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The physiopathology of chronic inflammatory intestinal diseases has proven to be not only complex but also complex and multi-factorial: in addition to genetic factors, it also involves environmental factors. More specifically, there has been talk of changes in the composition of the intestinal microflora and an alteration in the immune response against the resident intestinal flora.
The challenge is thus to know whether modulating the intestinal microflora through prebiotics, probiotics and/or synbiotics can have a preventive and/or curative effect on CIID.
PREBIOTICS, PROBIOTICS, SYNBIOTICS: DEFINITIONS
- Prebiotics
Prebiotics have been defined as ”non-digestible food ingredients that selectively stimulate the multiplication or activity of one or a limited number of bacterial groups in the colon, likely to improve the host’s physiology.” (Gibson 1995;Schrezenmeir 2001).
In order to fill this role, prebiotics must meet three criteria: first of all, this natural product must be neither hydrolyzed nor absorbed in the upper part of the gastro-intestinal tract, so as to be able to reach the microflora of the colon.
Secondly, in order to positively alter both the composition and activity of the gastro-intestinal microflora, prebiotics must be selectively fermented by one or a limited number of potentially beneficial bacteria in the colon.
Finally, prebiotics must preferentially induce beneficial health effects that can be demonstrated on human volunteer subjects.
The molecules that, to date, have satisfied these criteria are inulins, galactooligosaccharides
(GOS) and lactulose.
They are part of the composition of certain foods and dietary supplements. Inulins are combinations of oligo- and polysaccharides essentially consisting of fructose. The terms fructooligosaccharides (FOS) and oligofructose are used for inulins with low molecular weight. Other candidates exist (isomalto-oligosaccharides, lactosucrose, xylo-oligosaccharides, soy oligosaccharides, gluco-oligosaccharides,
Arabic gum, pectin hydrolysates, etc.) which have undergone or are currently undergoing preliminary testing, without having satisfied the above criteria as yet.
- Probiotics
A probiotic is a “living micro-organism that, when consumed in adequate amounts, produces a benefit for the host’s health” (FAO / WHO,
2001). The leading micro-organisms categorized as pro- Biotics are lactobacilli, bifidobacteria, Escherichia coli and Saccharomyces
Boulardii yeast. Probiotics are used either in the form of pure and characterized strains
(Lactobacillus casei DN-114 001, Lactobacillus casei Shirota, Lactobacillus rhamnosus GG, Bifidobacterium lactis Bb12, Bifidobacterium lactis DN-173 010, etc.) or in the form of mixtures of characterized strains incorporated into foods, dietary supplements or medicine.
Contrary to prebiotics, which constitute a very homogenous family, probiotics are known to have widely strain-specific effects, so that the results of a given study must refer solely to the strain used. The two compounds also differ in their mode of action on the intestinal flora. Prebiotics promote the growth of one or a few resident species. They work through this modification of the microflora.
In the case of probiotics, the observed effects are directly explained by the introduction of a new bacterial strain in the microflora (box 1).
- Prebiotics
Prebiotics have been defined as ”non-digestible food ingredients that selectively stimulate the multiplication or activity of one or a limited number of bacterial groups in the colon, likely to improve the host’s physiology.” (Gibson 1995;Schrezenmeir 2001).
In order to fill this role, prebiotics must meet three criteria: first of all, this natural product must be neither hydrolyzed nor absorbed in the upper part of the gastro-intestinal tract, so as to be able to reach the microflora of the colon.
Secondly, in order to positively alter both the composition and activity of the gastro-intestinal microflora, prebiotics must be selectively fermented by one or a limited number of potentially beneficial bacteria in the colon.
Finally, prebiotics must preferentially induce beneficial health effects that can be demonstrated on human volunteer subjects.
The molecules that, to date, have satisfied these criteria are inulins, galactooligosaccharides
(GOS) and lactulose.
