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Revista Española de Enfermedades Digestivas - Probiotics in arthralgia and spondyloarthropathies in patients with inflammatory bowel disease: Prospective randomized trials are necessary

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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. v.97 n.8 Madrid ago. 2005

http://dx.doi.org/10.4321/S1130-01082005000800005 

POINT OF VIEW


Probiotics in arthralgia and spondyloarthropathies in patients with inflammatory
bowel disease. Prospective randomized trials are necessary

O. Karimi and A. S. Peña

Specialist in Gastroenterology. Head Laboratory of Immunogenetics, Department of Pathology, VU University Medical Centre.
Amsterdam, The Netherlands

 

ABSTRACT

Arthralgias and spondyloarthropathies of the peripheral and axial joints are common in inflammatory bowel disease. Evidence for a strong association between these clinical manifestations and diseases of the joints has been provided by several clinical and epidemiological studies. Immunological studies have shown the presence of shared inflammatory cells both in the gut and the synovium in spondyloarthropathies. Genetic factors play a crucial role in the pathogenesis of spondyloarthropathies and inflammatory bowel disease. The role of the ubiquitous bacterial flora and pathogenic microorganisms present in the intestinal lumen may induce these joint diseases in patients with inflammatory bowel disease. In this review we will focus on the pathogenesis of spondyloarthropathies and arthralgia in patients suffering from inflammatory bowel disease. Based on preliminary clinical observations in patients with arthralgia and IBD, we put forward the hypothesis that probiotics may be helpful in the management of common extraintestinal manifestations such as arthralgia in patients with ulcerative colitis and Crohn's disease.

Key words: Arthralgias. Spondyloarthropathies. Inflammatory bowel disease. Crohn's disease.


Karimi O, Peña AS. Probiotics in arthralgia and spondyloarthropathies in patients with inflammatory bowel disease. Prospective randomized trials are necessary. Rev Esp Enferm Dig 2005; 97: 570-574.


Recibido: 29-03-05.
Aceptado: 29-03-05.

Correspondencia: A.S. Peña. Specialist in Gastroenterology. Head Laboratory of Immunogenetics. Department of Pathology. VU University Medical Centre. Tel +31 20 444 4705.
Fax: + 31 20 444 4737. P.O. Box 7057. 1007 MB Amsterdam. The Netherlands.

 

INTRODUCTION

Seronegative spondyloarthritides, a subgroup of spondyloarthropathies (SpA), enclose a group of arthropathies characterized by the consistent absence of the rheumatoid factor, the involvement of sacro-iliac joints and the involvement of peripheral inflammatory arthritis. These SpA are also known as non-erosive, non-deforming arthropathies (1). This group is clinically distinguishable from the group of patients with seropositive rheumatoid arthritis. The prevalence of SpA was shown to be higher in Crohn's disease (CD) than in ulcerative colitis (UC) (2). Immunopathological studies, such as increased E-cadherin/ catenin complex expression has been observed in clinically overt IBD and in the subclinically inflamed bowel mucosa from spondyloarthropathy (SpA) patients (3,4).

SpA is associated with the histocompatibility antigen HLA-B27. This marker and other yet unknown genetic and environmental factors explain the often observed familial aggregation of SpA and IBD (5-7). Involvement of the gastrointestinal tract is a feature of SpA (8). Subclinical inflammatory lesions of the gut can evolve to clinically overt CD. These lesions are found in 25-75% of SpA patients (9). Clinical articular manifestations compatible with SpA are shown by 39% of patients with IBD (7). A research group in Oxford showed that enteropathic peripheral arthropathy without axial involvement can be subdivided into a pauciarticular large joint arthropathy and a bilateral symmetrical polyarthropathy. Both subgroups can be distinguished by the different distribution of joint involvement and the natural history of the disease. Patients with recorded joint swelling or effusion were classified as type 1 (pauciarticular) when less than five joints were involved, and classified as type 2 (polyarticular) when five or more joints were swollen. Patients with joint pain but no evidence of swelling in the joints were classified as suffering from arthralgia (10).

THE GUT AND THE JOINT

Gastrointestinal infections associated with SpA usually involve the terminal ileum and sometimes also the colon, in most cases without joint symptoms (11,12). Generally two types of inflammation exist; an acute inflammation resembling enterocolitis and a chronic inflammation resembling CD.

