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Comparative Effect of the I3.1 Probiotic Formula in Two Animal Models of Colitis

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Abstract

Use of probiotic therapy is an active area of investigation to treat intestinal disorders. The clinical benefits of the I3.1 probiotic formula (Lactobacillus plantarum (CECT7484, CECT7485) and P. acidilactici (CECT7483)) were demonstrated in irritable bowel syndrome (IBS) patients in a randomized, double-blind, placebo-controlled clinical trial. The aim of this study was to evaluate the therapeutic effects of I3.1 in two experimental models of colitis, a dextran sulfate sodium (DSS)-induced colitis model and an interleukin (IL)-10-deficient mice model. Colitis was induced in 32 8-week-old Balb/c mice by administering 3% (w/v) DSS in drinking water for 5 days. Probiotics were administered orally (I3.1 or VSL#3, 1 × 109 CFU daily) for 10 days before the administration of DSS. Also, probiotics (I3.1 or VSL#3, 1 × 109 CFU daily) were administered orally to 36 6-week-old C57B6J IL-10(−/−) mice for 10 weeks. Body weight was recorded daily. Colon samples were harvested for histological examination and cytokine measurements. Body weight after DSS administration did not change in the I3.1 group, whereas the VSL#3 group had weight loss. Also, I3.1 normalized IL-6 to levels similar to that of healthy controls and significantly increased the reparative histologic score. In the IL-10-deficient model, both VSL#3 and I3.1 reduced the severity of colitis compared to untreated controls, and I3.1 significantly reduced the levels of IFN-γ compared to the other two groups. In conclusion, I3.1 displays a protective effect on two murine models of experimental colitis. Results suggest that the mechanism of action could be different from VSL#3.

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References

  1. Ananthakrishnan AN (2015) Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 12:205–217

    Article  Google Scholar 

  2. Kau AL, Ahern PP, Griffin NW et al (2011) Human nutrition, the gut microbiome and the immune system. Nature 474:327–336

    Article  CAS  Google Scholar 

  3. Bellaguarda E, Chang E (2015) IBD and the gut microbiota—from bench to personalized medicine. Curr Gastroenterol Rep 17:1–13

    Article  Google Scholar 

  4. Wasilewski A, Zielinska M, Storr M et al (2015) Beneficial effects of probiotics, prebiotics, synbiotics, and psychobiotics in inflammatory bowel disease. Inflamm Bowel Dis 21:1674–1682

    Article  Google Scholar 

  5. Ghouri YA, Richards DM, Rahimi EF et al (2014) Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clin Exp Gastroenterol 7:473–487

    Google Scholar 

  6. Fedorak RN, Feagan BG, Hotte N et al (2015) The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn’s disease. Clin Gastroenterol Hepatol 13:928–935.e2

    Article  CAS  Google Scholar 

  7. Jonkers D, Penders J, Masclee A et al (2012) Probiotics in the management of inflammatory bowel disease: a systematic review of intervention studies in adult patients. Drugs 72:803–823

    Article  Google Scholar 

  8. Cooper HS, Murthy SN, Shah RS et al (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Investig 69:238–249

    CAS  Google Scholar 

  9. Chassaing B, Aitken JD, Malleshappa M et al (2014) Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol 104 Unit 15.25

  10. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F et al (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241

    Article  CAS  Google Scholar 

  11. Berg DJ, Davidson N, Kühn R et al (1996) Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 98:1010–1020

    Article  CAS  Google Scholar 

  12. Schultz M, Veltkamp C, Dieleman LA et al (2002) Lactobacillus plantarum 299 V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient mice. Inflamm Bowel Dis 8:71–80

    Article  Google Scholar 

  13. Sellon RK, Tonkonogy S, Schultz M et al (1998) Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun 66:5224–5231

    CAS  Google Scholar 

  14. Madsen KL, Doyle JS, Jewell LD et al (1999) Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 116:1107–1114

    Article  CAS  Google Scholar 

  15. Etling MR, Davies S, Campbell M et al (2007) Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10−/−) mice. J Leukoc Biol 82:311–319

    Article  CAS  Google Scholar 

  16. Lorenzo-Zúñiga V, Llop E, Suárez C et al (2014) I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life. World J Gastroenterol 20:8709–8716

    Article  Google Scholar 

  17. Martinez C, Vicario M, Ramos L et al (2012) The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am J Gastroenterol 107:736–746

    Article  CAS  Google Scholar 

  18. Chadwick VS, Chen W, Shu D et al (2002) Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 122:1778–1783

    Article  Google Scholar 

  19. Talley NJ (2006) Irritable bowel syndrome. Intern Med J 36:724–728

    Article  CAS  Google Scholar 

  20. Piche T, Barbara G, Aubert P et al (2009) Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut 58:196–201

    Article  CAS  Google Scholar 

  21. Dieleman LA, Palmen MJ, Akol H et al (1998) Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol 114:385–391

    Article  CAS  Google Scholar 

  22. Mañé J, Pedrosa E, Lorén V et al (2009) Partial replacement of dietary (n-6) fatty acids with medium-chain triglycerides decreases the incidence of spontaneous colitis in interleukin-10-deficient mice. J Nutr 139:603–610