They are part of the composition of certain foods and dietary supplements. Inulins are combinations of oligo- and polysaccharides essentially consisting of fructose. The terms fructooligosaccharides (FOS) and oligofructose are used for inulins with low molecular weight. Other candidates exist (isomalto-oligosaccharides, lactosucrose, xylo-oligosaccharides, soy oligosaccharides, gluco-oligosaccharides,
Arabic gum, pectin hydrolysates, etc.) which have undergone or are currently undergoing preliminary testing, without having satisfied the above criteria as yet.
- Probiotics
A probiotic is a “living micro-organism that, when consumed in adequate amounts, produces a benefit for the host’s health” (FAO / WHO,
2001). The leading micro-organisms categorized as pro- Biotics are lactobacilli, bifidobacteria, Escherichia coli and Saccharomyces
Boulardii yeast. Probiotics are used either in the form of pure and characterized strains
(Lactobacillus casei DN-114 001, Lactobacillus casei Shirota, Lactobacillus rhamnosus GG, Bifidobacterium lactis Bb12, Bifidobacterium lactis DN-173 010, etc.) or in the form of mixtures of characterized strains incorporated into foods, dietary supplements or medicine.
Contrary to prebiotics, which constitute a very homogenous family, probiotics are known to have widely strain-specific effects, so that the results of a given study must refer solely to the strain used. The two compounds also differ in their mode of action on the intestinal flora. Prebiotics promote the growth of one or a few resident species. They work through this modification of the microflora.
In the case of probiotics, the observed effects are directly explained by the introduction of a new bacterial strain in the microflora (box 1).
BOX 1: PREBIOTIC AND PROBIOTIC MECHANISMS OF ACTION
- Synbiotics
Synbiotics are defined as products containing both Prebiotic(s) and Probiotic(s). The presence of Prebiotic(s) has a beneficial effect on both the stability of the Probiotic(s) in the product and its survival after introduction in the gastro-intestinal tract, throughout the presence of the Prebiotic.
STUDIES WITH MIXED RESULTS
- Prebiotics
Various forms of inulin have been evaluated in various experimental models and human clinical studies. These studies were intended to test the effectiveness of prebiotics in either the prevention or improvement of the symptoms associated with the leading inflammatory intestinal disorders.
Experimental studies used animal models: rats treated with dextran sulphate (CHR model), rats treated with trinitrobenzene sulphonate (Crohn’s disease model) and transgenic rats HLA-B27 (spontaneously developing an intestinal inflammation).
These studies showed modifications in the caecum and colon flora with an increase in bifidobacteria and lactobacilli (Prebiotic effect), an increase in the concentration of anti-inflammatory cytokines and immuno-modulating factors in the caecum mucosa, a reduction in the secretion of pro-inflammatory cytokines, and a reduction in the clinical signs of colitis and the overall and histological scores of inflammation.
Human studies have concerned Crohn’s disease, pouchitis and, indirectly, CHR.
For Crohn’s disease, a preliminary study on ten patients confirmed the Prebiotic effect of inulin, which increases the faecal concentration of bifidobacteria.
The study also demonstrated an increase (+76%) in the number of dendritic cells producing interleukin-10 (anti-inflammatory cytokine). These variations are accompanied by an improvement in the clinical gravity factor.
For CHR, no clinical results are available to date in patients suffering form a declared disorder. Nonetheless, a preliminary study (double blind, controlled against a placebo) has demonstrated that oligofructose (3 x 4 g/day), administered alone or in association with metronidazole(400 mg/day), could, in healthy individuals carrying sulphate-reducing bacteria, reduce the production of sulphydric acid (H2S). Indeed, this could play a role in the inflammation observed in this disorder. Parallel to this beneficial effect on the production of a toxic metabolite, the administration of oligofructose increases the faecal concentration of bifidobacteria and volatile fatty acids, and reduces the faecal pH balance.
In pouchitis, inflammation is associated with a reduction in the faecal concentration of butyrate, an increased in the pH in the stools, changes in the composition of the faecal flora and increased faecal concentration of secondary biliary acids.
