The efficacy of probiotics in the management of inflammatory bowel disease

Transcription

1 The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects The efficacy of probiotics in the management of inflammatory bowel disease Amanda Eileen VanGemert The University of Toledo Follow this and additional works at: This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

2 The Efficacy of Probiotics in the Management of Inflammatory Bowel Disease Amanda Eileen VanGemert The University of Toledo 2012

3 ii Dedication This paper is dedicated to all those who have encouraged me to achieve more out of myself than I thought possible. A huge thank you to my mom, my dad, my sister, and my beloved grandparents for being a source of encouragement throughout this process. I also dedicate this to Professor Sharon Gentry because of her tremendous work with this project and with her contributions to my future as a physician assistant. Thank you!

4 iii Acknowledgements I would like to acknowledge all those who contributed to the production and proofing of this paper including Sharon Gentry, Laura Manzey, and Anne Simopoulos.

5 iv Table of Contents Introduction... 1 Inflammatory Bowel Disease Background... 3 So Why Are Probiotics Worth Considering?... 8 Methods Discussion Conclusion References Abstract... 24

6 1 Introduction Former United States president Dwight Eisenhower, lead guitarist from the music group Pearl Jam Mike McCready, American Idol runner-up Casey Abrams, Jacksonville Jaguars quarterback David Garrard; what do these people have in common? They all suffer from inflammatory bowel disease (IBD) (Tresca, 2011). Each person has a unique story about his/her life struggles with the disease, covering a spectrum of mild to severe debilitating symptoms. At any extent, IBD is a life-changing condition that demands the careful attention of both the clinicians who treat and the patients who experience it. IBD encompasses both ulcerative colitis (UC) and Crohn s disease (CD). According to the Center for Disease Control and Prevention, the prevalence of UC worldwide is /100,000 persons and the prevalence of CD worldwide is /100,000 persons. In the United States alone, it is estimated that about 1.4 million people are diagnosed with IBD, with medical costs averaging $1.7 billion each year. One of the most important complications with IBD is the likelihood of surgery throughout the course of the disease: 75% of CD and 25% of UC patients will have surgery in an attempt to alleviate symptoms at some point in the disease process. IBD accounts for about 119,000 disabilities, 700,000 clinician visits, and 100,000 hospitalizations in the United States per year (Center for Disease Control and Prevention [CDC], 2011). These statistics are enough reason to recognize IBD as a major concern due to the fact that the current treatments are obviously inadequate for curation, induction, or maintenance of remission. Equally as important to mention is that the quality of life among IBD sufferers is often dismal. IBD typically has an early onset of fifteen to thirty

7 2 years of age. Ten percent are diagnosed prior to age eighteen and CD has a second spike of diagnosis between ages fifty and seventy. UC is more common in males, exsmokers, and nonsmokers; while CD is more commonly diagnosed in females and smokers. The role of genetics is becoming increasingly apparent, as most new cases are discovered in those with family members already diagnosed. Interestingly, IBD tends to be seen more often in Caucasian individuals, white collar occupations, and in urban communities compared to rural areas. Differences in diet, smoking prevalence, pollution, childhood infections, and hormonal contraception have all been included as undeniable trends considered as possible contributors (CDC, 2011). The concern lies not only in the prevalence of IBD but more so in the severity of life-altering symptoms that define the disease.

8 3 IBD Background Although the symptomatology of UC and CD is fairly similar, the disease process is quite different. Symptoms of UC include bloody diarrhea, abdominal pain, and significant weight loss. UC is characterized by inflammation in the large bowel only, beginning in the most distal portion of the rectum and ascending uniformly through the colon. The inflammation only affects the inner mucosal layer, sparing the deep intestinal wall tissue. CD on the other hand can affect any part of the digestive tract and involves the entire thickness of the intestinal wall. Bloody, mucous diarrhea, fever, weight loss, and extraintestinal manifestations, including inflammation of major joints, eyes, skin, and oral mucosa, present in about 30% of patients, are more common in CD. Those with CD are also at an increased risk for fistulas and strictures along the digestive tract, ultimately leading to surgical intervention. There is also an association between CD and ankylosing spondylitis, an autoimmune disease that attacks the vertebral joints. Both CD and UC carry an increased risk of thromboembolic complications, anemia, and vitamin deficiencies (Macfarlane, 2009). The ultimate goal in managing patients with IBD is improvement in quality of life. Current anti-inflammatory treatments include corticosteroids, salicylates, immunomodulators, and biologics (Quigley, 2011). Unfortunately these treatments are not without risks including leukemia, lymphoma, stomach ulcers, severe infection, and weight gain. Balancing the risks with the benefits of using these powerful drugs is the only way for many to find some sort of relief, in hopes of not creating more complications by doing so. Antibiotics have also been used in the treatment of IBD, although they may be contradictorily responsible for inducing IBD by allowing