    Article  Google Scholar 

  23. Murthy SN, Cooper HS, Shim H et al (1993) Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin. Dig Dis Sci 38:1722–1734

    Article  CAS  Google Scholar 

  24. Pedrosa E, Lorén V, Cabré E et al (2011) Bacteria and spontaneous experimental colitis: immunological changes. Eur J Clin Investig 41:1047–1053

    Article  CAS  Google Scholar 

  25. Nguyen TLA, Vieira-Silva S, Liston A et al (2015) How informative is the mouse for human gut microbiota research? Dis Model Mech 8:1–16

    Article  CAS  Google Scholar 

  26. Melgar S, Karlsson A, Michaëlsson E (2005) Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation. Am J Physiol Gastrointest Liver Physiol 288:G1328–G1338

    Article  CAS  Google Scholar 

  27. Fitzpatrick LR, Hertzog KL, Quatse AL et al (2007) Effects of the probiotic formulation VSL#3 on colitis in weanling rats. J Pediatr Gastroenterol Nutr 44:561–570

    Article  Google Scholar 

  28. Mennigen R, Nolte K, Rijcken E et al (2009) Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol 296:G1140–G1149

    Article  CAS  Google Scholar 

  29. Mar JS, Nagalingam NA, Song Y et al (2014) Amelioration of DSS-induced murine colitis by VSL#3 supplementation is primarily associated with changes in ileal microbiota composition. Gut Microbes 5:494–503

    Article  Google Scholar 

  30. McLean MH, Dieguez D, Miller LM et al (2015) Does the microbiota play a role in the pathogenesis of autoimmune diseases? Gut 64:332–341

    Article  CAS  Google Scholar 

  31. Peterson CT, Sharma V, Elmén L et al (2015) Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota. Clin Exp Immuno 179:363–377

    Article  CAS  Google Scholar 

  32. Darfeuille-Michaud A, Boudeau J, Bulois P et al (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127:412–421

    Article  Google Scholar 

  33. Machiels K, Joossens M, Sabino J et al (2014) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63:1275–1283

    Article  CAS  Google Scholar 

  34. Shukla R, Ghoshal U, Dhole TN et al (2015) Fecal microbiota in patients with irritable bowel syndrome compared with healthy controls using real-time polymerase chain reaction: an evidence of dysbiosis. Dig Dis Sci 60:2953–2962

    Article  Google Scholar 

  35. Pagnini C, Saeed R, Bamias G et al (2010) Probiotics promote gut health through stimulation of epithelial innate immunity. Proc Natl Acad Sci U S A 107:454–459

    Article  CAS  Google Scholar 

  36. Bassaganya-Riera J, Viladomiu M, Pedragosa M et al (2012) Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria. PLoS One 7:e34676

    Article  CAS  Google Scholar 

  37. von Schillde M-A, Hörmannsperger G, Weiher M et al (2012) Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. Cell Host Microbe 11:387–396

    Article  Google Scholar 

  38. 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 119:305–309

    Article  CAS  Google Scholar 

  39. Tursi A, Brandimarte G, Papa A et al (2010) Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 105:2218–2227

    Article  Google Scholar 

  40. Guandalini S, Magazzù G, Chiaro A et al (2010) VSL#3 improves symptoms in children with irritable bowel syndrome: a multicenter, randomized, placebo-controlled, double-blind, crossover study. J Pediatr Gastroenterol Nutr 51:24–30

    Article  Google Scholar 

  41. Yadav V, Varum F, Bravo R et al (2016) Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 176:38–68

    Article  CAS  Google Scholar 

  42. Neurath MF (2014) New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol 7:6–19

    Article  CAS  Google Scholar 

  43. Ito H, Takazoe M, Fukuda Y et al (2004) A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 126:989–996

    Article  CAS  Google Scholar 

  44. Taniguchi K, Wu L-W, Grivennikov SI et al (2015) A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519:57–62

    Article  CAS  Google Scholar 

  45. Grivennikov S, Karin E, Terzic J et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113

    Article  CAS  Google Scholar 

  46. Tanaka T, Narazaki M, Kishimoto T (2012) Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199–219

    Article  CAS  Google Scholar 

  47. Tursi A, Elisei W, Brandimarte G et al (2011) Tumour necrosis factor-alpha expression in segmental colitis associated with diverticulosis down-regulates after treatment. J Gastrointestin Liver Dis 20:365–370

    Google Scholar 

  48. Dai C, Zheng C-Q, Meng F-J et al (2013) VSL#3 probiotics exerts the anti-inflammatory activity via PI3k/Akt and NF-κB pathway in rat model of DSS-induced colitis. Mol Cell Biochem 374:1–11

