Volume 43 Number 6 2008

Probiotics and Prebiotics as Functional Ingredients in Inflammatory Bowel Disease

Mirjam A.C. Looijer-van Langen MD Nutrition Today Vimal Prajapati November/December 2008 Levinus A. Dieleman MD, PhD Volume 43 Number 6 Pages 235 - 242 Abstract Probiotics and prebiotics are promising nutraceuticals that may exert a beneficial effect in many medical conditions including inflammatory bowel disease. With the increasing occurrence of antibiotic resistance, the search for medication with little side effects, and the need for options for patients with inflammatory bowel disease who are unresponsive to current therapies, research into alternative therapeutic options is justified. Preclinical studies have provided insights into the effects of probiotics and prebiotics on the immune system and gut microbiota. This new information, along with the older evidence, shows that probiotics and prebiotics may ameliorate chronic intestinal inflammation. This article gives a short overview on current knowledge of probiotics and prebiotics.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders that include Crohn disease (CD), ulcerative colitis (UC), and chronic pouchitis. Crohn disease can affect the entire gastrointestinal tract anywhere from mouth to anus. The chronic inflammation is not limited to the lining of the bowel but affects the entire bowel wall, sometimes resulting in intra-abdominal abscesses and fistula (abnormal connections between the lumen of the bowel, other organs, or the surface of the skin) and intestinal obstruction. Patients typically experience symptoms of mild diarrhea, right lower quadrant pain, and low-grade fever. Ulcerative colitis is limited to the colon, and patients experience rectal bleeding, abdominal pain, and diarrhea. The inflammation in UC is confined to the upper layer of the colonic wall and the mucosa. Patients with CD and those with UC both experience periods of remission and relapses. Chronic pouchitis is a chronic inflammation of the ileoanal pouch. An ileoanal pouch is an internal reservoir, constructed for patients with UC who have had their large intestine surgically removed mostly because of severe inflammation refractory to medical treatment. Patients with pouchitis typically present with bloody diarrhea, urgency in passing stools, or discomfort while passing stools. Rarely, pain occurs with pouchitis. Inflammatory bowel disease is caused by multiple factors that disturb intestinal homeostasis. An abnormal immune response to commensal bacteria or dietary factors in genetically susceptible hosts plays a major role in the pathogenesis. Environmental factors including psychological stress, use of nonsteroidal anti-inflammatory drugs, and cigarette smoking can also contribute to IBD. The current treatment of IBD mainly consists of drugs directed against the overactive adaptive immune response, Nutrition Today Page 1

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such as 5-aminosalicylic acid compounds, steroids, azathioprine/6-mercaptopurine, methotrexate, cyclosporine, and biologics such as infliximab. Most patients respond well to these medications, but for some, it is inadequate or induces intolerable adverse effects. Therefore, interest has been raised in nutraceutical therapies such as probiotics, prebiotics, or a combination of these, called synbiotics, as a good therapeutic option for nonresponding patients with IBD.

The concept that ingestion of certain bacteria may promote health is not new. Fermented milk products have been consumed by human beings for thousands of years with the belief that they provide health benefits. For example, according to Persian tradition, Abraham of the Old Testament owed his longevity to sour milk. In the early 20th century, the Russian immunologist, Elie Metchnikoff, proposed that ingestion of lactic acid bacteria promoted health and longevity of life. He based his theory on the observation that Bulgarians who consumed large quantities of fermented milk lived longer than those who did not. Around the same time, the first attempt to treat disease with bacteria was made by Dr Henry Tissier, a French pediatrician, who discovered Y-shaped or "bifid" bacteria (now known as Bifidobacterium) and recommended administration of isolated bifid cultures to infants with diarrhea to help restore a healthy gut flora. Metchnikoff and Tissier are largely credited for being the first individuals to make scientific suggestions about probiotic bacteria, although the term probiotic was not coined until 1965. The term probiotic, which literally means "for life," was first introduced by Lilly and Stillwell in 1965 to describe "substances produced by one microorganism which stimulate the growth of another." Since that time, the definition has undergone many revisions. In an attempt to provide an agreed upon definition, a joint Food and Agricultural Organization/World Health Organization Expert Consultation Nutrition Today Page 2