9 4 opportunistic pathogenic bacteria to flourish following depletion of the normal host bacterial flora, including Clostridium difficile and necrotizing enterocolitis in neonates. Prebiotics, probiotics, and synbiotics are also potentially viable options in the management of IBD. Prebiotics are nondigestable food ingredients that encourage beneficial bacterial growth in the intestines; most common example is a substance called inulin. Probiotics potentially recolonize the appropriate healthy bacteria through oral administration of particular bacterial cultures. Synbiotics are a combination of preand pro-biotics used to achieve an additive affect on improving intestinal health through manipulation of normal bacterial flora. Actions and efficacy of these last three options is the foundation of this paper, as well as revealing potential proof of formerly unknown etiologies relating to IBD pathogenesis through the use of these non-traditional, yet increasingly popular, treatments. Although the fundamental etiology of IBD is uncertain at this time, there are many factors that have been associated with the disease including genetic susceptibility, intestinal bacteria (referred to as intestinal flora or microbiota), and immune responses of intestinal mucosa (Kwon, 2003). IBD has an autoimmune origin that is proposed to be a hypersensitivity to nonpathogenic bacteria that enter the intestine. A fairly well known hypothesis linking IBD to more developed countries stems from the extensive use of germ killing products that eliminate bacteria from hands and household surfaces. A child growing up in this type of environment is not exposed to as broad a range of bacteria; therefore, an immune response to typical bacterial triggers is never activated. As the child grows and is exposed to pathogens that should provoke an established immune memory plus an innate genetic predisposition, the immune system overreacts,

10 5 resulting in an over production of inflammation. This concept is known as the hygiene hypothesis and may be a contributor to the inflammatory nature of IBD (Cain, 2011). As mentioned, patients often have a genetic predisposition to IBD. Bacterial dysregulation in the intestine has been found in intestinal tissues of those with IBD. No specific pathogen has been identified; however, there is speculation regarding a few particular pathogens and their contribution. Various studies have shown there is an increase in bacterial count in areas of lesions in IBD patients. Diverting the fecal stream in an exacerbated IBD patient by a temporary colostomy procedure has been shown to improve symptoms. Reestablishing the fecal stream through the intestine tends to revert back to the ulcerated mucosa and returns the healed intestine to its previous disease state (VanGossum, 2006). It is becoming more apparent that the etiology of IBD is undeniably linked to altered function of the bacterial flora. Targeting this evidence, it is hypothesized to be more beneficial to manipulate the intestinal bacteria causing inflammation instead of responding to the resulting inflammatory damage (Kwon, 2003). In continuing discussion on the etiology of IBD, immune regulation must be analyzed to understand how the intestinal mucosa in an IBD patient behaves differently than that of a healthy patient. The following have been proposed problems in IBD intestinal tract: persistent infection, altered mucosal barrier causing a decrease in normal immune function, altered good/pathogenic bacterial balance, and dysregulation of host immune response (gene mutations, hypersensitivity) leading to a heightened immune response causing damage and irritation to mucosal walls (Kwon, 2003). Further, deficient T reg cells, CD4+CD25 cells, and T helper cells and increases in

