Probiotics and Inflammatory Bowel Disease Introduction There are two main diagnoses of Inflammatory Bowel Disease (IBD); Ulcerative Colitis and Crohn’s Disease. The symptoms of both diseases include; diarrhoea, pain, tiredness, weight loss and constipation. Patients may also experience inflammation in other parts of the body and suffer from disorders such as arthritis. Ulcerative colitis is characterised by inflammation in the colon and/or the rectum. Whereas Crohn’s disease, can occur anywhere in the gastrointestinal tract, it is commonly found in the terminal ileum or colon. It is this inflammation, which causes loss of function of the gut including; reduced ability to absorb nutrients and water, as well as the control of bowel movements. The disease is characterised by progression through stages of initiation, amplification and healing. There are three main factors thought to be responsible for intestinal inflammation associated with IBD; genetics, the immune system and gut microflora. A gene associated with Crohn’s Disease has already been identified and scientists are looking to find other markers. Researchers studying the immune responses in this disease have observed abnormal actives of the T-helper cells. Th1 cells, which produce proinflammatory proteins, are overactive, whilst Th2 cells, which produce anti-inflammatory proteins to not respond in the usual manner. The role of Bacteria in IBD Bacterial involvement in IBD has been proven in animal models of inflammatory bowel disease, where mice kept in a germ free environment did not develop the condition.(6) However, it is not practical to remove the entire gut microflora, as they have many beneficial effects on the human hosts, as well as the fact that the gut will quickly become re-colonised. In human studies, an imbalance in colonic bacteria has been described in patients with IBD. A reduction in potentially protective organisms such as Bifidobacteria spp. and Lactobacilli spp., was observed along with an increase in pathogenic organisms such as Escherichia coli. It is these kinds of pathogens along with inflammation of the intestinal mucosa, which results in the development of lesions on the gut wall.(10) The theory proposed to explain bacterial involvement in IBD is as follows; “a pathogen, possibly a bacterium, reaches the intestine in large numbers and triggers the immune system, but instead of stopping when the pathogen has been defeated, the inflammation carries on as though there were dangerous invaders still present.” (5) It is thought that this inflammation continues due to the immune system mistakenly reacting to the normal gut microflora. The cause of IBD may therefore be a malfunction in the mechanism by which the intestinal mucosa is able to avoid pro-inflammatory responses to commensal bacteria but able to respond appropriately to luminal pathogens.(7) Protexin Health Care – Technical Notes Probiotics and Inflammatory Bowel Disease June 2005 - This document supersedes all previous document Probiotics International Ltd., Matts Lane, Stoke sub Hamdon, Somerset, TA14 6QE www.protexin.com 1 This process however, does not occur in all individuals; it must be accompanied by one or more other environmental or genetic factors. The initial trigger for the inflammation will be when a pathogen passes through the gut mucosa of the intestinal wall. In normal subjects the epithelial cells form tight junctions and only allow small nutrient particles of digested food through but patients with IBD have increased gut permeability (‘leaky gut’), which may also allow bacteria to pass through the gut wall. Several bacteria have been implicated as possible candidates for the onset and/or persistence of IBD, including Bacteroides vulgatus for colitis and a specific strain of Escherichia coli for Crohn’s disease, which has the ability to cross the intestinal barrier and cause inflammation. Treatment of IBD Unfortunately there is no cure for patients with this condition. However, pharmaceuticals, including anti-inflammatories and immuno-suppresants, have been used to treat some of the symptoms of IBD. These drugs have largely prevented deaths from this disease but unfortunately patients taking these drugs often experience side effects, which are sometimes serious. Antibiotics are also often used to control overgrowth of pathogenic bacteria in specific parts of the gastrointestinal tract.(9) However, these too can have side effects and broad spectrum antibiotics may also kill off beneficial bacteria, further exasperating the problem of dysbiosis (gut imbalance/0. In severe cases of IBD, surgery may even be required to remove part of the intestine. Food intolerances are often associated with IBD and many patients may experience a reduction in the severity of symptoms if certain foods are avoided. Special diets are also used to improve the nutrition of patients and prevent weight loss. How Probiotics can help It is thought that if the introduction of beneficial bacteria, in the form of probiotics, can change the types of bacteria in the gut, then they may be able to alter the immune response of the gut to it’s microflora. In other words if you increase the number of beneficial bacteria and reduce the number of pathogenic bacteria then the immune system may react in the correct way and not cause continual inflammation. There are several suggestions as to how probiotic bacteria may do this: Adhesion to the wall of the intestine, therefore preventing pathogenic species becoming established Competition for nutrients, resulting in harmful bacteria being starved and unable to increase in number Production of lactic acid, reducing the pH within the gut, which is not favourable for many undesirable bacteria Secretion of bacteriocidal chemicals, which can kill unwanted bacteria Influence the immune system to stop incorrect inflammatory responses Lactobacillus spp. are the most common group of probiotic bacteria and have been studied for their benefits in treating IBD. Bifidobacteria are also an important part of Protexin Health Care – Technical Notes Probiotics and Inflammatory Bowel Disease June 2005 - This document supersedes all previous document Probiotics International Ltd., Matts Lane, Stoke sub Hamdon, Somerset, TA14 6QE www.protexin.com 2 the normal gut flora and are also often used in probiotic preparations. A single bacterial strain in unlikely to work for all people with IBD, so a mixed/multi strain probiotic may be the best choice. Treatment with probiotics has been shown to reduce intestinal inflammation and inflammatory response in experimental models of colitis and to reduce symptoms and inflammatory scores in patients with IBD. A study in Ireland used Lactobacillus salivarius and Bifidobacterium longum in experiments with both mice and humans, concluding that that they had a beneficial effect of inflammatory bowel disease.