics with S. New York, NY: Springer; 2002.
• [35]Breiman L: Random forests. Mach Learn 2001, 45(1):5-32.
• [36]Chambers JM, Hastie TJ: Statistical models in S. Pacific Grove, CA: Wasdsworth & Brooks/Cole; 1992.
• [37]Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I: Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001, 125:279-284.
• [38]Siegel S, Castellan NJ: Non parametric statistics for the behavioural sciences. New York, NY: MacGraw-Hill; 1988.
• [39]Zoetendal EG, Raes J, van de Bogert B, Arumugam M, Booijink CC, Troost FJ, Bork P, Wels M, de Vos WM, Kleerebezem M: The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates. ISME J 2012, 6:1415-1426.
• [40]Sullivan A, Tornblom H, Lindberg G, Hammarlund B, Palmgren AC, Einarsson C, Nord CE: The micro-flora of the small bowel in health and disease. Anaerobe 2003, 9:11-14.
• [41]Ricanek P, Lothe SM, Frye SA, Rydning A, Catn MH, Tønjum T: Gut bacterial profile in patients newly diagnosed with treatment-naive Crohn's disease. Clin Exp Gastroenterol 2012, 5:173-186.
• [42]Mukhopadhya I, Hansen R, Nicholl CE, Alhaidan YA, Thomson JM, Berry SH, Pattinson C, Stead DA, Russell RK, EI-Omar EM, Hold GL: A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease. PLoS One 2011, 6:e27076.
• [43]Wang X, Heazlewood SP, Krause DO, Florin TH: Molecular characterization of the microbial species that colonize human ileal and colonic mucosa by using 16S rDNA sequence analysis. J Appl Microbiol 2003, 95:508-520.
• [44]Sanchez E, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y: Intestinal Bacteroides species associated with coeliac disease. J Clin Pathol 2010, 63:1105-1111.
• [45]Polilli E, Parruti G, Fazii P, D'Antonio D, Palmieri D, D'Incecco C, Mangifesta A, Garofalo G, Del Duca L, D'Amario C, Scimia M: Rapidly controlled outbreak of Serratia marcescens infection/colonisations in a neonatal intensive care unit, Pescara General Hospital, Pescara, Italy. Eurosurveillance 2011, 16:16-18.
• [46]Adamson V, Mitt P, Pisarev H, Metsvaht T, Telling K, Naaber P, Maimets M: Prolonged outbreak of Serratia marcescens in Tartu University Hospital: a case–control study. BMC Infect Dis 2012, 12:281. BioMed Central Full Text
• [47]Ze X, Duncan SH, Louis P, Flint HJ: Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. ISME J 2012, 6:1535-1543.
• [48]Defnoun S, Labat M, Ambrosio M, Garcia JL, Patel BKC: Papillibacter cinnamivorans gen. nov., sp nov., a cinnamate-transforming bacterium from a shea cake digester. Int J Syst Evol Microbiol 2000, 50:1221-1228.
• [49]Flint HJ, Scott KP, Louis P, Duncan SH: The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012, 9:577-589.
• [50]Mondot S, Kang S, Furet JP, de Carcer DA, McSweeney C, Morrison M, Marteau P, Dore J, Leclerc M: Highlighting new phylogenetic specificities of Crohn's disease microbiota. Inflamm Bowel Dis 2011, 17:185-192.
• [51]Cario E, Gerken G, Podolsky DK: Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 2004, 127:224-238.
• [52]Cario E, Gerken G, Podolsky DK: Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 2007, 132:1359-1374.
• [53]Ey B, Eyking A, Gerken G, Podolsky DK, Cario E: TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury. J Biol Chem 2009, 284:22332-22343.
• [54]Pizzuti D, Bortolami M, Mazzon E, Buda A, Guariso G, D'Odorico A, Chiarelli S, D'Inca R, De Lazzari F, Martines D: Transcriptional downregulation of tight junction protein ZO-1 in active coeliac disease is reversed after a gluten-free diet. Dig Liver Dis 2004, 36:337-341.