11 6 macrophages, neutrophils, cell adhesion molecule expression and cell injury may all play a part in inadequate immune regulation. Overregulation can cause an increase in white blood cells, further enhancing the inflammatory cascade (Baroja, 2007). High bacterial counts in certain areas of the intestine may also stimulate the immune system (Macfarlane, 2009). Different bacteria have been identified as possible pathogens in UC and CD. In CD, these pathogens may include Mycobacterium paratuberculosis, paramyxovirus, Listeria monocytogenes, Mycobacterium kansasii, Chlamydia trachomatis, and Pseudomonas maltophilia (Sartor, 2000). Alterations in known healthy bacterial intestinal inhabitants include decreases in bifidobacteria and lactobacillus species, increases in bacteroides species and hemorrhagic Escherichia coli species (Macfarlane, 2009). Lactic acid producing bacteria are thought to hinder the healthy activity of other resident flora (Quigley, 2011). Higher amounts of bacteria are found on the intestinal walls of IBD patients in comparison to healthy control groups, which may coincide with severity of disease (Cong, 2003). In UC patients, Escherichia coli and other opportunistic bacteria seem to contribute to disease. Increases in sulphates present in today s typical Western diet seem to play a substantial role in bacterial regulation. In addition, defects in host flora responsible for digesting sulphates is also apparent. Sulphates are found in food additives, preservatives, bleaching, and chemically added antioxidants that are often included into processed food products (Macfarlane, 2009). Consuming large amounts of protein can also increase sulphide concentrations. Brassica vegetables can have a protective effect by decreasing sulphur concentrations in the intestine; these include whole foods

12 7 typically less appetizing to the typical Western diet consumer: cabbage, kale, broccoli, cauliflower, Brussels sprouts, and turnips. Equally important is the role of peristalsis and gastric secretions in preventing bacterial overgrowth in normally low concentrated areas of the intestine, more specifically the duodenum and jejunum (Quigley, 2011). This overgrowth can stimulate an immune response, causing inflammation that over time increases permeability of the intestinal wall, encouraging sepsis by the offending bacteria. Obesity is linked to deficiencies in intestinal motility that may contribute to the issues explained previously regarding bacterial overgrowth by allowing bacteria to congregate in certain parts of the intestine.

13 8 So why are probiotics worth considering? Probiotics are living organisms taken orally to potentially recolonize the intestine with beneficial bacteria. The theory behind the use of probiotics is that by reintroducing the good bacteria to both healthy and diseased portions of the intestine, normal intestinal digestion and immune regulation may be restored and healthy digestion resumed. By utilizing the anti-inflammatory affects probiotics may produce, proinflammatory cytokines responsible for the mounted immune response in the intestinal mucosa may be decreased (Cong, 2003). Probiotics have been observed in studies both by themselves and in tandem with conventional pharmacological treatments. Evidence in various studies is currently showing that probiotics may reduce intestinal inflammation by producing bacteroicins and metabolites that have antimicrobial properties, support healthy mucosal barrier function, and improve regulation of the mucosal immune system (Tursi, 2010). There is insufficient evidence that certain bacterial strains are more beneficial for CD versus UC; however, this theory may still be valid and more research is necessary. An eight week study observing the anti-inflammatory capabilities of a probiotic called VSL#3 is one of the most promising studies in the use of probiotics in the treatment/prevention of pouchitis in UC patients following a procedure called ileal pouch-anal anastomosis (IPAA) (Tursi, 2010). Pouchitis is inflammation in the terminal ileum following the resection of the entire colon, resulting in an anastomosis between the ileum and anus. The strains in this probiotic include four strains of Lactobacilli (L. paracasei, L. Plantarum, L. acidophilus, and L. Delbrueckii), three strains of Bifidobacteria (B. longum, B. breve, and B. infantis), and one strain of Streptococcus