(12) These species were particularly effective in preventing the weight loss associated with this illness and showed a good ability to colonise the gut and influence the microflora. It has been shown that treatment with Lactobacillus plantarum stabilises the gut mucosal barrier in patients with ulcerative colitis(2) This was measured by a reduction in gut permeability and a reduction in the concentration of circulating antibody to endotoxin.(3) It is possible that the mechanism by which probiotics reduce intestinal inflammation in cases of IBD, is by enhancing the gut barrier. Therefore, colonic permeability can be influenced by the quality of the flora colonising the mucosal surfaces. A type of gut bacterium called Bacteroides are thought to be able to cause IBD, particularly the pathogenic strain Bacteroides vulgatus, which has been shown to cause colitis in mice.(11) This may be due to these species ability to drive intestinal inflammation, whereas Lactobacillus spp. and Bifidobacterium spp. have an ability to regulate pro-inflammatory and anti-inflammatory responses. Bifidobacterium infantis strongly inhibited the growth of Bacteroides vulgatus in the coculture and also significantly suppressed the systemic antibody response raised by B. vulgatus colonising the gut in germ free mice.(4) These results suggest that Bifidobacterium infantis protected the gut epithelial layer including the Peyer’s patches from being invaded by Bacteroides, thereby suppressing the systemic antibody response raised by Bacteroides. People with Crohn’s may suffer from lactose intolerance as the inflammation of the small intestine reduces it’s ability to produce enzymes including lactase. Probiotics can help as many lactic acid bacteria produce lactase themselves and can therefore improve the ability to digest milk products. Lactobacillus acidophilus and Lactobacillus bulgaricus, were added to milk and given to people who were lactose intolerant, a significant improvement in digestion of lactase was observed.(15) Protexin Health Care – Technical Notes Probiotics and Inflammatory Bowel Disease June 2005 - This document supersedes all previous document Probiotics International Ltd., Matts Lane, Stoke sub Hamdon, Somerset, TA14 6QE www.protexin.com 3 The Value of Prebiotics Prebiotics are defined as ‘non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and or activity of one or a limited number of bacteria in the colon, that can improve host health’.(1) In other words prebiotics are food for the beneficial bacteria within the gut, in this way they complement probiotic bacteria and strengthen their effect. Bacteria feed on undigested food that has passed into the intestines, by fermentation which produces smaller molecules, energy and gases. Prebiotic compounds are usually indigestible carbohydrates, a soluble form of dietary fibre, which reach the lower part of the gut. Most commercially available prebiotics are oligosaccharides such as fructooligosaccharide (FOS) or longer chain molecules including inulin and arabinogalactan. Shorter chain sugars are broken down in the upper portion of the gut, whilst long chain prebiotics like inulin are fermented in the colon. Lactobacilli spp. and Bifidobacteria spp. specifically ferment carbohydrates, whereas many pathogenic bacteria ferment protein. In this way prebiotics encourage the growth of beneficial bacteria, increasing the number of beneficial bacteria particularly Bifidobacteria. This in turn will help the competitive exclusion process and reduce the number of harmful bacteria. Prebiotics also benefit the gut microflora by helping to prevent pathogenic bacteria colonising the gut wall. Most harmful bacteria can bind to these carbohydrates but not utilise them as a food source, therefore these bacteria are drawn away from the gut wall preventing them binding to the epithelial cells. How prebiotics help IBD Patients with IBD often have a lower concentration of beneficial bacterial species within their gut microflora. The addition of these beneficial bacteria in the form of probiotics on their own or in combination with prebiotics (synbiotics) has been shown to increase the numbers of Lactobacilli spp. and Bifidobacteria spp, within the gut.(8) Both diarrhoea and constipation are symptoms of IBD. Probiotics and prebiotics have been seen to improve the rate of gut transit and stool frequency. Prebiotics have also been shown to help to prolong remission times in patients with ulcerative colitis. In stimulating the action of Bifidobacteria, prebiotics can increase the amount of butyrate produced, which in turn can have an anti-inflammatory action.(13) Summary The evidence suggests that increasing the number of beneficial bacteria in the small intestine and colon, may improve the health of patients suffering from IBD. The result can include a reduction in the severity of symptoms, increased length of remission periods and improved immune function. Patients may also be able to reduce their prescribed medication and even delay or prevent the need for surgery. Protexin Health Care – Technical Notes Probiotics and Inflammatory Bowel Disease June 2005 - This document supersedes all previous document Probiotics International Ltd., Matts Lane, Stoke sub Hamdon, Somerset, TA14 6QE www.protexin.com 4 References 1. Gibson, G and Roberfroid, MB (1995). Dietary modulation of the Human Colonic Microbota: Introducing the Concept of Prebiotics. Journal of Nutrition 125: 1401-1412 2. 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The beneficial effects of microflora, especially obligate anaerobes, and their products on the colonic environment in inflammatory bowel disease. Curr Pharm Des. 11(8):1047-53. 14. Lin MY, Yen CL, Chen SH (1998). Management of lactose maldigestion by consuming milk containing lactobacilli. Dig Dis Sci. 43(1):133-7. 15. Lin MY, Yen CL, Chen SH. Management of lactose maldigestion by consuming milk containing lactobacilli (1998). Dig Dis Sci. 43(1):133-7. Protexin Health Care – Technical Notes Probiotics and Inflammatory Bowel Disease June 2005 - This document supersedes all previous document Probiotics International Ltd., Matts Lane, Stoke sub Hamdon, Somerset, TA14 6QE www.protexin.com 5