The involvement of the genetic marker HLA-B27 may explain the pathogenesis of joint inflammation. The HLA-B27 marker is an HLA class-I molecule that binds microbial antigenic peptides known as arthritogenic peptides. HLA-B27 presents these peptides to CD8+ cytotoxic T-cells in the synovium, thus inducing inflammation. Bacteria that are present in the intestinal lumen of IBD patients may share epitopes with HLA-B27 antigens. Recently, IBD-specific autoantibodies were found in patients with HLA-B27-associated SpA (13). According to Orchard et al. pauciarticular arthropathy (type 1) is clinically and immunogenetically similar to the manifestations of SpA. According to these authors, different HLA associations may define phenotypically distinct subgroups. In type 1: HLA-DRB1*0103 in 33% (relative risk (RR) = 12.1), B*35 in 30% (RR = 2.2), and B*27 in 26% (RR = 4.0). In type 2, i.e., polyarticular arthropathy: HLA-B*44 in 62% (RR, 2.1)(14). In IBD and SpA there is a polygenic predisposition and a high prevalence of increased intestinal permeability (15-18). This may suggest a common etiopathogenesis for arthralgia and SpA in IBD. Endoscopy and the histology of ileal biopsy specimens have shown a high prevalence of asymptomatic intestinal inflammation in patients with assumed idiopathic ankylosing spondylitis (chronic SpA) with or without the HLA-B27 marker (19-21).

The role of increased intestinal permeability was confirmed by abdominal scintigraphy with technetium-99m hexamethylpropylene amine oxime in SpA patients (22). Colonoscopy showed a statistically significant concordance with abdominal scintigraphy (23).

Immunohistochemical studies in mucosal biopsy specimens of SpA patients showed an increase in immunoglobulin-containing cells, similar to CD and UC (24). Among immune alterations, an increased number of the macrophage scavenger receptor CD163 was found in the synovium and colonic mucosa of SpA patients (25-27). Several studies have suggested a link between Gram-negative enterobacteria and IBD (21,28). The involvement of Yersinia and Salmonella in reactive arthritis, as well as Shigella, Campylobacter spp. and Klebsiela, was reported (28,29). The observations by Orchard and Jewell are consistent with the hypothesis that luminal bacteria in this region are important in the pathogenesis of reactive arthritis. They compared a group of CD patients with ileocecal resection to a group of CD patients without ileocecal resection. Patients who underwent ileocecal resection had less arthritic complications (30).

NOT ALL PROBIOTICS ARE ALIKE; COMPARATIVE STUDIES ARE NECESSARY

In order to understand the mechanisms of action of probiotics, two different concepts have been approached -one based on the effects of one single strain used as a food supplement (e.g., Lactobacillus GG and L. casei Shirota), the other derived from observations made using a mixture of Lactobacilli, bifidobacteria, and streptococcus (VSL#3) in patients with IBD and arthralgia (31). With the exception of a recently published study (32), no comparative studies of different strains or mixtures are available to date. The choice for one particular strain is empiric, and a careful recording of their effects is necessary. In the only comparative study that has been published, two different strains (Lactobacillus salivarius and Bifidobacterium infantis) were compared in patients with irritable bowel syndrome. Bifidobacterium infantis was found to normalize the antiinflammatory-to-proinflammatory cytokines ratio, whereas no changes in the cytokine profiles were induced by L. salivarius and placebo. More comparative studies are needed to find the superiority of each specific strain for a specific symptom (32,33).

PROBIOTICS IN POUCHITIS AND IBD

Probiotics are live microbial feed supplements that benefit the host by improving intestinal microbial balance, and that probably induce benefits in health that normal nutrition is not able to achieve (34). The lumen of the intestine contains bacteria, bacterial products, and dietary antigens capable of initiating and sustaining inflammation. Although the mechanisms of action of probiotics are still unclear, their beneficial effects on the improvement of intestinal microbial balance have already been described for decades (35).

Evidence for a therapeutic role of probiotics in the remission and prevention of patients with pouchitis, a non-specific ileal inflammation occurring in the ileal reservoir after proctocolectomy for UC, was provided by Gionchetti et al. (36).

