December 26, 2007

Supplements for Inflammatory Bowel Disorders — The Inside Tract on Treatment
By Gerard E. Mullin, MD, MHS, FACN, CNSP, CNS, AGAF,
and Kathie M. Swift, MS, RD, LDN
For The Record
Vol. 19 No. 26 P. 26

Mary flew from San Francisco to our integrative medical center (UltraWellness) in Lenox, Mass. She had seen at least one dozen practitioners in the past two years for help in managing Crohn’s disease (CD). Mary had consulted with gastroenterologists, acupuncturists, naturopaths, nutritionists, and herbalists and had traveled to our center for another opinion.

George was diagnosed with ulcerative colitis (UC) and didn’t wait long before seeking a second opinion at Johns Hopkins’ division of gastroenterology, hoping that a gastroenterologist with specialized training in nutrition would offer him some hope and help.

Mary and George shared more than the pain and frustration common in patients with inflammatory bowel disease (IBD). Both are treating digestive disorders such as CD and UC with nutraceuticals. In many cases, patients have concocted their own formulary of supplements with the help of Google, while others have been prescribed a laundry list of products recommended by various practitioners.

The use of nutraceutical supplements by patients with gastrointestinal disorders is widespread and growing, especially since more than 90 million Americans have been diagnosed with such conditions. Most studies cite that 50% of patients with digestive disorders use supplements.

Many clinical trials demonstrate the efficacy of nutraceutical supplements for IBD. Probiotics, prebiotics, butyric acid enemas, Curcuma longa, Boswellia serrata, and fish oils have been shown to be superior to placebo and, in some cases, equal to standard medical therapy in randomized trials.

IBD: The Fire Within
IBD is a chronic condition characterized by frequent relapses, hospitalizations, diminished quality of life, complications that require surgery, and intestinal cancer.1 The pathophysiology of IBD involves an unremitting intestinal inflammation, proinflammatory cytokines, increased reactive oxygen species, and tissue injury oftentimes triggered by luminal bacteria.1 Opportunities for natural product therapy include modulation of mediators involved in the inflammatory process, altering luminal bacteria, modifying the immune response, and rejuvenation of intestinal healing.

Supplement Use in Digestive Health and Disease
Surveys of complementary and alternative approaches used by patients with gastrointestinal complaints have reported usage rates ranging from 21% to 68%.2-16 The use of complementary and alternative medicine (CAM) for all digestive indications appears to be more prevalent in North America than Europe, although the growth of the industry in Europe is now probably faster. As in other contexts, the single most used type of CAM for gastrointestinal disorders is herbal therapy.17-20 Usage appears to be most common in patients with IBD and irritable bowel syndrome.2,9,16 This may be related to the chronic and refractory nature of these disorders, as well as psychological factors.20,21

Indeed, recent surveys in the United Kingdom and Hong Kong have shown that the use of CAM by patients with IBD is most common in those with poor quality of life.14,22 In a national survey from Germany, 51% of IBD patients had experience with CAM, with the use of homeopathy and herbal therapy being the most popular. Patients’ total systemic steroid intake, suggesting poorly controlled disease, was a strong predictor of CAM use.5 Surveys have addressed the reasons why patients used nutraceutical supplements for IBD and which ones they felt were the most effective.5,23 Doctors, dietitians, and gastroenterologists can no longer ignore the widespread usage and potential benefits of nutraceutical supplements for IBD.

Herbal Therapies

Traditional Chinese Medicine (TCM)
Numerous reports in Chinese literature concern the treatment of UC with herbal remedies. However, only three clinical trials have compared combination herbs in both the oral and enema form with conventional medical therapy for UC. In all studies, TCM was superior to both placebo and conventional medical therapy.24-26 Interpreting the results of these comparative studies is compromised by a lack of randomization, standardization of extracts, and blinding.