14 9 thermophilus (VSL Pharmaceuticals). The total bacterial count was 900 billion. Eligible patients were randomly assigned to the VSL#3 group (n=65) or placebo group (n=66). Results showed a fifty percent improvement with VSL#3, compared to placebo, in Ulcerative Colitis Disease Activity Index (UCDAI). The UCDAI is a self survey quantifying stool frequency, rectal bleeding, mucosal appearance, and physician s rating of disease activity, noted in Table 1 below. Table 1 VSL#3 was also statistically significant in inducing remission compared to placebo (Tursi, 2010). An additional study also upholds the proposed theory of beneficial VSL#3 in prevention of pouchitis post IPAA (Pronio, 2007). This randomized study included sixteen patients in probiotic group and twelve in the control group and baseline, three, six, and twelve month assessments of patient clinical status were obtained throughout the study. Endoscopic histological assessment of ileal pouch tissue and blood inflammatory markers were also recorded at each visit. Pouchitis Disease Activity Index (PDAI) scores decreased in VSL#3 group compared to the placebo group consistently over the three, six, and twelve month intervals (Pronio, 2007). 1. Stool frequency Normal Stools/day>normal Stools/day>normal 2 >4 Stools/day>normal 3 2. Rectal bleeding None 0 Streaks of blood 1 Obvious blood 2 Mostly blood 3 3. Mucosal appearance Normal 0 Mild friability 1 Moderate friability 2 Exudation, spontaneous bleeding 3 4. Physician's rating of disease activity Normal 0 Mild 1 Moderate 2 Severe 3 The ulcerative colitis disease activity index assesses four variables, which include stool frequency, severity of bleeding, colonic mucosal appearance, and the physician's overall assessment of disease activity. Each variable is scored from 0 3 so that the total index score ranges from 0 12; 0 2: remission; 3 6: mild; 7 10: moderate; >10: severe UC. Reprinted by permission from MacMillan Publishers Ltd: The American Journal of Gastroenterology (Tursi, , ), copyright 2010 American Journal of Gastroenterology This table used with Nature s Publishing Group Permission

15 10 PDAI scores were both subjective and objective based on rectal bleeding, fecal urgency, fever, stool frequency, and abdominal cramps. Scores greater than seven were considered positive for acute pouchitis. The VSL#3 group also showed an increase in CD4+CD25 cell ratio among other inflammatory markers, indicating significant control of local inflammation. Another study using VSL#3 intervention in active mild to moderate UC patients not responding to conventional therapy demonstrates a significant beneficial response in 53% of the thirty-two patients evaluated (n=18) (Bibiloni, 2005). Other outcomes included a response in 24% (n=8), no response in 9% (n=3), worsening in 9% (n=3), and failure to complete final sigmoidoscopy in 5% (n=2). Primary outcome was measured using the same UCDAI criteria as in the aforementioned study. Conventional therapies were allowed as long as they remained stable throughout the study. Although the sample size was small, it is important to note that none of the patients studied had adverse events related to VSL#3. There was no difference in the baseline UCDAI scores of those who had a positive response to the probiotic compared to those who had a worsening or no change in symptoms. Significance was seen in the change in UCDAI score among those who achieved remission or responded, eluding to the proposed clinical significance of VSL#3 (Bibiloni, 2005). Similar to VSL#3 and UC, a randomized study of the affect of Lactobacillus johnsonii (formerly called Lactobacillus acidophilus) on the recurrence of CD after ileocaecal resection (twelve weeks post-surgery) shows that L. johnsonii decreased the intestine s response to a substance called lipopolysaccharide, which is present on the surface of some pathogenic bacterial cell surfaces. Identification of this substance by

16 11 the immune system causes an immune response. Although the results identified a small change in immune response, there was no statistical significance in this study between those patients taking the probiotic compared to placebo (Van Gossum, 2006). Lactobacillus species has also been considered beneficial in CD due to its proposed capacity to increase mucosal IgA release; therefore, increasing the mucosal barrier to pathogenic bacteria (Malin, 1996). Lactobacillus casei is a particular subspecies that has been studied due to its presence in healthy intestinal mucosa and its potential ability to influence immune regulation in the intestine (Llopis, 2008). In this study, intestinal biopsies were obtained from sixteen CD patients unresponsive to conventional pharmacotherapy and undergoing surgical intervention for an intestinal stricture. Cultured L. casei, E. coli, or a mixture of both were combined with the mucosal biopsies, both diseased and healthy tissue. Results indicated that L. casei had a protective affect against exposure to nonpathogenic E. coli; although the amount of resistance was not statistically significant. E. coli caused an exaggerated immune response when exposed to the intestinal mucosal tissue. L. casei was able to compensate by inhibiting TNF-α, a pro-inflammatory chemokine. Other inflammatory chemokines were decreased to a lesser degree, including IFN-γ, IL-6, and IL-2 (Llopis, 2008). Sulfasalazine and the probiotics Lactobacillus delbruekii and Lactobacillus fermentum were studied in a group of thirty patients with mild to moderate UC. Inflammatory markers including myeloperoxidase, interleukin-6, fecal calprotectin, NFkB p65, and tumor necrosis factor alpha proteins were measured in colonic tissue prior to and following treatment with sulfasalazine alone and sulfasalazine with the probiotic