During a randomized preliminary clinical study conducted double blind against placebo, 20 patients received 24 g/day of inulin for three weeks.
The effectiveness was evaluated based on the composition of the stools and the endoscopic and histological aspects of the mucosa. The results showed an increase in the concentration of faecal butyrate (+62%), a drop in the faecal pH balance, a reduction in the number of Bacteroides, and a reduction in the faecal concentration of secondary biliary acids (-62%), associated with a reduction in the severity of endoscopic and histological signs of inflammation.
- Probiotics
Several probiotics or combinations of probiotics have been evaluated in various experimental models and human clinical studies.
In the experimental studies, three models were used: mice deficient in interleukin-10 (“knockout” mice), rats treated with trinitrobenzene sulphonate (Crohn’s disease model), and rats treated with dextran sulphate
(CHR model). These studies show a preventive or curative effect of colitis by various strains of the lactobacillus, a restoration of the barrier effect in the inflammation damaged mucosa, and prevention of the biochemical and cytological changes induced by inflammation.
Human studies have concerned Crohn’s disease, pouchitis and hemorrhagic rectocolitis. For Crohn’s disease, six clinical studies have evaluated the effect of a Probiotic treatment or a treatment combining a drug with a Probiotic on remission at 6, 12 or 24 months.
These studies were conducted on various strains:
Escherichia coli (one study), Saccharomyces boulardii (one study) and Lactobacillus (four studies). None of these treatments have shown statistically significant effects.
In CHR, the probiotics were studied alone or in association with medicinal products. Three studies evaluating the effect of a treatment with Probiotics alone (Escherichia coli) on remission at three or twelve months did not furnish statistically significant results. Similarly, three clinical studies associating medicinal treatment with a blend of probiotics on remission at two or twelve months or the clinical index at three did not provide conclusive data regarding a significant systemic effect. Nevertheless, the association between medicine and bifidobacteria has shown, in two studies, statistically significant effects on the morbidity index at 3 months (3.7 vs. 5.8) and the remission rate at 12 months (70 vs. 10%). Regarding pouchitis, three studies were conducted to evaluate the effect of a mixture of probiotics (VSL#3) on remission or prevention of the disease: it increases the remission rate at 9 months (85 vs. 0%) and 12 months (85 vs. 6%) and prevents the appearance of pouchitis (90 vs. 60%). By contrast, one study intended to evaluate the effect of a single strain of Probiotics (Lactobacillus rhamnosus GG) on the morbidity index at 3 months did not show statistically significant effects.
- Synbiotics
To date, only one study has tested the effectiveness of a symbiotic (Bifidobacterium longum plus inulin) in the evolution of parameters associated with CHR. In this protocol, 18 patients (aged from 24 to 67) received a synbiotic and a placebo for four weeks. The results showed an improvement in the histological integrity of the mucosa, a reduction in the concentration of pro-inflammatory cytokines defensins (anti-bacterial peptides over-expressed in CHR), and a significant increase in faecal bifidobacteria.
Synbiotics are defined as products containing both Prebiotic(s) and Probiotic(s). The presence of Prebiotic(s) has a beneficial effect on both the stability of the Probiotic(s) in the product and its survival after introduction in the gastro-intestinal tract, throughout the presence of the Prebiotic.
STUDIES WITH MIXED RESULTS
- Prebiotics
Various forms of inulin have been evaluated in various experimental models and human clinical studies. These studies were intended to test the effectiveness of prebiotics in either the prevention or improvement of the symptoms associated with the leading inflammatory intestinal disorders.
Experimental studies used animal models: rats treated with dextran sulphate (CHR model), rats treated with trinitrobenzene sulphonate (Crohn’s disease model) and transgenic rats HLA-B27 (spontaneously developing an intestinal inflammation).
These studies showed modifications in the caecum and colon flora with an increase in bifidobacteria and lactobacilli (Prebiotic effect), an increase in the concentration of anti-inflammatory cytokines and immuno-modulating factors in the caecum mucosa, a reduction in the secretion of pro-inflammatory cytokines, and a reduction in the clinical signs of colitis and the overall and histological scores of inflammation.
