Complementary and alternative medicines, including probiotics, are in widespread use by inflammatory bowel disease patients, despite little evidence supporting a treatment effect. Clinicians treating such patients need to be aware of these treatments and their mechanisms of action, and advise patients accordingly. Dr. Jeffry Katz has summarized this information in this issue of VHJOE which I suspect will be of great interest to you and to your patients.

Complementary and Alternative Therapy, Probiotics, and Prebiotics for Inflammatory Bowel Disease Jeffry A. Katz, M.D. Associate Professor of Medicine Case Western Reserve University University Hospitals Case Medical Center

Introduction

Inflammatory bowel disease (IBD) is typically a chronic relapsing illness with an unpredictable clinical course. The less than perfect utility of medical therapy, the recurrence of illness after surgical resection of Crohn’s disease (CD), and the potential toxicity and risk of IBD medications explain the widespread use of and interest in complementary and alternative medicine (CAM) and pre-and probiotics by IBD patients. Given the widespread use of these treatments by patients with ulcerative colitis (UC) and CD, it is important that doctors in general, and gastroenterologists in particular, become familiar with the potential benefits, risks, and efficacy of these various therapeutic modalities.

Complementary and Alternative Medicine

CAM therapies encompass a wide range of diagnostic and therapeutic techniques, including, but not limited to, homeopathy, traditional Chinese medicine, acupuncture, herbal therapy, hypnotherapy, meditation, dietary manipulation and supplements, chiropractic, osteopathy, and massage therapy¹. (Table 1) As UC and CD are chronic, relapsing disorders and since conventional therapy with aminosalicylates, corticosteroids, immunomodulators, or biologic therapy is less than perfectly effective, it is not surprising that CAM use is common among IBD patients. Studies from around the globe reveal that a significant number of IBD patients use CAM, with use estimates ranging from 21% to 51% ^2-5. A lack of success with conventional treatments and the wish to take a more holistic therapeutic approach are some of the reasons IBD patients chose CAM therapies⁶. Herbal therapies and prayer are among the more commonly used alternative treatments. Additionally, the perceived safety of CAM treatment relative to conventional therapy is another reason IBD patients choose alternative treatment approaches. However, both direct and indirect toxicities of CAM have been reported, including hepatic and renal failure¹.

Despite the widespread use of CAM therapies among patients with IBD, reliable data on effectiveness is quite limited, with many studies being small, poorly designed, and poorly controlled. Among herbal therapies, one of the more widely used CAM approaches is the oral ingestion of extracts from the aloe vera plant. Aloe vera gel given for 4 weeks to patients with active UC has produced clinical response in 47% of treated patients compared to 14% of patients receiving placebo⁷. Another intriguing preliminary study investigated curcumin, the major pigment in turmeric which possesses both anti-inflammatory and antioxidant properties. This small, pilot study suggests clinical benefit of curcumin in both UC and CD with improvement in clinical symptoms, endoscopic scores (UC), and sedimentations rates (CD)⁸. Although these preliminary data are intriguing, the rigorous evaluation of CAM therapies in IBD remains far smaller than their widespread use. Attempts at regulation, standardization, and evaluation of CAM therapies is just beginning and it remains unclear if convincing data on efficacy through well-designed and sufficiently powered clinical trials will ever be generated⁹, though study continues.

Probiotics

A growing appreciation of the complex interaction between the enteric microflora and programmed mucosal immune responses has led to a widening interest in manipulation of the gut flora for therapeutic purposes. This alteration in gut flora can be accomplished with antibiotic therapy, or through the use of probiotics or prebiotics. Probiotics are live microorganisms which when consumed in adequate amounts confer health benefits to the host. Prebiotics, in contrast, are non-digestible substrates that act as a selective nutrient source supporting the intestinal growth of beneficial bacteria. The commonly used probiotics are lactic acid fermenting bacteria, including lactobaciili and bifidobacteria, but can also include other bacteria, such as E. coli Nissle 1917, or yeasts. (Table 2) The precise mechanism(s) for the beneficial effects of probiotics remain under investigation, but include stimulation of mucosal defense, increase in secretory IgA, enhanced mucosal defense and barrier integrity, antagonism of pathogenic bacteria, and attenuation of proinflammatory cytokines¹⁰. In general, probiotics are considered safe, though bacteremia and sepsis has been reported with both LGG and S. boulardii. As shown in Table 3, there are multiple different reasons why probiotics should be effective therapy for patients with IBD, however, current enthusiasm for their usefulness outstrips the available convincing clinical data.