Aloe Vera
A randomized, double-blind, controlled study showed that aloe vera gel given for four weeks to patients with moderately active UC was superior to placebo.27 Clinical remission, improvement, and response occurred in nine (30%), 11 (37%), and 14 (47%), respectively, of 30 patients given aloe vera compared with one (7%), one (7%), and two (14%; P < 0.05), respectively, of 14 patients taking placebo (using a 2:1 ratio of aloe vera to placebo randomization schedule). The Simple Clinical Colitis Activity Index and histological scores decreased during treatment with aloe vera but not with placebo.

Wheatgrass Juice
In a randomized, double-blind, controlled trial, 23 patients with active distal UC were given oral wheatgrass juice or placebo for four weeks.28 Treatment with wheatgrass juice was associated with greater reductions in a composite clinical disease activity index, the severity of rectal bleeding, and the doctor’s global assessment than occurred in the placebo group. No side effects were reported.

Germinated Barley Foodstuff (GBF)
Two open-label Japanese trials suggested efficacy in UC for GBF, consisting mainly of dietary ?ber and glutamine-rich protein that the authors believe to act primarily as a prebiotic.29-32 In the ?rst report, 11 patients given GBF for four weeks as an adjunctive treatment showed a greater fall in clinical disease activity than nine patients given conventional therapy alone. In a follow-up study, 24 weeks of treatment of 21 patients with GBF together with continuing 5-aminosalicylic acid (5-ASA) and steroid therapy reduced rectal bleeding and nocturnal diarrhea. Adjunctive GBF also produced a lower relapse rate over 12 months when given to 22 patients with UC in remission than did conventional therapy in 37 patients.33 GBF was well tolerated and appeared safe in all three reports.

Polyphenols
Polyphenols are phytochemicals found in food substances produced from plants. They are separated from essential micronutrients in which a deficiency state has not been identified; nevertheless, these chemicals are believed to play a biologically active role and have been shown to be potentially immune-modulating.34 For IBD, downregulation of inflammatory mediators and nuclear factor kappa beta are broad mechanisms of action for polyphenols’ therapeutic effects.

Although numerous polyphenols have been identified, five in particular have evidence of benefit for animal and human studies in IBD: resveratrol, epigallocatechin, curcumin, quercetin, and Boswellia.

Boswellia Serrata
Boswellia serrata, more commonly known as frankincense, is a traditional Ayurvedic remedy and a component of incense. In India, the effect of the gum resin from Boswellia serrata in moderately active UC was compared with sulfasalazine. Remission rate in the Boswellia group (82%) resembled that occurring in patients given conventional therapy (75%).35 The same authors reported a similar study in 2001 that resulted in a 70% remission rate in 20 patients taking Boswellia for six weeks compared with 40% in 10 patients on sulfasalazine.36 In a randomized, double-blind, controlled eight-week trial, the Boswellia serrata extract H15 was compared with mesalamine for active CD.37 The study included 102 patients and was powered to show noninferiority. The mean Crohn’s Disease Activity Index fell in both groups, and H15 was well tolerated. This result was similar to results in previous trials with 5-ASA preparations.38,39

Curcuma Longa
Curcumin is the yellow pigment of turmeric (Curcuma longa), a major ingredient of curry. In animal and in vitro studies, it has a range of immunomodulatory and anti-in?ammatory effects.40-43 In a recent pilot study, curcumin, when given orally, was reported to benefit ?ve patients with proctitis and ?ve with CD.44 Hanai and colleagues recently published the results of the first randomized, multicenter, double-blind, placebo-controlled trial from Japan to study curcumin’s effect on UC maintenance.45 All 97 patients who enrolled and 89 patients who completed the study took a standard dose of mesalamine or sulfasalazine and either 1 gram of curcumin or placebo twice daily for six months and then were followed for another six months off study medications. The relapse rate at six months on therapy was greater for the placebo group than for those who took curcumin (p = 049). Thus, curcumin may confer some additional therapeutic advantages when used in combination with conventional anti-inflammatory medications in UC.