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redefined probiotics as "live microorganisms which when administered in adequate amounts confer a health benefit on the host." Currently, this is the most widely accepted definition. Probiotics can be bacteria or yeast, although the vast majority is bacteria. The most common bacteria used as probiotics are lactic acid bacteria from the genera Lactobacillus and Bifidobacterium. Certain species from other genera such as Streptococcus, Enterococcus, and Escherichia have also been used but to a lesser extent. The only yeast that is considered a probiotic is Saccharomyces boulardii (Table 1). Probiotics are available in a variety of food products, especially dairy products such as yogurt, milk, cottage cheese, and dietary supplement products. Dietary supplements containing freeze-dried probiotics in capsule, powder, or tablet form are becoming a popular choice. Table 1. Common Probiotic Organisms Multiple mechanisms of action have been postulated to account for the beneficial effects of probiotics in IBD. In broad terms, probiotics are thought to improve the epithelial barrier function of the intestine, alter the composition of the intestinal microflora, and modulate the immune response of the intestinal mucosa. However, the exact mechanism is likely to vary from one probiotic organism to another (Table 2). Table 2. Proposed Benefits of Probiotics to the Well-being and Health of the Animal Host Normal epithelial barrier function of the intestine requires an intact layer of epithelial cells and an adequate production of overlying mucus to prevent uptake of potentially harmful organisms and substances into the body. A disrupted and leaky intestinal epithelial barrier may be one of the initiating events in the pathogenesis of IBD. In addition, increased apoptosis (programmed cell death) of intestinal epithelial cells and decreased mucus production have been documented in patients with IBD and are thought to contribute to the pathogenesis. Several probiotics have demonstrated the ability to enhance the epithelial barrier function of the intestine. For example, Lactobacillus rhamnosus GG improves barrier function by inhibiting apoptosis of intestinal epithelial cells. Streptococcus salivarius subsp thermophilus and Lactobacillus acidophilus have been shown to enhance the tight junctions between epithelial cells, thereby preventing infection from the invasion of pathogenic bacteria such as enteroinvasive Escherichia coli. Also, several Lactobacillus strains have been found to increase mucus production. Madsen showed that a synthetic probiotic mixture, VSL#3 (containing 4 Lactobacillus spp, 3 Bifidobacterium spp, and S salivarius subsp thermophilus), also restored the epithelial barrier function in a chronic colitis mouse model. The improvement of the barrier function is probably the result of a direct effect of probiotic bacteria or their secreted bacterial products. Normally, there is a balance between the beneficial bacterial species and the detrimental bacterial species that make up the intestinal microflora. In IBD, a number of genetic and environmental factors are thought to upset this balance such that there is a relative predominance of detrimental diseaseinducing bacteria that contribute to the chronic inflammatory process in IBD. Probiotics can help restore a healthy intestinal microflora by directly increasing the population of beneficial bacteria and by suppressing the growth and function of detrimental bacteria. For example, Bifidobacterium infantis