Human studies have concerned Crohn’s disease, pouchitis and, indirectly, CHR.
For Crohn’s disease, a preliminary study on ten patients confirmed the Prebiotic effect of inulin, which increases the faecal concentration of bifidobacteria.
The study also demonstrated an increase (+76%) in the number of dendritic cells producing interleukin-10 (anti-inflammatory cytokine). These variations are accompanied by an improvement in the clinical gravity factor.
For CHR, no clinical results are available to date in patients suffering form a declared disorder. Nonetheless, a preliminary study (double blind, controlled against a placebo) has demonstrated that oligofructose (3 x 4 g/day), administered alone or in association with metronidazole(400 mg/day), could, in healthy individuals carrying sulphate-reducing bacteria, reduce the production of sulphydric acid (H2S). Indeed, this could play a role in the inflammation observed in this disorder. Parallel to this beneficial effect on the production of a toxic metabolite, the administration of oligofructose increases the faecal concentration of bifidobacteria and volatile fatty acids, and reduces the faecal pH balance.
In pouchitis, inflammation is associated with a reduction in the faecal concentration of butyrate, an increased in the pH in the stools, changes in the composition of the faecal flora and increased faecal concentration of secondary biliary acids.
During a randomized preliminary clinical study conducted double blind against placebo, 20 patients received 24 g/day of inulin for three weeks.
The effectiveness was evaluated based on the composition of the stools and the endoscopic and histological aspects of the mucosa. The results showed an increase in the concentration of faecal butyrate (+62%), a drop in the faecal pH balance, a reduction in the number of Bacteroides, and a reduction in the faecal concentration of secondary biliary acids (-62%), associated with a reduction in the severity of endoscopic and histological signs of inflammation.
- Probiotics
Several probiotics or combinations of probiotics have been evaluated in various experimental models and human clinical studies.
In the experimental studies, three models were used: mice deficient in interleukin-10 (“knockout” mice), rats treated with trinitrobenzene sulphonate (Crohn’s disease model), and rats treated with dextran sulphate
(CHR model). These studies show a preventive or curative effect of colitis by various strains of the lactobacillus, a restoration of the barrier effect in the inflammation damaged mucosa, and prevention of the biochemical and cytological changes induced by inflammation.
Human studies have concerned Crohn’s disease, pouchitis and hemorrhagic rectocolitis. For Crohn’s disease, six clinical studies have evaluated the effect of a Probiotic treatment or a treatment combining a drug with a Probiotic on remission at 6, 12 or 24 months.
These studies were conducted on various strains:
Escherichia coli (one study), Saccharomyces boulardii (one study) and Lactobacillus (four studies). None of these treatments have shown statistically significant effects.
In CHR, the probiotics were studied alone or in association with medicinal products. Three studies evaluating the effect of a treatment with Probiotics alone (Escherichia coli) on remission at three or twelve months did not furnish statistically significant results. Similarly, three clinical studies associating medicinal treatment with a blend of probiotics on remission at two or twelve months or the clinical index at three did not provide conclusive data regarding a significant systemic effect. Nevertheless, the association between medicine and bifidobacteria has shown, in two studies, statistically significant effects on the morbidity index at 3 months (3.7 vs. 5.8) and the remission rate at 12 months (70 vs. 10%). Regarding pouchitis, three studies were conducted to evaluate the effect of a mixture of probiotics (VSL#3) on remission or prevention of the disease: it increases the remission rate at 9 months (85 vs. 0%) and 12 months (85 vs. 6%) and prevents the appearance of pouchitis (90 vs. 60%). By contrast, one study intended to evaluate the effect of a single strain of Probiotics (Lactobacillus rhamnosus GG) on the morbidity index at 3 months did not show statistically significant effects.