PROBIOTICS IN THE MANAGEMENT OF ARTHRALGIA IN PATIENTS WITH IBD

To study the safety and efficacy of probiotics in patients with quiescent IBD who suffered from arthralgia for more than two weeks, Karimi et al. administered oral probiotics (VSL#3) to these patients. Preliminary results suggested that this probiotic mixture may be an alternative treatment for arthralgia in some patients with IBD, without inducing exacerbation of inflammatory bowel disease as NSAIDs do (37,38).

OBSERVATIONS AND RATIONALE SUPPORTING AN INDICATION FOR PROBIOTICS IN ARTHRALGIA AND SPA IN PATIENTS WITH IBD

The beneficial effects of Lactobacillus GG both in the prevention and treatment of T-cell-dependent experimental arthritis were also demonstrated in two animal models suggesting a beneficial effect of the use of probiotics in experimental arthropathy (39).

BASIC MECHANISMS

The modulation of COX2 expression is an important mechanism of the anti-inflammatory and anticarcinogenic property of some probiotics (40). The probiotic Lactobacillus rhamnosus GG was found to induce COX2 expression in human T84 colon epithelial cells (41). The importance of COX2-dependent arachidonic acid metabolites as immunoregulatory molecules in the intestinal mucosa is emphasized by the observation that NSAIDs, often efficacious in the treatment of arthropathy, may induce a flare-up of IBD (42-44). COX2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis (45).

Recently, a mitogen-activated protein kinase (MAPK) called p38 has been reported as a mediator of endotoxin-induced production of COX2 in enterocytes (46). The inhibition of the p38 MAPK pathway may inhibit COX2 expression. This is relevant because previous studies have shown that probiotic bacteria inhibit the p38 MAPK pathway (47). We therefore hypothesize that the link between p38 and COX2 may explain the beneficial effect of probiotics in the treatment of arthralgia since probiotic bacteria inhibit this pathway and have a role in preventing intestinal cancer.

INFLIXIMAB (ANTI-TNF-a), NF-κB AND PROBIOTICS IN PATIENTS WITH ANKYLOSING SPONDYLITIS, IBD, AND SPA, AND IN EXPERIMENTAL ANIMAL MODELS OF COLITIS

The efficacy and safety of infliximab in patients with ankylosing spondylitis has been tested in a randomized, placebo-controlled trial showing that infliximab was well tolerated and effective in a large cohort of patients with ankylosing spondylitis during a 24-week study period (48). Patients with Crohn's disease and SpA have also been effectively treated with infliximab, a tumor necrosis factor alpha (TNF-a) blockade (49,50). In an experimental study, the administration of VSL#3 to IL-10 deficient mice showed a reduction of microscopic infection together with a reduction in the mucosal secretion of TNF-a and IFN-g (51). These studies may suggest that probiotics may facilitate an anti-inflammatory effect of TNF-a blockade. Probiotic VSL#3 appears to reduce the inflammation of the gut mucosa by blocking NF-κB activity and to increase cytoprotection through heat shock protein induction, mediated by inhibition of the proteasome (52).

INTESTINAL PERMEABILITY, IL-10 AND PROBIOTICS IN PATIENTS WITH IBD AND IN EXPERIMENTAL ANIMAL MODELS OF COLITIS

Treatment with the probiotic VSL#3 has demonstrated a reduction of colonic permeability in both IL-10 gene-deficient mice and control mice. This may suggest that the type and quantity of bacterial species in the colon modulate intestinal permeability (53-55). Furthermore, Ulisse et al. have shown that VSL#3 probiotics induce a significant increase in the expression of the anti-inflammatory cytokine IL-10 in the mucosal reservoir of patients with pouchitis compared to similar patients treated with antibiotics (56). The administration of VSL#3 probiotic has been studied in a Th1 T-cell colitis, which was induced by trinitrobenzene sulfonic acid treatment in SJL/J mice. Daily administration of VSL#3 to these mice for a period of 3 weeks, during a remission period between a first and second course of trinitrobenzene sulfonic acid, resulted in a milder form of recurrent colitis than observed in mice administered PBS during this same period. This outcome was due to the induction of an immunoregulatory response involving TGF-ß-bearing regulatory cells since anti-IL-10R or anti-TGF-ß abolished the beneficial effects of the probiotic mixture (57).

