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Probiotics and barrier function in colitis
  1. P Gionchetti,
  2. K M Lammers,
  3. F Rizzello,
  4. M Campieri
  1. Policlinic S Orsola, University of Bologna, Department of Internal Medicine and Gastroenterology, Bologna, Italy
  1. Correspondence to:
    Dr P Gionchetti
    Policlinic Sant’Orsola, Department of Internal Medicine and Gastroenterology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; paolomed.unibo.it

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Probiotic administration may exert a protective effect in colitis by preventing mucosal barrier disruption and influencing the extent of mucosal injury

There is strong evidence of a role for the indigenous flora in driving inflammatory responses in inflammatory bowel disease (IBD) in genetically predisposed individuals.1 For years, researchers have tried in vain to identify a specific pathogen as the cause of these chronic intestinal inflammatory disorders but the possibility that one or more bacterial agents are responsible cannot be ruled out. Considering the implications of a pathogen in IBD, as yet undiscovered due to technical limitations, it was hypothesised that modulation of an abnormal microflora in these patients by introducing high titres of ”protective” bacteria might overwhelm the ”aggressive” strain(s) and inhibit its deleterious effects. On this basis, probiotic treatment was proposed as a therapeutic approach.2

Probiotics are defined as “living organisms which, on ingestion in certain numbers, exert health benefits beyond inherent basic nutrition”.3 Bacteria associated with probiotic activity are most commonly lactobacilli, bifidobacteria, and streptococci but other non-pathogenic bacteria such as some strains of Escherichia coli and microorganisms such as the yeast Saccharomyces boulardii have been used in IBD.

Encouraging results have been obtained with probiotics in several experimental animal models of IBD.4–7 In humans, probiotics are effective in the prevention of pouchitis onset and relapse.8,9,10 Results in ulcerative colitis are promising, both in prevention of relapse and treatment of mild to moderate attacks.11–13 Results in Crohn’s disease are not yet clear because of conflicting data and the limited number of well performed studies.14–16

Efforts are being made by many researchers to unravel the precise mechanisms by which probiotic bacteria and their metabolic products (short chain fatty acids, vitamins) exert their beneficial effects. Several mechanisms have been proposed to account for probiotic action. These include: (a) antagonistic activity against pathogenic bacteria by competing for binding sites17,18; (b) stimulation of mucosal defence at the level of both immune and epithelial function, by increasing sIgA production,19 decreasing proinflammatory and increasing anti-inflammatory cytokine levels,20–26 and inducing production of protective substances by the epithelium, such as antimicrobial peptides (bacteriocins) and hydrogen peroxide, mucins,17,27 and heat shock proteins,28 respectively; and (c) inhibition of bacterial translocation and reinforcement of barrier function20,21 by mechanisms that have yet to be established in detail.

The paper presented in this issue of Gut29 describes the effect of modulation of the microflora by Lactobacillus casei on disease course and extent in the trinitrobenzene sulphonic acid (TNBS) model of experimental colitis (see page 955). The elegance of this study lies in the experimental set up, which allowed controlled mucosal colonisation with indigenous flora and selected bacterial strains after removal of the native flora by antibiotics, and in the straightforward hypothesis and performance of the study; TNBS exerted a direct toxic effect on epithelial cells and disrupted the intestinal barrier, and the effect of L casei on impaired barrier function and bacterial translocation in the TNBS model was examined. Colonisation of bacterial strains, measure of bacterial translocation, neutrophil tissue influx, and degree of inflammation were evaluated.

The data from this study suggest that L casei administration exerts a protective effect by preventing barrier disruption by TNBS, as translocation of bacteria to mesenteric lymph nodes was significantly reduced in rats colonised with standard rat flora and L casei compared with rats colonised with only standard rat flora. L casei intervention influenced further extension of mucosal injury induced by TNBS, but not the nature of the colonic lesions (transmural lesions were similar in depth compared with TNBS colitis), and resulted in lower myeloid peroxidase activity, a measure of tissue neutrophil infiltration.

The exact mechanisms by which probiotics can influence barrier function remain to be elucidated. It is known that certain lactobacilli adhere to mucosal surfaces, inhibit attachment of pathogenic bacteria, and enhance secretion of mucins.17,18,27 These properties may be instrumental in improving mucosal barrier function and decreasing permeability to macromolecules and toxins. Recently it has been shown that a mixture of probiotic bacteria, in addition to decreasing proinflammatory cytokines—which increase intestinal permeability (interferon γ) and induce a cascade of inflammatory events (interleukin (IL)-1β, tumour necrosis factor α, IL-8) resulting in mucosal injury by invading immune cells (neutrophils, tissue macrophages, dendritic cells20–26—reinforce barrier function by secretion of soluble factors that enhance barrier integrity and by regulation of tight junctions (TJ).20,21 TJ are dynamic structures which represent the major barrier within the paracellular pathway and regulate in a rapid and coordinated way paracellular permeability. Many pathogenic bacteria modulate intestinal permeability by alteration of TJ.30 Probiotics prevent Salmonella induced alteration of the distribution of the TJ protein zonula occludens 1 and Salmonella induced enhanced permeability by increasing transepithelial resistance and decreasing mannitol flux.20,21

Maintenance of epithelial barrier function is essential for the preservation of mucosal integrity. Altered TJ structure in ulcerative colitis results in impaired barrier function.31 Increased permeability in IBD is observed during the active phase of the disease and therefore reinforcement of barrier function, together with their immune modulatory and metabolic properties, may be central in the mechanism of action of probiotic bacteria. Further investigations on how probiotics regulate the TJ complex and influence intestinal permeability are warranted.

Probiotic administration may exert a protective effect in colitis by preventing mucosal barrier disruption and influencing the extent of mucosal injury

REFERENCES

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  • Conflict of interest: None declared.

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