Ulcerative colitis

The majority of clinical trials in UC have evaluated probiotics for maintenance of remission. The most extensive data on the utility of probiotics in UC exists for the non-pathogenic E. coli Nissle 1917, a probiotic currently not available in the United States. Three large, randomized, controlled studies have evaluated this probiotic in comparison to mesalamine for either the maintenance of steroid induced remission¹¹ or the continued maintenance of quiescent disease^{12, 13}. Patients received either E. coli Nissle 1917, at a dose of 2.5-5 x 1010 viable bacteria twice daily, or mesalamine at a dose of only 1200-1500 mg daily. These trials showed similar efficacy for the maintenance of remission between E. coli Nissle 1917 and low dose mesalamine. Trials of varying design, size and duration have suggested some benefit for additional probiotics, including VSL#3¹⁴, Saccharomyces boulardii¹⁵, Lactobacillus rhamnosus GG (LGG)¹⁶, and bifidobacteria¹⁷ in maintaining remission in UC, but overall the data remains unconvincing.

Very few studies have been performed evaluating probiotics for the treatment of active UC. VSL#3, a mixture of 8 different probiotic bacteria, has been used to treat active mild to moderate UC at a dose of 3.6 x 10¹² bacteria daily¹⁸. In an open label trial, among 32 patients treated with VSL#3 for 6 weeks, remission was obtained in 53% of patients with clinical response in an additional 24%. These results have yet to be replicated in a controlled trial.

Pouchitis

Approximately 50% of patients with a proctocolectomy and ileal-pouch anal anastomosis will develop pouchitis. Pouchitis reproduces the symptoms of UC and is believed to be directly related to changes in the pouch microbial flora. Most cases of pouchitis respond to a brief course of antibiotics and do not quickly recur, but roughly 10% of patients will develop chronic, recurrent pouchitis. Probiotics have been shown to maintain antibiotic-induced remission in patients with chronic pouchitis. Two placebo-controlled, double-blinded trials have shown a marked benefit of VSL#3 over placebo for the maintenance of remission in patients with chronic, relapsing pouchitis^{19, 20}. Among VSL#3 treated patients 34/40 (85%) remained in remission over 9-12 months compared with just 1/36 (4%) of placebo treated patients^{19, 20}. Both VSL#3²¹ and LGG²² have also been shown to delay the initial onset of pouchitis as well as decrease stool frequency²¹. An open label trial of very high dose VSL#3 (3.6 x 10¹² bacteria daily for four weeks) in patients with mild, active pouchitis reported remission in 69% of study patients²³. However, not all patients with pouchitis tolerate probiotics well and not all studies have found clinically significant benefit²⁴.

Crohn’s Disease

To date, there exist only a few trials evaluating probiotics for the treatment of active disease, maintenance of remission, or prevention of post-operative recurrence in CD. Two small, open label trials have treated mildly active CD with probiotics, one using LGG²⁵ and the other using a combination of Bifidobacterium, Lactobacillus, and a prebiotic²⁶, suggested clinical benefit without side effects, but no large series or controlled data exists. Both S. boulardii²⁷ and E. coli Nissle 1917²⁸ have shown promise for maintenance of CD in remission in pilot trials, but a larger randomized, placebo-controlled study in children with CD showed no additional benefit of adding LGG to standard maintenance treatment²⁹.

Most patients with CD will undergo surgical resection during their lifetime and the great majority of these will have a recurrence of disease in the region of the surgical anastomosis. It is clear that the fecal stream plays a crucial role in anastomotic disease recurrence, since patients with a loop ileostomy do not get recurrent disease until closure of the loop and restoration of the fecal stream³⁰. Thus, modification of the bacterial flora at the anastomotic area with probiotic therapy makes clinical sense. There have now been three published, randomized, placebo-controlled trials evaluating different probiotic preparations for the maintenance of postoperative remission in CD none of which have shown either endoscopic or clinical benefit up to 24 month follow-up^31-33. Despite these disappointing clinical results, a recently reported placebo-controlled trial showed an immunologic effect of post-operative probiotic therapy, with reduced levels of pro-inflammatory cytokines and increased levels of transforming growth factor(TGF)-ß from anastomotic biopsies³⁴. Thus, there remains some possibility that future trials of other probiotics, prebiotics, or a combination of both, so-called synbiotics, may yet show a clinical benefit. (Table 4)

Table 4: Probiotic Use in IBD: What We Know in 2008

Maintenance of remission in UC		Some controlled data for E. coli Nissle 1917
Treatment of active UC		No controlled data
Maintenance of remission in chronic pouchitis		Good controlled data for VSL#3
Prophylaxis against pouchitis onset		Some controlled data for VSL#3 and LGG
Maintenance of remission in CD		No controlled data
Treatment of active CD		No controlled data
Maintenance of post-operative remission in CD		Multiple negative controlled trials