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has been shown to suppress the growth of Bacteroides vulgatus, a pathogenic microbe possibly responsible for the induction and perpetuation of IBD. Probiotic organisms can inhibit pathogenic bacteria in several ways. First of all, they competitively exclude pathogens by occupying the limited physical space available for colonization in the gut. In addition, probiotic organisms can either directly secrete antimicrobial substances (eg, organic acids, hydrogen peroxide, and bacteriocins) and/or stimulate host intestinal cells to secrete antimicrobial substances (ie, defensin molecules), which destroy pathogens before they can colonize the gut. Several probiotics have demonstrated the ability to prevent epithelial adhesion and invasion of pathogenic bacteria. For example, E coli Nissle 1917 inhibits epithelial adhesion and invasion of a pathogenic E coli strain isolated from patients with CD. Inflammatory bowel disease is thought to be caused by an overly aggressive immune response to the endogenous gut microflora in genetically susceptible individuals. This results in an increased production of chemical signals that promote inflammation. These proinflammatory cytokines include, for example, tumor necrosis factor [alpha] and interferon [gamma]. Anti-inflammatory cytokines are interleukin 10 and transforming growth factor [beta]. Probiotic organisms are generally thought to modify the immune system of the intestinal mucosa by reducing the production of proinflammatory cytokines and increasing the production of anti-inflammatory mediators. Studies have shown that Lactobacillus plantarum, L rhamnosus GG, and VSL#3 can increase the production of interleukin 10 and that specific lactobacilli and bifidobacteria species can reduce the production of tumor necrosis factor [alpha] and interferon [gamma]. The mechanisms by which probiotics exert their immunomodulatory effects are complex and beyond the scope of this review. Probiotics are generally well tolerated and have an excellent overall safety record. This is not surprising because many of the organisms used as probiotics are commensal, nonpathogenic inhabitants of the human gut and have been used safely in the production of fermented foods for centuries. The most common adverse effects of probiotics include bloating, flatulence, and constipation. There have been some reports of probiotics inducing serious infections such as bacterial and fungal sepsis. However, these cases occurred in immunocompromised patients. There are no reports of such cases in healthy people. Animal models have been used extensively to study the efficacy of probiotics in treating chronic intestinal inflammation and to elucidate the mechanisms by which probiotics work. Successful reduction of intestinal inflammation in many of these experimental models has provided the support for human clinical trials (Table 3). Escherichia coli Nissle 1917, VSL#3, and bifidobacteria-fermented milk have been shown to have some success at inducing and maintaining remission of UC and reducing disease activity. Table 3. Clinical Studies Testing Probiotics in the Treatment of Human Inflammatory Bowel Disease VSL#3 proved to be effective in maintaining remission of chronic relapsing pouchitis, preventing the development of pouchitis compared with placebo treatment; in addition, it also significantly improved patient quality of life. One study with L rhamnosus GG, however, was ineffective in reducing pouchitis disease activity. Nutrition Today Page 4

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The efficacy of probiotics in CD is still controversial. For example, Lactobacillus salivarius, VSL#3, and S boulardii in combination with conventional therapy (mesalamine) have had some success. On the other hand, there are numerous studies reporting the ineffectiveness of various probiotics in CD.

Because the viability of probiotics in some food products and during transit through the gastrointestinal tract is variable, the prebiotic concept has been developed. Prebiotics are nondigestible short-chain carbohydrates, originally defined as selectively fermented ingredients that allow specific changes, both in the composition and/or activity in the gastrointestinal microflora that confer benefits upon host's well-being and health. Substances are considered prebiotics according to the following conditions: (1) when they are not broken down nor absorbed by enzymes in the upper part of the mammalian gastrointestinal tract, (2) when they are selectively fermented by one or a limited number of potentially beneficial bacteria in the intestine, and (3) when they are able to alter the colonic microflora toward a healthier composition. Prebiotics have become very popular food ingredients. The most commonly used prebiotics, inulin and oligofructose, are natural food ingredients or dietary fibers present in plants as storage carbohydrates. Wheat, chicory, bananas, onions, leeks, Jerusalem artichokes, asparagus, and garlic contain prebiotics. Most commercially used prebiotics are synthesized from sucrose or extracted from chicory roots. They are used in, for example, confectioneries, bakery products, fruit juices, desserts, Nutrition Today Page 5