    Article  CAS  Google Scholar 

  49. Büchler G, Wos-Oxley ML, Smoczek A et al (2012) Strain-specific colitis susceptibility in IL10-deficient mice depends on complex gut microbiota-host interactions. Inflamm Bow Dis 18:943–954

    Article  Google Scholar 

  50. Maharshak N, Packey CD, Ellermann M et al (2013) Altered enteric microbiota ecology in interleukin 10-deficient mice during development and progression of intestinal inflammation. Gut Microbes 4:316–324

    Article  Google Scholar 

  51. Madsen K, Cornish A, Soper P et al (2001) Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121:580–591

    Article  CAS  Google Scholar 

  52. Takayama T, Kamada N, Chinen H et al (2010) Imbalance of NKp44(+)NKp46(−) and NKp44(−)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn’s disease. Gastroenterology 139:882–892

    Article  CAS  Google Scholar 

  53. Gonsky R, Deem RL, Landers CJ et al (2011) Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens. Inflamm Bowel Dis 17:171–178

    Article  Google Scholar 

  54. Darkoh C, Comer L, Zewdie G et al (2014) Chemotactic chemokines are important in the pathogenesis of irritable bowel syndrome. PLoS One 9:e93144

    Article  Google Scholar 

  55. Montufar-Solis D, Schaefer J, Hicks MJ et al (2008) Massive but selective cytokine dysregulation in the colon of IL-10−/− mice revealed by multiplex analysis. Int Immunol 20:141–154

    Article  CAS  Google Scholar 

  56. Gomes-Santos AC, Moreira TG, Castro-Junior AB et al (2012) New insights into the immunological changes in IL-10-deficient mice during the course of spontaneous inflammation in the gut mucosa. Clin Dev Immunol. doi:10.1155/2012/560817

    Google Scholar 

  57. Liu Z, Zhang P, Ma Y et al (2011) Lactobacillus plantarum prevents the development of colitis in IL-10-deficient mouse by reducing the intestinal permeability. Mol Biol Rep 38:1353–1361

    Article  CAS  Google Scholar 

  58. Kühn R, Löhler J, Rennick D et al (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–274

    Article  Google Scholar 

  59. Clark E, Hoare C, Tanianis-Hughes J et al (2005) Interferon gamma induces translocation of commensal Escherichia coli across gut epithelial cells via a lipid raft-mediated process. Gastroenterology 128:1258–1267

    Article  CAS  Google Scholar 

  60. Sarrabayrouse G, Bossard C, Chauvin JM et al (2014) CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLoS Biol 12:e1001833

    Article  Google Scholar 

  61. Yadav H, Lee J-H, Lloyd J et al (2013) Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem 288:25088–25097

    Article  CAS  Google Scholar 

  62. Dai C, Zhao DH, Jiang M et al (2012) VSL#3 probiotics regulate the intestinal epithelial barrier in vivo and in vitro via the p38 and ERK signaling pathways. Int J Mol Med 29:202–208

    CAS  Google Scholar 

  63. Ishiguro K, Ando T, Maeda O et al (2014) Suppressive action of acetate on interleukin-8 production via tubulin-[alpha] acetylation. Immunol Cell Biol 92:624–630

    Article  CAS  Google Scholar 

  64. Macia L, Tan J, Vieira AT et al (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 6:6734

    Article  CAS  Google Scholar 

  65. Duncan SH, Hold GL, Barcenilla A et al (2002) Roseburia intestinalis sp. nov., a novel saccharolytic, butyrate-producing bacterium from human faeces. Int J Syst Evol Microbiol 52:1615–1620

    CAS  Google Scholar 

  66. Duncan SH, Hold GL, Harmsen HJM et al (2002) Growth requirements and fermentation products of fusobacterium prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii gen. nov., comb. Nov. Int J Syst Evol Microbiol 52:2141–2146

    CAS  Google Scholar 

  67. Segawa S, Fujiya M, Konishi H et al (2011) Probiotic-derived polyphosphate enhances the epithelial barrier function and maintains intestinal homeostasis through integrin–p38 MAPK pathway. PLoS One 6:e23278

    Article  CAS  Google Scholar 

  68. Tanaka K, Fujiya M, Konishi H et al (2015) Probiotic-derived polyphosphate improves the intestinal barrier function through the caveolin-dependent endocytic pathway. Biochem Biophys Res Commun 467:541–548

    Article  CAS  Google Scholar 

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Correspondence to Josep Manyé.

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V. Lorén, J. Manyé, E. Cabré and I. Ojanguren declare that they have no conflict of interest. M.C Fuentes and J. Espadaler are full-time employees of AB-Biotics S.A.

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Lorén, V., Manyé, J., Fuentes, M.C. et al. Comparative Effect of the I3.1 Probiotic Formula in Two Animal Models of Colitis. Probiotics & Antimicro. Prot. 9, 71–80 (2017). https://doi.org/10.1007/s12602-016-9239-5

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