Prebiotics

There are three criteria that define a prebiotic: 1) it must be non-digestible by host enzymes, 2) it must be fermented in the gastrointestinal tract, and 3) there must be selective stimulation of intestinal flora and of metabolic activity³⁵. These properties have been convincingly demonstrated for only a few food ingredients, including the inulin-type fructans, galactooligosaccharides, and lactulose. These compounds naturally occur in a variety of foods, including artichokes, leeks, asparagus, soy beans, bananas, and chicory root. Microbiologically, prebiotics are known to preferentially stimulate the growth of both fecal and mucosal Bifidobacteria and Lactobacillus in healthy adults. Thus, the functional effect of prebiotics is expected to be similar to the exogenous administration of probiotics, especially bifidobacteria. Since some bifidobacteria are immunoregulatory, increasing levels of bifidobacteria through ingestion of prebiotics could help modulate intestinal inflammation in IBD. Additionally, prebiotics have been reported to: improve the efficiency of mineral absorption from the gut, have anti-carcinogenic effects, and improve lipid metabolism^35. Given the evident overall safety of prebiotics, this approach to therapy for IBD has wide appeal to both patients and physicians.

Although only a few prebiotic clinical trials have been performed in IBD patients, the preliminary results are encouraging. A multi-center, open label Japanese trial reported that germinated barley could produce a significant decrease in clinical UC activity compared to control patients³⁶. Likewise, a small randomized, placebo controlled trial in active UC of a synbiotic, combining Bifidobacterium longum with an inulin-oligofructose prebiotic, showed significant endoscopic and histologic improvement after four weeks of therapy. In this trial, reductions in mucosal tumor necrosis factor (TNF)-α, interleukin 1α, and human beta defensins were also noted³⁷. In CD fructo-oligosaccharide 15 g/day has shown clinical, microbiologic and immunologic benefit in a preliminary 10-patient trial³⁸. These exciting preliminary results await confirmation with larger controlled trials.

Other Microbial Therapies

One additional therapy for IBD involving manipulation of gut microbes deserves consideration alongside probiotics and prebiotics. Recent clinical trials have evaluated the ova of the pig whipworm, Trichuris suis, as a treatment for IBD. Epidemiological, experimental and clinical observations support the hypothesis, that helminth therapy can alter the balance between Th1 pro-inflammatory cytokine and Th2 anti-inflammatory cytokines. In a 12-week double blind, placebo-controlled trial in fifty-four patients with active UC, suspensions of 2,500 Trichuris suis ova at two-week intervals induced a significant improvement in 43% in the whipworm treated patients compared to only 16% of placebo patients³⁹. There were no side effects or complications attributable to the therapeutic agent in this trial. This same therapy has also been tried in patients with active CD, and in an open-label trial enrolling 29 patients, 21 (72%) of the Trichuris suis treated patients entered remission⁴⁰. These early studies are encouraging, but more data will be necessary before helminth therapy can be routinely recommended.

Conclusion

There exists great enthusiasm for the potential of pre- and probiotic treatment of IBD, and many patients already use these treatments and other CAM as part of their therapy. However, despite positive supportive findings from in vitro studies of pre- and probiotics and therapeutic trials in animal models of IBD, at this time rigorous clinical investigation and proof of therapeutic efficacy for prebiotics and probiotics lags behind both physician and patient enthusiasm for their use. For most all other CAM therapy, no rigorous evaluation is currently available and patient preference more than science will likely drive their use. The available probiotic and prebiotic human trials have generally been small, provided mixed results, and suffered from significant methodologic limitations. The best evidence for the efficacy of probiotics in IBD comes from studies of maintenance of remission in chronic pouchitis with VSL#3. Some data also support the use of probiotics, particularly E. coli Nissle 1917, in the maintenance of remission in UC. At this time, there is no good evidence suggesting a benefit of probiotic therapy in the in the treatment of CD. Also, no large or well designed studies have shown a benefit of prebiotics or probiotics in the treatment of active IBD, and these therapies currently if used are suited only for maintenance of inactive disease in remission.

The failure of clinical probiotic trials in IBD to consistently show benefit should be viewed not as a condemnation of the entire concept of therapeutic manipulation of the intestinal flora, but rather as a humbling reminder of how much we still have to learn about the complex micro-ecology of the gut and its role in inflammation. As the initial fervor for probiotic and prebiotic therapies cools somewhat and the hype fades, we must continue to ask and investigate fundamental unanswered therapeutic questions. Basic investigators will continue to isolate, describe, and genetically manipulate more probiotic organisms, prebiotics, and synbiotics, and further investigate potential mechanisms of action. At the same time, clinical scientists must conduct larger, better designed clinical trials, head-to-head comparisons of different probiotic and prebiotic compounds, and dose-ranging studies. Given the evident safety of pre- and probiotics, the public interest in such complementary therapy, and both government and private funding resources, now is the time to look beneath the surface and discover which CAM therapies and pre- and probiotics work in IBD and how they work.

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