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spreads, taste improver, sweetener, and fat replacers and sometimes used as viscosity-increasing agents. Inulin and oligofructose, also called [beta]-fructans, are composed of fructose units joined by [beta]glycosidic links. Because of their different fructose chain lengths, inulin and oligofructose are used for different purposes. Inulin has a longer chain length and is therefore less soluble and suitable as a fat replacer. Oligofructose is composed of a shorter chain length of fructose molecules and is, for example, used to replace sugar. Depending on the diet, the daily intake of prebiotics in Western societies varies from 3 to 13 g per day. Many substances are claimed to have prebiotics effects but only fructo-oligosaccharides, galactooligosaccharides, lactulose, and inulin have been shown to meet all 3 before mentioned criteria. Other potential prebiotic candidates are mentioned in Table 4. Table 4. Potential Candidate Prebiotic Substrates Different medical conditions have been speculated to ameliorate upon treatment with prebiotics, including improvement of mineral absorption, reduced risk for colon cancer, improvement of food allergies, alleviation of constipation, regulation of lipid metabolism, and reduction of antibioticinduced diarrhea. The working mechanisms of prebiotics are not fully understood yet, but many theories have been formed (Table 5). In broad terms, the beneficial effects are believed to be due to the stimulation of protective intestinal organisms and the production of short-chain fatty acids (SCFAs) as fermentation products of prebiotics. Table 5. Proposed Benefits of Prebiotics to the Well-being and Health of the Animal Host The intestinal barrier functions to protect the individual from potential bacterial threats. The mucus layer in the gastrointestinal tract plays a major role by preventing the attachment and translocation of bacteria across the epithelial wall. A decrease in mucus production is seen in IBD. Prebiotics have been shown to increase the mucus layer in a rat model of colitis. As mentioned before, intestinal bacteria play an important role in the pathogenesis and attenuation of IBD. Prebiotics change the intestinal microflora in animal models and human studies by increasing the numbers of intestinal protective bacteria, for example, lactobacilli and bifidobacteria, and decreasing the proportion of pathogenic bacteria. Several studies performed in infants confirmed this, showing that the intestinal microbiota of breast-fed infants (containing milk oligosaccharides) is generally dominated by bifidobacteria and lactic acid bacteria. In contrast, formula-fed infants' intestinal microflora contains lower numbers of bifidobacteria and lactic acid bacteria and contains more bacteroides, clostridia, and enterobacteriaceae. However, after the prebiotic diet is stopped, these microflora changes gradually return to baseline levels.

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Short-chain fatty acids include butyrate, acetate, and propionate. Butyrate is the major energy source for colonic epithelial cells and plays an essential role in the maturation of colonic epithelium, regeneration of mucosa, induction of epithelial cell differentiation, and stimulation of their apoptosis. A reduced level of luminal SCFAs may play a role in the onset of IBD. The amount of SCFAs produced in the colon depends on the composition of intestinal microflora, their substrates, and the gut transit time. Fermentation of prebiotics by colon bacteria results in higher luminal SCFA production, which results in acidification of the colonic content. Intraluminal acidification may inhibit the growth of harmful or disease-inducing bacteria. Several studies show that the prebiotic effects are different for each prebiotic substance and that these depend on intestinal pH, prebiotic dosages, intraluminal concentrations of prebiotics, duration of intake, locations in the gut where fermentation occurs, and composition of endogenous intestinal microflora. Prebiotics have been part of human diets for centuries and are generally recognized as safe to consume. However, they can cause symptoms of abdominal pain, eructation, flatulence, bloating, abdominal cramps, and diarrhea. There are some reports of increased bacterial translocation of pathogenic bacteria during prebiotic treatment, such as Salmonella, and in sepsis models, but these results are controversial and are not seen in patients. More research in this area is needed. The effects of prebiotics are most extensively studied in different rodent models of IBD. Various efficacy of prebiotics and synbiotics (combination of probiotics and prebiotics) in different IBD models was found, but in most studies, prebiotics seem to ameliorate intestinal inflammation. Inulin, starch, lactulose, combination of oligofructose and inulin, and goat milk oligosaccharides reduced colitis. Some fructo-oligosaccharides showed mixed results, whereas galacto-oligosaccharides failed to reduce intestinal inflammation. Currently, only a few studies with prebiotics in patients with IBD have been published. Emerging small short-term studies using prebiotics or synbiotics showed reduction of inflammation in patients with pouchitis, UC, and CD (Table 6). A small open-label study in patients with active ileocolonic CD treated with a combination of oligofructose and inulin showed a significant reduction in disease activity. A recent pilot study investigated the adjunct effect of oligofructose-enriched inulin in patients with mild to moderate UC with concomitant 5-aminosalicylic acid treatment (n = 19). This placebo-controlled study reported a significant reduction of fecal calprotectin (marker of intestinal inflammation) in the prebiotic-treated patients compared with the placebo group, suggesting that these prebiotics reduced chronic intestinal inflammation. Table 6. Clinical Studies Testing Prebiotics or Synbiotics in the Treatment of Human Inflammatory Bowel Disease A randomized double-blind crossover study in pouchitis patients after colectomy for UC treated with inulin resulted in the reduction of mucosal inflammation However, Chermesh et al could not show prevention of relapse of CD after surgical resection with synbiotic treatment, although this study may be underpowered. Conclusion and Future Perspectives Nutrition Today Page 7