17 12 mentioned above. Histological analysis showed mucosal erosion and edema, focal hemorrhage, vascular congestion, and infiltration of polymorphonuclear cells, plasma cells, and neutrophils in colonic mucosa of active UC prior to treatment. Compared to healthy controls, these inflammatory components were up-regulated in those with UC. Many of the inflammatory markers seen in the diseased colonic mucosa were significantly decreased or eliminated following treatment with sulfasalazine plus the probiotic versus sulfasalazine alone. The implication of the probiotic in this study is the potential amelioration of colitis symptoms, maintenance of remission, and prevention of relapse using conventional treatment paired with probiotics (Hegazy, 2010). Regarding E. coli, there is evidence that CD patients may benefit from the use of a nonpathogenic strain of E. coli, known as the Nissle strain. This particular strain has been shown to prevent adherence of pathogenic strains of E. coli to the intestinal mucosa (Boudeau, 2003). Another study shows a greater percentage of remission in patients taking the E. coli probiotic after one year with only 33.3% relapsed in E. coli group compared to 63.6% in placebo group (Malchow, 1997). Saccharomyces boulardii is a nonpathogenic yeast that has shown antiinflammatory properties in CD patients. Combining this probiotic yeast with the antiinflammatory drug Mesalamine decreased rates of relapse after six months compared to Mesalamine alone (Guslandi, 2000). Similarly, the aforementioned VSL#3 has been combined with the anti-inflammatory drug 5-aminosalicylic acid in studies, resulting in an increased rate of remission and prevention of pouchitis post-surgery in UC patients (Guslandi, 2000).

18 13 Although there is promising evidence regarding the use of probiotics alone or with conventional treatments, the use of probiotics with prebiotics, also called synbiotics, is becoming a popular consideration in managing IBD. Prebiotics may potentiate the affects seen in probiotic use alone (Steed, 2010). In a study, 24 patients with active CD were placed in two groups, 13 in synbiotic group and 11 in placebo group. Groups were given probiotic B. longum and prebiotic Synergy 1 (consisting of Orafti, Tienen, and Belgium) or a placebo. Tissue biopsies were initially obtained and changes in symptoms were recorded at three and six months using the Crohn s Disease Activity Index (CDAI), which documented patient well being, abdominal pain, stool habit, extraintestinal manifestations, body weight, hematocrit, presence of inflammatory mass, and use of codeine (Steed, 2010). This self survey is considered the gold standard in many studies due to its ability to record patient satisfaction and symptomatology. Results of this study showed improvements in CDAI of the synbiotic group only (synbiotic p=0.020, placebo p=0.810). Remarkably, sixty-two percent of the synbiotic group was in remission by the end of the trail; whereas only forty-five percent of the placebo was in remission. Histological improvements on tissue biopsy were significantly better in the synbiotic group compared to placebo group. TNF-α was a major inflammatory marker identified in the study due to its observed increase within inflamed intestinal mucosa. At the three month visit, TNF-α was significantly decreased. By six months it remained at a level similar to what was recorded at three months. There was an increase in Bifidobacterium species seen in the synbiotic patients, which is a known healthy part of normal intestinal flora (Steed, 2010). A significant consideration of this study is that although anti-inflammatory changes were noted, the