• [55]Pedersen RM, Holt HM, Justesen US: Solobacterium moorei bacteremia: identification, antimicrobial susceptibility, and clinical characteristics. J Clin Microbiol 2011, 49:2766-2768.
• [56]Shimaoka T, Nakayama T, Kume N, Takahashi S, Yamaguchi J, Minami M, Hayashida K, Kita T, Ohsumi J, Yoshie O, Yonehara S: Cutting edge: SR-PSOX/CXC chemokine ligand 16 mediates bacterial phagocytosis by APCs through its chemokine domain. J Immunol 2003, 171:1647-1651.
• [57]Uza N, Nakase H, Yamamoto S, Yoshino T, Takeda Y, Ueno S, Inoue S, Mikami S, Matsuura M, Shimaoka T, Kume N, Minami M, Yonehara S, Ikeuchi H, Chiba T: SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation. Gut 2011, 60:1494-1505.
• [58]Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N, Hartmann D, Sedlacek R, Dietrich S, Muetze B, Schuster B, Kallen KJ, Saftig P, Rose-John S, Ludwig A: The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol 2004, 172:6362-6372.
• [59]Hase K, Murakami T, Takatsu H, Shimaoka T, Iimura M, Hamura K, Kawano K, Ohshima S, Chihara R, Itoh K, Yonehara S, Ohno H: The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and m cells mediates lympho-epithelial interaction in GALT. J Immunol 2006, 176:43-51.
• [60]Diegelmann J, Seiderer J, Niess J, Haller D, Goeke B, Reinecker H, Brand S: Expression and regulation of the chemokine CXCL16 in Crohn's disease and models of intestinal inflammation. Inflamm Bowel Dis 2010, 16:1871-1881.
• [61]Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S: A Toll-like receptor recognizes bacterial DNA. Nature 2000, 408:740-745.
• [62]Krieg A: CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002, 20:709-760.
• [63]Yu D, Putta MR, Bhagat L, Li Y, Zhu F, Wang D, Tang JX, Kandimalla ER, Agrawal S: Agonists of Toll-like receptor 9 containing synthetic dinucleotide motifs. J Med Chem 2007, 50:6411-6418.
• [64]de Kivit S, van Hoffen E, Korthagen N, Garssen J, Willemsen LEM: Apical TLR ligation of intestinal epithelial cells drives a T(h)1-polarized regulatory or inflammatory type effector response in vitro. Immunobiology 2011, 216:518-527.
• [65]Forsberg G, Hernell O, Melgar S, Israelsson A, Hammarstrom S, Hammarstrom ML: Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology 2002, 123:667-678.
• [66]Salvati VM, Mazzarella G, Gianfrani C, Levings MK, Stefanile R, De Giulio B, Iaquinto G, Giardullo N, Auricchio S, Roncarolo MG, Troncone R: Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa. Gut 2005, 54:46-53.
• [67]Gianfrani C, Levings MK, Sartirana C, Mazzarella G, Barba G, Zanzi D, Camarca A, Iaquinto G, Giardullo N, Auricchio S, Troncone R, Roncarolo MG: Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol 2006, 177:4178-4186.
• [68]Nilsen EM, Lundin KEA, Krajci P, Scott H, Sollid LM, Brandtzaeg P: Gluten specific, Hla-Dq restricted T-cells from celiac mucosa produce cytokines with Thl or Th0 profile dominated by interferon-gamma. Gut 1995, 37:766-776.
• [69]Nilsen EM, Jahnsen FL, Lundin KEA, Johansen FE, Fausa O, Sollid LM, Jahnsen J, Scott H, Brandtzaeg P: Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 1998, 115:551-563.
• [70]Lahdenperä A, Ludvigsson J, Falth-Magnusson K, Högberg L, Vaarala O: The effect of gluten-free diet on Th1-Th2-Th3-associated intestinal immune responses in celiac disease. Scand J Gastroenterol 2011, 46:538-549.