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Probiotics and prebiotics are emerging as promising therapeutic options for the treatment and prevention of flare-ups of IBD. A significant number of studies in both animal models and human IBD have documented the efficacy of these therapies in ameliorating chronic intestinal inflammation. In addition, these studies have led to a greater understanding of the mechanisms by which probiotics and prebiotics exert their beneficial effects. However, it is important to remember that the mechanisms elucidated cannot be generalized, as not all probiotics and prebiotic have similar therapeutic effects. Probiotics and prebiotics are widely available, are easy to consume, and are recognized as safe to consume. Side effects are rare, but some adverse effects such as bloating and flatulence tend to limit subsequent intake. The results obtained thus far warrant further rigorous welldesigned and larger clinical trials to firmly establish the safety and efficacy of probiotics and prebiotics in IBD. REFERENCES 1. Boyle RJ, Robins-Browne RM, Tang MLK. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83:1256-1264. 2. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics-approaching a definition. Am J Clin Nutr. 2001;73(suppl):361S-364S. 3. Metchnikoff E. The prolongation of life: optimistic studies. London, England: ButterworthHeinemann; 1907. 4. FAO/WHO. Health and nutritional properties in food including powder milk with live lactic acid bacteria. 2001. http://www.fao.org/ag/agn/agns/micro_probiotics_en.asp . Accessed June 9, 2007. 5. Lilly DM, Stillwell RH. Probiotics: growth promoting factors produced by microorganisms. Science. 1965;147:747-748. 6. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640. 7. Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem. 2002;277:50959-50965. 8. Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut. 2003;52:988-997. 9. Mack DR, Michail S, Wei S, et al. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. Am J Physiol. 1999;276:G941-G950. 10. Madsen KL. Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse. Clin Invest Med. 2001;24:250-257. 11. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521-533. Nutrition Today Page 8