19 14 overall decrease in symptomatology in patients, leading to a better quality of life, was not observed. Overall, further studies need to be conducted to include a greater sample size in order to increase the accuracy of the results. The results of these small studies is promising and indicates the need for larger scale research. The timing, dosage, and amount of strains present in the probiotic formula may be important keys as to why certain studies have had unpromising outcomes; for example, compare the extremely positive results of the multiple probiotic formula VSL#3 studies to those of less significant single strain formulas that prove to be much less efficacious (Van Gossum, 2006). The use of multiple strains together to enhance the affect of probiotics is referred to as strain synergism. The genetic makeup of the host also contributes to the efficacy of the probiotic, including the location and severity of disease. Due to the chronic nature of IBD and the limited potentially dangerous resources used in treatment, the use of complimentary alternative medicine (CAM) has become increasingly popular, including the use of probiotics. As a member of the medical profession, it is important to become knowledgeable regarding the current remedies patients are using for relief of symptoms. A study regarding this very idea showed that less than half of IBD patients who use probiotics discussed their use with a clinician; according to the patients studied, the information encouraging the use of probiotics came primarily from commercial advertising (Hedin, 2010). Probiotic knowledge scores were evaluated by assessing the patient s understanding of what probiotics are; patients were given points if certain descriptors were used in his/her definition (i.e. bacteria or living organism, health benefits, or if they used the name of a probiotic). The same

20 15 idea was used in an assessment of prebiotics. Although IBD patients scored higher probiotic knowledge scores than the control group, twenty percent of those who currently used probiotics for IBD symptoms could not define what a probiotic is. Most probiotic formulas used were those found in yogurts, although other probiotic preparations were also included. The most common ones included: Actimel, Activia, Acidophilus, Yakult, and VSL#3. According to the survey, half of those with IBD and half of those in the control group reported probiotics to be unhelpful or unsure of the positive effect on his/her health, while the other half reported a little, moderately, or very helpful (Hedin, 2010). There could be many explanations for this, including the lack of communication between patient and clinician, resulting in incorrect or inadequate use of probiotic formulas. In regard to the probiotic yogurt preparations mentioned previously, yogurt is one of the most commercialized sources linking probiotics with healthy digestion. Media encourages the use of probiotic-infused yogurt to restore the healthy balance of intestinal digestion for both healthy people and those with IBD/IBS (Irritable Bowel Syndrome) symptoms. A study involving yogurt supplemented with L. rhamnosus and L. reuteri strains of bacteria measured various immune response cells in the blood and in the feces following consistent ingestion (Baroja, 2007). Regulatory T cells and the cytokine release from monocytes and dendritic cells were measured. Deficient T reg cells have been implicated in exacerbating chronic inflammatory diseases. The aim of the study was to test for any degree of benefit, not monitoring for other treatments the patient may be using in combination with the probiotic. All subjects were women with a majority having CD. Patient medications were not altered throughout the course of the

21 16 study. The results showed a significant increase in CD4+CD25 cells following treatment with probiotic yogurt (p=0.007) compared to placebo yogurt (p=0.03). Important to maintenance of remission in IBD patients, decreases in the percentages of TNF-α and IL-12 producing monocytes were observed (Baroja, 2007). Probiotic yogurt was also associated with many anti-inflammatory affects in the blood and intestinal lumen. These changes were seen in both the IBD patients and in the control patients, although to a greater degree in IBD patients.

22 17 Methods A clinical literature review was performed to better understand the effectiveness of probiotics in the management of IBD. Information gathered in this paper was obtained from search engines including PubMed, CINAHL, JAMA, Medscape, and UptoDate. Original research, literature review, and basic informational articles were obtained, analyzed, and compiled. All articles were published in with the exception of two well-respected articles written in 1993 and Search terms included inflammatory bowel disease, probiotics, Crohn s disease, Ulcerative colitis, prebiotics, synbiotics, diet and IBD, microbiota, normal intestinal flora, and alternative therapies for IBD. Peer reviewed articles were of first priority and originated in multiple countries including Italy, United Kingdom, United States of America, Ireland, and Belgium. All articles were written in English. All studies included were performed using adults from age eighteen to sixty-five. Elderly and very young were excluded due to the proposed focus of this literature review and the lack of studies performed in these age groups.