Although the safety of probiotics containing lactobacilli and bifidobacteria has been evaluated critically, and probiotics were considered to be at least as safe as appropriate traditional reference food (58), one has to take into consideration that not all probiotic bacteria have similar therapeutic effects as stated earlier.

The terminal ileum, and in particular the increased permeability of the terminal ileum, play a key role in the link between intestinal inflammation and SpA. It seems that the most important effect of probiotics in ameliorating arthralgia in patients with IBD and SpA is the enhancement of the intestinal barrier. This hypothesis is supported by experimental observations in mice described by Madsen et al. (59). Isolauri et al. (55) described that prolonged cow milk challenge in suckling rats increases gut permeability to intact proteins, whereas Lactobacillus GG counteracts this permeability disorder.

CONCLUSION

Based on the results of experimental animal models, the concepts described in this review and our preliminary clinical observations, we believe that the use of probiotics may be effective in the management of patients with IBD suffering from arthralgia and/or SpA. Controlled randomized clinical trials to investigate the unresolved issues related to efficacy, dose, and duration of use, single or multi-strain formulation, are necessary to prove the beneficial effect of probiotics in patients with IBD, arthralgia and/or SpA.

REFERENCES

1. Gravallese EM, Kantrowitz FG. Arthritic manifestations of inflammatory bowel disease. Am J Gastroenterol 1988; 83: 703-9.         [ Links ]

2. Veloso FT, Carvalho J, Magro F. Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol 1996; 23: 29-34.        [ Links ]

3. Demetter P, Baeten D, De Keyser F, De Vos M, Van Damme N, Verbruggen G, et al. Subclinical gut inflammation in spondyloarthropathy patients is associated with upregulation of the E-cadherin/catenin complex. Ann Rheum Dis 2000; 59: 211-6.        [ Links ]

4. Demetter P, De Vos M, Van Damme N, Baeten D, Elewaut D, Vermeulen S, et al. Focal up-regulation of E-cadherin-catenin complex in inflamed bowel mucosa but reduced expression in ulcer-associated cell lineage. Am J Clin Pathol 2000; 114: 364-70.        [ Links ]

5. González S, García-Fernández S, Martínez-Borra J, Blanco-Gelaz MA, Rodrigo L, Sánchez del Río J, et al. High variability of HLA-B27 alleles in ankylosing spondylitis and related spondyloarthropathies in the population of northern Spain. Hum Immunol 2002; 63: 673-6.        [ Links ]

6. Brophy S, Pavy S, Lewis P, Taylor G, Bradbury L, Robertson D, et al. Inflammatory eye, skin, and bowel disease in spondyloarthritis: genetic, phenotypic, and environmental factors. J Rheumatol 2001; 28: 2667-73.        [ Links ]

7. de Vlam K, Mielants H, Cuvelier C, De Keyser F, Veys EM, De Vos M. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association. J Rheumatol 2000; 27: 2860-5.        [ Links ]

8. De Keyser F, Elewaut D, De Vos M, De Vlam K, Cuvelier C, Mielants H, et al. Bowel inflammation and the spondyloarthropathies. Rheum Dis Clin North Am 1998; 24: 785-813, ix-x.        [ Links ]

9. De Vos M, Mielants H, Cuvelier C, Elewaut A, Veys E. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 1996; 110: 1696-703.        [ Links ]

10. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998; 42: 387-91.        [ Links ]

11. Leirisalo-Repo M, Turunen U, Stenman S, Helenius P, Seppala K. High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum 1994; 37: 23-31.        [ Links ]

12. Smale S, Natt RS, Orchard TR, Russell AS, Bjarnason I. Inflammatory bowel disease and spondylarthropathy. Arthritis Rheum 2001; 44: 2728-36.        [ Links ]

13. Torok HP, Glas J, Gruber R, Brumberger V, Strasser C, Kellner H, et al. Inflammatory bowel disease-specific autoantibodies in HLA-B27-associated spondyloarthropathies: increased prevalence of ASCA and pANCA. Digestion 2004; 70: 49-54.        [ Links ]

14. Orchard TR, Thiyagaraja S, Welsh KI, Wordsworth BP, Hill Gaston JS, Jewell DP. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology 2000; 118: 274-8.        [ Links ]

15. Holden W, Orchard T, Wordsworth P. Enteropathic arthritis. Rheum Dis Clin North Am 2003; 29: 513-30, viii.        [ Links ]