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12. Shiba T, Aiba Y, Ishikawa H, et al. The suppressive effect of bifidobacteria on Bacteroides vulgatus, a putative pathogenic microbe in inflammatory bowel disease. Microbiol Immunol. 2003;47:371-378. 13. Fedorak RN, Madsen KL. Probiotics and the management of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:286-299. 14. Boudeau K, Glasser AL, Julien S, et al. Inhibitory effect of probiotic Escherichia coli strain Nissle 1917 on adhesion and invasion of intestinal epithelial cells by adherent-invasive E. coli strains isolated from patients with Crohn's disease. Aliment Pharmacol Ther. 2003;18:45-56. 15. Ulisse S, Gionchetti P, D'Alo S, et al. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am J Gastroenterol. 2001;96:2691-2699. 16. Dieleman LA, Goerres MS, Arends A, et al. Lactobacillus GG prevents recurrence of colitis in HLAB27 transgenic rats after antibiotic treatment. Gut. 2003;52:370-376. 17. Madsen KI, Doyle JS, Jewell LD, et al. Lactobacillus species prevents colitis in interleukin 10 genedeficient mice. Gastroenterology. 1999;116:1107-1114. 18. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:305-309. 19. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003;124:1202-1209. 20. Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent and refractory pouchitis. Gut. 2004;53:108-114. 21. Rembacken BJ, Snelling AM, Hawkey PM, et al. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet. 1999;354:635-639. 22. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut. 2004;53:1617-1623. 23. Bibiloni R, Fedorak RN, Tannock GW, et al. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 2005;100:1539-1546. 24. Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther. 1999;13:1103-1108. 25. Kato K, Mizuno S, Umesaki Y, et al. Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermented milk on active ulcerative colitis. Aliment Pharmacol Ther. 2004;20:11331141. Nutrition Today Page 9

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26. Ishikawa H, Akedo I, Umesaki Y, et al. Randomized controlled trial of the effect of bifidobacteriafermented milk on ulcerative colitis. J Am Coll Nutr. 2003;22:56-63. 27. McCarthy K, O'Mahony L, Dunne C. An open trial of a novel probiotic as an alternative to steroids in mild/moderately active Crohn's disease. Gut. 2001;49(suppl III):A2447. 28. Campieri M, Rizzello F, Venturi A. Combination of antibiotic and probiotic treatment is efficacious in prophylaxis of postoperative recurrence of Crohn's disease: a randomised controlled trial with Lactobacillus GG. Gastroenterology. 2000;118:A781. 29. Guslandi M, Mezzi G, Sorghi M, et al. Saccharomyces boulardii in maintenance treatment of Crohn's disease. Dig Dis Sci. 2000;45:1462-1464. 30. Kuisma J, Mentula S, Jarvinen J, et al. Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation and microbial flora. Aliment Pharmacol Ther. 2003;17:509-515. 31. Marteau P, Lemann M, Seksik P, et al. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn's disease: a randomised, double blind, placebo controlled GETAID trial. Gut. 2006;55:842-847. 32. Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial with Lactobacillus GG. Gut. 2002;51:405-409. 33. Bousvaros A, Guandalini S, Baldassano RN, et al. A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease. Inflamm Bowel Dis. 2005;11:833-839. 34. Schultz M, Timmer A, Herfarth HH, Sartor RB, Vanderhoof JA, Rath HC. Lactobacillus GG in inducing and maintaining remission of Crohn's disease. BMC Gastroenterol. 2004;4:5. 35. Prantera C, Scribano ML. Probiotics and Crohn's disease. Dig Liver Dis. 2002;34(suppl 2):S66-S67. 36. Roberfroid M. Prebiotics: the concept revisited. J Nutr. 2007;137:830S-837S. 37. Gibson G, Roberfroid M. Dietary modulation of the human colonic microflora: introducing the concept of prebiotics. J Nutr. 1995;125:1401-1412. 38. Swennen K, Courtin CM, Delcour JA. Non-digestible oligosaccharides with prebiotic properties. CRC Crit Rev Food Sci Nutr. 2006;46:456-471. 39. Niness K. Inulin and oligofructose: what are they? J Nutr. 1999;129:1402S-1406S. 40. Delzenne N, Cherbut C, Neyrincka A. Prebiotics: actual and potential effects in inflammatory and malignant colonic diseases. Curr Opin Clin Nutr Metab Care. 2003;6:581-586.