- Synbiotics
To date, only one study has tested the effectiveness of a symbiotic (Bifidobacterium longum plus inulin) in the evolution of parameters associated with CHR. In this protocol, 18 patients (aged from 24 to 67) received a synbiotic and a placebo for four weeks. The results showed an improvement in the histological integrity of the mucosa, a reduction in the concentration of pro-inflammatory cytokines defensins (anti-bacterial peptides over-expressed in CHR), and a significant increase in faecal bifidobacteria.
TABLE 2: EXPERIMENTAL STUDY RESULTS ON THE EFFECTS OF PREBIOTICS, PROBIOTICS AND SYNBIOTICS IN INFLAMMATORY INTESTINAL DISORDERS
TABLE 3: CLINICAL STUDY RESULTS ON THE EFFECTS OF PREBIOTICS, PROBIOTICS and SYNBIOTICS IN INFLAMMATORY INTESTINAL DISORDERS
Conclusion
Experimental data available both for prebiotics and probiotics draw promising perspectives with respect to these products’ benefits in the prevention and/or improvement of the symptoms of inflammation.
Nonetheless, hopes are not always confirmed by clinical studies.
Results for probiotics are relatively mitigated given that, among all tested treatments, only a mixture of probiotics (VSL#3) and an association of probiotics (bifidobacteria) + and medicine have demonstrated clinical effectiveness in pouchitis and CHR respectively.
For prebiotics (exclusively inulins) and a symbiotic (inulin and bifidobacteria), results, though preliminary, appear encouraging. Indeed, regarding Crohn’s disease and pouchitis in the case of the Prebiotic and CHR in the case of the synbiotic, these products have confirmed their clinical effectiveness generally accompanied by beneficial effects on various histological and biochemical parameters. These studies were considered sufficiently promising in order to justify the interest of clinicians. Several multi-centre clinical studies on large cohorts of patients are currently being planned.
Experimental data available both for prebiotics and probiotics draw promising perspectives with respect to these products’ benefits in the prevention and/or improvement of the symptoms of inflammation.
Nonetheless, hopes are not always confirmed by clinical studies.
Results for probiotics are relatively mitigated given that, among all tested treatments, only a mixture of probiotics (VSL#3) and an association of probiotics (bifidobacteria) + and medicine have demonstrated clinical effectiveness in pouchitis and CHR respectively.
For prebiotics (exclusively inulins) and a symbiotic (inulin and bifidobacteria), results, though preliminary, appear encouraging. Indeed, regarding Crohn’s disease and pouchitis in the case of the Prebiotic and CHR in the case of the synbiotic, these products have confirmed their clinical effectiveness generally accompanied by beneficial effects on various histological and biochemical parameters. These studies were considered sufficiently promising in order to justify the interest of clinicians. Several multi-centre clinical studies on large cohorts of patients are currently being planned.
References
- Bibiloni R, Fedorak RN, Tannock GWet al. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. AmJ Gastroenterol. 2005 ; 100 : 1539- 46.
- Furet JP, Relano P, Langella Ph. Corthier G. Les probiotiques consommés comme aliments ou compléments alimentaires, in : Les aliments fonctionnels, M. Roberfroid, V. Coxam, N. Delzenne, éditeurs, Lavoisier in press.
- Gibson GR, RoberfroidMB. Dietarymodulation of the colonic microbiota : introducing the concept of prebiotics. J. Nutr 1995 ; 125 : 1401-1412.
- Gibson GR, Probert HM, Van Loo JAE, Rastall RA, RoberfroidMB. Dietarymodulation of the human colonicmicrobiota : updating the concept of prebiotics, Nutr. Res. Rev. 2004 ; 17 : 259-275.
- Kato K,Mizuno S, Umesaki Y et al. Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermentedmilk on active ulcerative colitis. Aliment. Pharmacol. Ther. 2004 ; 15 : 1133 - 41.
- Leenen C, Dieleman LA. Inulin and oligofructose in chronic inflammatory bowel disease, J. Nutr. 2007 ; In press.
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