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Diabetologia
Published in: Diabetologia 8/2005

01-08-2005 | Article

Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse

Authors: F. Calcinaro, S. Dionisi, M. Marinaro, P. Candeloro, V. Bonato, S. Marzotti, R. B. Corneli, E. Ferretti, A. Gulino, F. Grasso, C. De Simone, U. Di Mario, A. Falorni, M. Boirivant, F. Dotta

Published in: Diabetologia | Issue 8/2005

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Abstract

Aims/hypothesis

Recent observations suggest the involvement of the gastrointestinal tract in the pathogenesis of islet autoimmunity. Thus, the modulation of gut-associated lymphoid tissue may represent a means to affect the natural history of the disease. Oral administration of probiotic bacteria can modulate local and systemic immune responses; consequently, we investigated the effects of oral administration of the probiotic compound VSL#3 on the occurrence of diabetes in non-obese diabetic (NOD) mice.

Methods

VSL#3 was administered to female NOD mice three times a week starting from 4 weeks of age. A control group received PBS. Whole blood glucose was measured twice a week. IFN-γ and IL-10 production/expression was evaluated by ELISA in culture supernatants of mononuclear cells isolated from Peyer’s patches and the spleen, and by real-time PCR in the pancreas. Insulitis was characterised by immunohistochemistry and histomorphometric studies.

Results

Early oral administration of VSL#3 prevented diabetes development in NOD mice. Protected mice showed reduced insulitis and a decreased rate of beta cell destruction. Prevention was associated with an increased production of IL-10 from Peyer’s patches and the spleen and with increased IL-10 expression in the pancreas, where IL-10-positive islet-infiltrating mononuclear cells were detected. The protective effect of VSL#3 was transferable to irradiated mice receiving diabetogenic cells and splenocytes from VSL#3-treated mice.