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41. Cherbut C. Inulin and oligofructose in the dietary fibre concept. Br J Nutr. 2002;87(suppl 2):S159S162. 42. Gibson GR, Probert HM, Van Loo J, et al. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev. 2004;17:259-275. 43. Macfarlane S, Macfarlane GT, Cummings JH. Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther. 2006;24:701-714. 44. Korzenik JR, Podolsky DK. Evolving knowledge and therapy of inflammatory bowel disease. Nat Rev Drug Discov. 2006;5:197-209. 45. Gibson GR. Dietary modulation of the human gut microflora using the prebiotics oligofructose and inulin. J Nutr. 1999;129(suppl S):1438s-1441s. 46. Fontaine N, Meslin JC, Lory S, et al. Intestinal mucin distribution in the germ-free rat and in the heteroxenic rat harbouring a human bacterial flora: effect of inulin in the diet. Br J Nutr. 1996;75:881892. 47. Gibson GR, Beatty ER, Wang X. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology. 1995;108:975-982. 48. Coppa GV, Zampini L, Galeazzi T, et al. Prebiotics in human milk: a review. Dig Liver Dis. 2006;38(suppl 2):S291-S294. 49. Bouhnik Y, Raskine L, Simoneau G, et al. The capacity of nondigestible carbohydrates to stimulate fecal bifidobacteria in healthy humans: a double-blind, randomized, placebo-controlled, parallelgroup, dose-response relation study 1-3. Am J Clin Nutr. 2004;80:1658-1664. 50. Wong JMW, Russell de Souza RD, et al. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40:235-243. 51. Ten Bruggencate SJM, Bovee-Oudenhoven IMJ, Lettink-Wissink MLG, et al. Dietary fructooligosaccharides and inulin decrease resistance of rats to Salmonella: protective role of calcium. Gut. 2004;53:530-535. 52. Videla S, Vilaseca J, Antol[latin dotless i]n M, et al. Dietary inulin improves distal colitis induced by dextran sodium sulfate in the rat. Am J Gastroenterol. 2001;96:5. 53. Moreau NM, Martin LJ, Toquet CS, et al. Restoration of the integrity of rat caeco-colonic mucosa by resistant starch, but not by fructo-oligosaccharides, in dextran sulfate sodium-induced experimental colitis. Br J Nutr. 2003;90:75-85. 54. Rumi G, Tsubouchi R, Okayama M, et al. Protective effect of lactulose on dextran sulfate sodiuminduced colonic inflammation in rats. Dig Dis Sci. 2004;49:1466-1472.

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55. Hoentjen F, Welling GW, Harmsen HJM, et al. Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis. 2005;11:11. 56. Daddaoua A, Puerta V, Requena P, et al. Goat milk oligosaccharides are anti-inflammatory in rats with hapten-induced colitis. J Nutr. 2006;136:672. 57. Holma R, Juvonen P, Asmawi MZ, et al. Galacto-oligosaccharides stimulate the growth of bifidobacteria but fail to attenuate inflammation in experimental colitis in rats. Scand J Gastroenterol. 2002;37:1042-1047. 58. Welters CFM, Heineman E, Thunissen FBJM, et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum. 2002;45:621-627. 59. Furrie E, Macfarlane S, Kennedy A, et al. Synbiotic therapy (Bifidobacterium longum/synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut. 2005;54:242-249. 60. Lindsay JO, Whelan K, Stagg AJ, et al. Clinical, microbiological, and immunological effects of fructooligosaccharide in patients with Crohn's disease. Gut. 2006;55:348-355. 61. Chermesh I, Tamir A, Reshef R, et al. Failure of synbiotic 2000 to prevent postoperative recurrence of Crohn's disease. Dig Dis Sci. 2007;52:385-389. 62. Casellas F, Norruel N, Torrjeo A, et al. Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin. Aliment Pharmacol Ther. 2007;25:1061-1067. Copyright 1996-2004 Lippincott Williams & Wilkins, Inc., A Wolters Kluwer Company. All rights reserved.

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