23 18 Discussion The evidence clearly indicates probiotics are useful in the sustainment of remission and the prevention of recurrence following surgical bowel resection but has yet to have a proven role in the induction of remission in those with IBD (Hedin, 2010). At the present time, probiotics are predominately used in combination with conventional pharmacologic treatment, as evidence for their solo use has not been supported. The positive aspect of using probiotics is that the most serious side effects include mild nausea, diarrhea, and flatulence, which are all proven to be a very low risk of experiencing. This allows safety in using probiotics in patients with mild to moderate IBD. If the probiotics do not produce a beneficial affect, no short or long term risks are associated with use or with discontinuation, providing a substantial benefit to using probiotics when comparing the short and long term risks of many conventional pharmacologic therapies. It is becoming increasingly evident that the amount and types of bacterial strains present within the probiotic formula make a significant difference on the beneficial affects it may provide. For CD, Saccharomyces boulardii, E. coli (Nissle strain), and Lactobacillus species have been supported in studies as beneficial. For UC, Saccharomyces boulardii, bifidobacterium, Lactobacillus rhamnosus, and L. acidophilus have been supported (Cain, 2011). Formulations including multiple bacterial species listed above have been shown to be even more efficacious than their solo use. An open communication between clinician and patient is imperative. For those suffering with IBD, a vast majority are willing to try almost anything for any degree of relief from debilitating symptoms. For clinicians to learn about various complimentary

24 19 alternative medicine (CAM) treatments, including probiotics, is of utmost importance. An open line of communication between clinician and patient regarding the use and information regarding different alternative treatments will not only improve present patient health and safety but potentially improve the health of future patients. The responsibility falls on the clinician to make sure patients feel comfortable sharing the types of CAM/medical treatments he/she is experimenting with in order to assess patient safety as well as product efficacy. Monitoring patient responses and results will benefit future patients.

25 20 Conclusion At the very least, probiotics should be one of the first steps to consider in the treatment/management of IBD. If no benefit is achieved, other more potent/toxic conventional drugs can be progressed. How great it would be to keep patients in remission using probiotics, not only for safety purposes but also for the money saved in clinician visits, hospital admissions, and pharmaceutical costs. Probiotics may also be used as an adjunct to current pharmacological treatments to enhance the efficacy of current drugs. If the intestine is in a healthier state, its ability to efficiently fight disease is increased. Probiotics may have the ability to contribute to optimal intestinal health, whether there is evidence of disease or perfectly healthy intestinal mucosa. The tremendous importance of other aspects of dietary intake need to be emphasized at every clinician visit. There is evidence that diets rich in complex carbohydrates, low in processed foods, high in lean meats, and loaded with whole food items, as tolerated, can have a tremendous positive outcome in managing IBD. The focus of treating the patient with IBD has to focus on quality of life with prevention of symptoms being the ultimate goal.

26 21 References Andreoli, A., Falasco, G., Luzi, C., Prantera, C., & Scribano, M. L. (2002). Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn s disease: A randomised controlled trial with lactobacillus GG. Gut, 51(3), Annese, V., Brandimarte, G., D Amico, T., Danese, S., Di Guilio, E., Di Rosa, S.,... Tursi, A. (2010). Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: A double-blind, randomized, placebo-controlled study. American Journal of Gastroenterology, 105, doi: /ajg Antolin, M., Borruel, N., Carol, M., Casellas, F., Espin-Basany, E., Guarner, F.,... Martinez, C. (2009). Lactobacillus casei downregulates commensals inflammatory signals in Crohn s disease mucosa. Inflammatory Bowel Disease, 15(2), doi: /ibd Baert, F., de Hertogh, G., DeVos, M., Dewit, O., Enslen, M., Fontaine, F.,... Gossum, A. (2007) Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early endoscopic recurrence of Crohn s disease after ilio-caecal resection. Inflammatory Bowel Disease, 13(2), doi: /ibd Bahrami, B., Blackett, K. L., Cummings, J. H., Macfarlane, G. T., Macfarlane, S., Reynolds, N.,... Walsh, S. V. (2010). Clinical trial: The microbiological and immunological effects of synbiotic consumption-a randomized double-blind