16. Mielants H, Veys EM, Cuvelier C, de Vos M. Ileocolonoscopic findings in seronegative spondylarthropathies. Br J Rheumatol 1988; 27 (Supl. 2): 95-105.        [ Links ]

17. Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology 1995; 108: 1566-81.        [ Links ]

18. Martínez-González O, Cantero-Hinojosa J, Paule-Sastre P, Gómez-Magán JC, Salvatierra-Ríos D. Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol 1994; 33: 644-7.        [ Links ]

19. Mielants H, Veys EM, Cuvelier C, De Vos M, Botelberghe L. HLA-B27 related arthritis and bowel inflammation. Part 2. Ileocolonoscopy and bowel histology in patients with HLA-B27 related arthritis. J Rheumatol 1985; 12: 294-8.        [ Links ]

20. Cuvelier C, Barbatis C, Mielants H, De Vos M, Roels H, Veys E. Histopathology of intestinal inflammation related to reactive arthritis. Gut 1987; 28: 394-401.        [ Links ]

21. Leirisalo-Repo M, Repo H. Gut and spondyloarthropathies. Rheum Dis Clin North Am 1992; 18: 23-35.        [ Links ]

22. Alonso JC, López-Longo FJ, Lampreave JL, González CM, Vegazo O, Carreno L, et al. Abdominal scintigraphy using 99mTc-HMPAO-labelled leucocytes in patients with seronegative spondylarthropathies without clinical evidence of inflammatory bowel disease. Eur J Nucl Med 1996; 23: 243-6.        [ Links ]

23. El Maghraoui A, Dougados M, Freneaux E, Chaussade S, Amor B, Breban M. Concordance between abdominal scintigraphy using technetium-99m hexamethylpropylene amine oxime-labelled leucocytes and ileocolonoscopy in patients with spondyloarthropathies and without clinical evidence of inflammatory bowel disease. Rheumatology (Oxford) 1999; 38: 543-6.        [ Links ]

24. Cuvelier C, Mielants H, De Vos M, Veys E, Roels H. Immunoglobulin containing cells in terminal ileum and colorectum of patients with arthritis related gut inflammation. Gut 1988; 29: 916-25.        [ Links ]

25. Baeten D, Demetter P, Cuvelier CA, Kruithof E, Van Damme N, De Vos M, et al. Macrophages expressing the scavenger receptor CD163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy. J Pathol 2002; 196: 343-50.        [ Links ]

26. Baeten D, Demetter P, Cuvelier C, Van Den Bosch F, Kruithof E, Van Damme N, et al. Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity. Ann Rheum Dis 2000; 59: 945-53.        [ Links ]

27. Smeets TJ, Dolhain RJ, Breedveld FC, Tak PP. Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis. J Pathol 1998; 186: 75-81.        [ Links ]

28. Hermann E, Yu DT, Meyer zum Buschenfelde KH, Fleischer B. HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 1993; 342: 646-50.        [ Links ]

29. Mattila L, Leirisalo-Repo M, Koskimies S, Granfors K, Siitonen A. Reactive arthritis following an outbreak of Salmonella infection in Finland. Br J Rheumatol 1994; 33: 1136-41.        [ Links ]

30. Orchard TR, Jewell DP. The importance of ileocaecal integrity in the arthritic complications of Crohn's disease. Inflamm Bowel Dis 1999; 5: 92-7.        [ Links ]

31. Karimi O, Pena AS. Probiotics: isolated bacteria strain or mixtures of different strains? Two different approaches in the use of probiotics as therapeutics. Drugs Today (Barc) 2003; 39: 565-97.        [ Links ]

32. O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005; 128: 541-51.        [ Links ]

33. Spiller R. Probiotics: an ideal anti-inflammatory treatment for IBS? Gastroenterology 2005; 128: 783-5.        [ Links ]

34. Berg RD. Probiotics, prebiotics or 'conbiotics'? Trends Microbiol 1998; 6: 89-92.        [ Links ]

35. Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr 2004; 80: 245-56.        [ Links ]

36. Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003; 124: 1202-9.        [ Links ]