Conclusions/interpretation

Orally administered VSL#3 prevents autoimmune diabetes and induces immunomodulation by a reduction in insulitis severity. Our results provide a sound rationale for future clinical trials of the primary prevention of type 1 diabetes by oral VSL#3 administration.
Literature
1.
Notkins AL, Lernmark A (2001) Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 108:1247–1252CrossRefPubMed
2.
3.
Todd JA, Wicker LS (2001) Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models. Immunity 15:387–395CrossRefPubMed
4.
Adorini L, Gregori S, Harrison LC (2002) Understanding autoimmune diabetes: insights from mouse models. Trends Mol Med 8:31–38CrossRefPubMed
5.
Vaarala O (2002) The gut immune system and type 1 diabetes. Ann N Y Acad Sci 258:39–46
6.
Holmes GKT (2001) Celiac disease and type 1 diabetes mellitus—the case for screening. Diabet Med 18:169–177CrossRefPubMed
7.
Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E (2003) Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 290:1721–1728CrossRefPubMed
8.
Norris JM, Barriga K, Klingensmith G et al (2003) Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 290:1713–1720CrossRefPubMed
9.
Akerblom HK, Vaarala O, Hyoty H, Ilonen J, Knip M (2002) Environmental factors in the etiology of type 1 diabetes. Am J Med Genet 115:18–29CrossRefPubMed
10.
Jaakkola I, Jalkanen S, Hänninen A (2003) Diabetogenic T cells are primed both in pancreatic and gut-associated lymph nodes in NOD mice. Eur J Immunol 33:3255–3264
11.
Scott FW, Cloutier HE, Kleemann R et al (1997) Potential mechanisms by which certain foods promote or inhibit the development of spontaneous diabetes in BB rats: dose, timing, early effect on islet area, and switch in infiltrate from Th1 to Th2 cells. Diabetes 46:589–598PubMed
12.
Haavenar R, Ten Brink B, Huis In ‘t Veld JHJ (1992) Selection of strains for probiotics use. In: Fuller R (ed) Probiotics, the scientific basis. Chapman & Hall, London, pp 209–224
13.
Gorbach SL, Chang TW, Goldin B (1987) Successful treatment of relapsing Clostridium difficile colitis with lactobacillus GG. Lancet 2:1519CrossRef
14.
Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T (1991) A human lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children. Pediatrics 88:90–97PubMed
15.
Oksanen PJ, Salminen S, Saxelin M et al (1990) Prevention of travellers’ diarrhoea by lactobacillus GG. Ann Med 22:53–56PubMed
16.
Hilton E, Kolakowski P, Singer C, Smith M (1997) Efficacy of lactobacillus GG as a diarrheal preventive in travelers. Travel Med 4:41–43
17.
Gionchetti P, Rizzello F, Venturi A et al (2000) Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 119:305–309PubMed
18.
Madsen K, Cornish A, Soper P et al (2001) Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121:580–591PubMed
19.
Schultz M, Veltkamp C, Dieleman LA et al (2002) Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient mice. Inflamm Bowel Dis 8:71–80CrossRefPubMed
20.
Ghosh S, van Heel D, Playford RJ (2004) Probiotics in inflammatory bowel disease: is it all gut flora modulation? Gut 53:620–622CrossRefPubMed
21.
Chauviere G, Coconnier MH, Kerneis S, Fourniat J, Servin AL (1992) Adhesion of human Lactobacillus acidophilus strain LB to human enterocyte-like caco-2 cells. J Gen Microbiol 138:1689–1696
22.
Cunningham-Rundles S, Ahrne S, Bengmark S et al (2000) Probiotics and immune response. Am J Gastroenterol 95:S22–S25CrossRefPubMed
23.
Ulisse S, Gionchetti P, D’Alo S et al (2001) Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am J Gastroenterol 96:2691–2699CrossRefPubMed
24.
Miettinen M, Vuopio-Varkila J, Varkila K (1996) Production of human tumor necrosis factor alpha, interleukin-6, and interleukin-10 is induced by lactic acid bacteria. Infect Immun 64:5403–5405
25.
Matsuzaki T, Nagata Y, Kado S et al (1997) Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei. APMIS 105:643–649PubMed
26.
Marselli L, Dotta F, Piro S et al (2001) Th2 cytokines have a partial, direct protective effect on the function and survival of isolated human islets exposed to combined proinflammatory and Th1 cytokines. J Clin Endocrinol Metab 86:4974–4978CrossRefPubMed
27.
Wang T, Brown MJ (1999) mRNA quantification by real time Taqman polymerase chain reaction: validation and comparison with RNase protection. Anal Biochem 269:198–201CrossRefPubMed
28.
Hanninen A, Taylor C, Streeter PR et al (1993) Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid cell binding to islet endothelium. J Clin Invest 92:2509–2515PubMed
29.
Yang XD, Michie SA, Tisch R, Karin N, Steinman L, McDevitt HO (1994) A predominant role of integrin alpha 4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 91:12604–12608PubMed
30.
Hänninen A, Salmo M, Simell O, Jalkanen S (1996) Mucosa-associated (β7-integrinhigh) lymphocytes accumulate early in the pancreas of NOD mice and show aberrant recirculation behavior. Diabetes 45:1173–1180PubMed
31.
Kommajosyula S, Reddy S, Nitschke K, Kanwar JR, Karanam M, Krissansen GW (2001) Leukocytes infiltrating the pancreatic islet of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy. J Leukoc Biol 70:510–517PubMed
32.
Paronen J, Klemetti P, Kantele JM et al (1997) Glutamate decarboxylase-reactive peripheral blood lymphocytes from patients with IDDM express gut-specific homing receptor α4β7-integrin. Diabetes 46:583–588PubMed
33.
Pennline KJ, Roque-Gaffney E, Monahan M (1994) Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol 71:169–175CrossRefPubMed
34.
Nitta Y, Tashiro F, Tokui M et al (1998) Systemic delivery of interleukin 10 by intramuscular injection of expression plasmid DNA prevents autoimmune diabetes in nonobese diabetic mice. Hum Gene Ther 9:1701–1707PubMed
35.
Goudy K, Song S, Wasserfall C et al (2001) Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice. Proc Natl Acad Sci U S A 98:13913–13918CrossRefPubMed
36.
Yang Z, Chen M, Wu R et al (2002) Suppression of autoimmune diabetes by viral IL-10 gene transfer. J Immunol 168:6479–6485PubMed
37.
Phillips JM, Parish NM, Drage M, Cooke A (2001) Cutting edge: interactions through the IL-10 receptor regulate autoimmune diabetes. J Immunol 167:6087–6091PubMed
38.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765CrossRefPubMed
39.
Groux H, O’Garra A, Bigler M et al (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742CrossRefPubMed
40.
Singh B, Read S, Asseman C et al (2001) Control of intestinal inflammation by regulatory T cells. Immunol Rev 182:190–200CrossRefPubMed
41.
Fuss IJ, Boirivant M, Lacy B, Strober W (2002) The interrelated roles of TGF-β and IL-10 in the regulation of experimental colitis. J Immunol 168:900–908PubMed
42.
Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK (2001) Type 1 T regulatory cells. Immunol Rev 182:68–79CrossRefPubMed
43.
Cong Y, Weaver CT, Lazenby A, Elson CO (2002) Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol 169:6112–6119PubMed
44.
Kullberg MC, Jankovic D, Gorelick PL et al (2002) Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med 196:505–515CrossRefPubMed
45.
Madsen KL, Doyle JS, Jewell LD, Tavernini MM, Fedorak RN (1999) Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 116:1107–1114PubMed
46.
Vaarala O (2003) Immunological effects of probiotics with special reference to lactobacilli. Clin Exp Allergy 33:1634–1640CrossRefPubMed
47.
Neish AS, Gewirtz AT, Zeng H et al (2000) Prokaryotic regulation of epithelial responses by inhibition of IkB-α ubiquitination. Science 289:1560–1563CrossRefPubMed
48.
Petrof EO, Kojima K, Ropeleski MJ et al (2004) Probiotics inhibit nuclear factor-kB and induce heat shock proteins in colonic epithelial cells trough proteasome inhibition. Gastroenterology 127:1474–1487PubMed
49.
Rachmilewitz D, Katakura K, Karmeli F et al (2004) Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126:520–528CrossRefPubMed
50.
Christensen HR, Frokiaer H, Pestka JJ (2002) Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. J Immunol 168:171–178PubMed
51.
52.
Gionchetti P, Rizzello F, Helwig U et al (2003) Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 124:1202–1209CrossRefPubMed
53.
Kim HJ, Camilleri M, McKinzie S et al (2003) Randomized, controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 17:895–904CrossRefPubMed
54.
Mimura T, Rizzello F, Helwig U et al (2004) Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 53:108–114CrossRefPubMed
Metadata
Title
Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse
Authors
F. Calcinaro
S. Dionisi
M. Marinaro
P. Candeloro
V. Bonato
S. Marzotti
R. B. Corneli
E. Ferretti
A. Gulino
F. Grasso
C. De Simone
U. Di Mario
A. Falorni
M. Boirivant
F. Dotta
Publication date
01-08-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 8/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-1831-2

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