27 22 placebo-controlled study in active Crohn s disease. Alimentary Pharmacology and Therapeutics, 32, doi: /j x Baroja, M. L., Hekmat, S., Kirjavainen, P. V., & Reid, G. (2007). Anti-inflammatory effects of probiotic yogurt in inflammatory bowel disease patients. Clinical and Experimental Immunology, 149, doi: /j x Bibiloni, R., Fedorak, R. N., Tannock, G. W., Madsen, K. L., Gionchetti, P., Campieri, M.,... Sartor, R. B. (2005). VSL#3 Probiotic-mixture induces remission in patients with active ulcerative colitis. American Journal of Gastroenterology, 100(7), doi:10.111/j x Blackett, K. L., Macfarlane, G. T., Macfarlane, S., Nakayama, S., & Steed, H. (2009). The gut microbiota in inflammatory bowel disease. Current Pharmaceutical Design, 15, Boirivant, M., Butteroni, C., Montesani, C., Mumolo, G., Pronio, A., Vecchione, S.,... Vitolo, D. (2008). Probiotic administration in patients with ileal pouch-anal anastamosis for ulcerative colitis is associated with expansion of mucosal regulatory cells. Inflammatory Bowel Disease, 14(5), doi: /ibd Boudeau, J., Glasser, A. L., & Julien, S. (2003). Inhibitory effect of probiotic Escherichia coli strain Nissle 1917 on adhesion to and invasion of intestinal epithelial cells by adherent invasive E. coli strains from isolated patients with Crohn s disease. Alimentary Pharmacology and Therapeutics, 18, Cain, A. M. & Dowhower Karpa, K. (2011). Clinical utility of probiotics in inflammatory bowel disease. Alternative Therapies, 17(1),

28 23 Cong, Y., Elson, C. O., Iqbal, N., & Konrad, A. (2003). Probiotics and immune regulation of inflammatory bowel diseases. Current Drug Targets-Inflammation & Allergy, 2(2), Djemal, S., Hedin, C. R. H., Howe, L. C., Jansen, C., Lindsay, J. O., Mullard, M.,... Whelan, K. (2010). Probiotic and prebiotic use in patients with inflammatory bowel disease: A case-control study. Inflammatory Bowel Disease, 16(12), doi: /ibd Guslandi, M., Mezzi, G., Sorghi, M., & Testoni, P. A. (2000). Saccharomyces boulardii in maintenance treatment of Crohn s disease. Digestive Diseases and Sciences, 45, Hegazy, Sahar K. & Mohamed M. El-Bedewy. (2010). Effect of probiotics on proinflammatory cytokines and NF-kB activation in ulcerative colitis. World Journal of Gastroenterology, 16(33), doi: /wjg.v16.i Hotz, J., & Plein, K. (1993). Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable phase of Crohn s disease with special respect to chronic diarrhea--a pilot study. Zeitschrift für Gastroenterologie, 31, Isolauri, E., Malin, M., Saxelin, & M., Suomalainen, H. (1996). Promotion of IgA immune response in patients with Crohn s disease by oral bacteriotherapy with Lactobacillus GG. Annals of Nutrition and Metabolism, 40, Kwon, J. H. & Farrell, R. J. (2003). Probiotics and inflammatory bowel disease. Biodrugs, 17(3),

29 24 Malchow, H. A. (1997). Crohn s disease and Escherichia coli: A new approach in therapy to maintain remission of colonic Crohn s disease? Journal of Clinical Gastroenterology, 25, Quigley, E. M. M. (2011). Therapies aimed at the gut microbiota and inflammation: Antibiotics, prebiotics, probiotics, synbiotics, anti-inflammatory therapies. Gastroenterology Clinics, 40(1). Veerappan, G. R., Betteridge, J., & Young, P. E. (2012). Probiotics for the treatment of inflammatory bowel disease. Current Gastroenterology Report, 14, doi: /s

30 25 Abstract Objective. This is a literature review discussing recent evidence concerning the efficacy of probiotics in managing inflammatory bowel disease (IBD), as its prevalence is increasing in developing countries today. Method. Information gathered in this paper was obtained from search engines including PubMed, CINAHL, JAMA, Medscape, and UptoDate. Search terms included Crohn s Disease, Ulcerative Colitis, probiotics, inflammatory bowel disease, prebiotics, synbiotics, microbiota, and IBD alternative therapies. Results. Peer reviewed articles were chosen from countries including United States, Italy, United Kingdom, Ireland, and Belgium. Background articles were obtained from journals including The American Journal of Gastroenterology, Alternative Therapies, Inflammation & Allergy, and Journal of Clinical Gastroenterology. Conclusion. Current treatments for IBD have toxic side effects. Probiotics may provide a safer alternative for maintaining remission in these patients. The importance of clinicians to be aware of all the possible treatments is imperative in providing the highest care and improve quality of life.