37. Karimi O, Peña AS, van Bodegraven AA. Probiotics (VSL#3) in Arthralgia. Preliminary results of an ongoing open trial in patients with ulcerative colitis and Crohn disease. Gastroenterology (abstract presented at the digestive disease weeks of the America Gastroenterology Association) 2004; 126: A-627.        [ Links ]

38. Karimi O, Peña AS, van Bodegraven AA. Probiotics (VSL#3) in Arthralgia. Preliminary results of an ongoing open trial in patients with ulcerative colitis and Crohn disease. Drugs of Today 2005; 41 (7): 000-00038.        [ Links ]

39. Baharav E, Mor F, Halpern M, Weinberger A. Lactobacillus GG bacteria ameliorate arthritis in Lewis rats. J Nutr 2004; 134: 1964-9.        [ Links ]

40. Nurmi JT, Puolakkainen PA, Rautonen NE. Bifidobacterium Lactis sp. 420 Up-Regulates Cyclooxygenase (Cox)-1 and Down-Regulates Cox-2 Gene Expression in a Caco-2 Cell Culture Model. Nutr Cancer 2005; 51: 83-92.        [ Links ]

41. Korhonen R, Kosonen O, Korpela R, Moilanen E. The expression of COX2 protein induced by Lactobacillus rhamnosus GG, endotoxin and lipoteichoic acid in T84 epithelial cells. Lett Appl Microbiol 2004; 39: 19-24.        [ Links ]

42. Kaufmann HJ, Taubin HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-6.        [ Links ]

43. Aabakken L, Osnes M. Non-steroidal anti-inflammatory drug-induced disease in the distal ileum and large bowel. Scand J Gastroenterol Suppl 1989; 163: 48-55.        [ Links ]

44. Hayllar J, Bjarnason I. NSAIDs, Cox-2 inhibitors, and the gut. Lancet 1995; 346: 521-2.        [ Links ]

45. Newberry RD, Stenson WF, Lorenz RG. Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 1999; 5: 900-6.        [ Links ]

46. Grishin A, Wang J, Hackam D, Qureshi F, Upperman J, Zamora R, et al. p38 MAP kinase mediates endotoxin-induced expression of cyclooxygenase-2 in enterocytes. Surgery 2004; 136: 329-35.        [ Links ]

47. Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem 2002; 277: 50959-65.        [ Links ]

48. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005; 52: 582-91.        [ Links ]

49. Baeten D, Kruithof E, Van den Bosch F, Demetter P, Van Damme N, Cuvelier C, et al. Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: histologic findings in eight patients from an open-label pilot study. Arthritis Rheum 2001; 44: 186-95.        [ Links ]

50. Paul S, Keat A. Assessment of patients with spondyloarthropathies for treatment with tumour necrosis factor alpha blockade. Rheumatology (Oxford) 2005; 44: 17-23.        [ Links ]

51. Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001; 121: 580-91.        [ Links ]

52. Petrof EO, Kojima K, Ropeleski MJ, Musch MW, Tao Y, De Simone C, et al. Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 2004; 127: 1474-87.        [ Links ]

53. Montgomery RD. Side effects of carbenoxolone sodium: a study of ambulant therapy of gastric ulcer. Gut 1967; 8: 148-50.        [ Links ]

54. Mitchison A, Sieper J. Immunological basis of oral tolerance. Z Rheumatol 1995; 54: 141-4.        [ Links ]

55. Isolauri E, Majamaa H, Arvola T, Rantala I, Virtanen E, Arvilommi H. Lactobacillus casei strain GG reverses increased intestinal permeability induced by cow milk in suckling rats. Gastroenterology 1993; 105: 1643-50.        [ Links ]

56. Ulisse S, Gionchetti P, D'Alo S, Russo FP, Pesce I, Ricci G, et al. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am J Gastroenterol 2001; 96: 2691-9.        [ Links ]

57. Di Giacinto C, Marinaro M, Sánchez M, Strober W, Boirivant M. Probiotics Ameliorate Recurrent Th1-Mediated Murine Colitis by Inducing IL-10 and IL-10-Dependent TGF-{beta}-Bearing Regulatory Cells. J Immunol 2005; 174: 3237-46.        [ Links ]

58. Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, Vaara M, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 2003; 36: 775-80.        [ Links ]

59. Madsen KL, Malfair D, Gray D, Doyle JS, Jewell LD, Fedorak RN. Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis 1999; 5: 262-70.        [ Links ]