Prebiotics, Probiotics, and Synbiotics

Probiotics
As the microbial environment has been shown to play a role in the development and perpetuation of IBD, targeting of the microbiota presents an option for therapeutic intervention.46-48 One potential method to manipulate the intestinal microbiota in an attempt to reduce the inflammatory response is via the administration of friendly live bacteria.

Probiotics have been described as “live microorganisms that, when consumed in adequate quantities, confer a health benefit on the host.”49-52 They have been used in the treatment of numerous inflammatory conditions, including UC, CD, and experimental colitis.53-64 The mode of action of probiotics is complex and not completely understood; however, multiple mechanisms have been described in vitro.

Based on the success of preventing and treating experimental colitis with VSL#3, Lactobacillus GG, and other strains, a number of clinical trials have been executed for both CD and UC. Overall, the data for CD have shown mixed results for benefiting as either an induction or maintenance adjunct to standard medical therapy. In contrast, probiotics have been shown to benefit UC for both induction and continued remission of disease.65-73

Prebiotics
As the intestinal microbiota has been linked to the pathogenesis of IBD, probiotic treatment is an avenue for therapeutic intervention. Another is the administration of prebiotics, which are described as “nondigestible 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, thus improving host health.”74,75

The rationale behind prebiotic use is to elevate the endogenous numbers of beneficial bacterial strains, including Lactobacillus and Bifidobacterium.76,77 This increase will impart the beneficial effects seen by probiotic administration, including an increase in short-chain fatty acid (SCFA) production, particularly butyrate, which is deficient in the colonic mucosa of UC patients and can provide fuel for enterocytes, prevention of pathogenic adherence, production of antibacterial substances, and decreased luminal pH.32,78-81 Administration of SCFA enemas have been shown effective for left-sided UC that is refractory to medical therapy.78-82

Common prebiotics include inulin, resistant maltodextrin, and oligosaccharides such as fructooligosaccharide and galactooligosaccharide. The body of research involving the use of prebiotics to treat IBD is not currently as extensive as that underlying probiotic therapy. Overall, the four published studies to date all support prebiotic use in the treatment of active UC.

Synbiotics
In addition to probiotic and prebiotic administration, another viable option is to use both prebiotic and probiotic administration in conjunction, referred to as synbiotics.74,83 The rationale behind synbiotic treatment is that the desired probiotic and prebiotic (presumably with demonstrated efficacy on their own) would exert a beneficial effect greater than would be observed when administered individually. However, it may be the case that a prebiotic not efficacious when administered alone stimulates the probiotic species, significantly elevating its beneficial effects.

There are few studies demonstrating the positive effects of synbiotic therapy, but it is becoming a more logical and viable treatment option for future IBD studies.

Fish Oil
Omega-3 fatty acids have been promoted as conferring broad health benefits by preventing and treating a wide variety of diseases.84 In cell culture and animal studies, these essential fatty acids have potent immunomodulatory effects that appear to be mediated through both modulation of eicosanoid synthesis and an eicosanoid-independent inhibitory effect on the proinflammatory cytokines. Thus, it has been proposed that supplemental omega-3 fatty acids may be beneficial in treating or preventing relapse in chronic inflammatory diseases.

For IBD, there are animal in vivo and in vitro studies that show omega-3 fatty acids can effectively prevent and treat mice models of colitis.85-90 An early report on the use of enteric-coated formulation for CD found a markedly lower relapse rate for the fish oil group than the control group (28% compared with 69%; P < 0.001).91 However, on the basis of a comprehensive literature review, the available data are insufficient to draw conclusions about the effects of omega-3 fatty acids on clinical, endoscopic, or histologic scores or induced remission or relapse rates.88,90,92-101

The data that pertain to the effects of omega-3 fatty acids on steroid requirements suggest that omega-3 fatty acids may reduce the dosage of corticosteroids needed among patients with IBD. Future studies should assess the effects of pharmaceutical-grade enteric-coated omega-3 fatty acids on clinical outcomes in IBD, including requirements for corticosteroids.

Vitamin D
Vitamin D from sunlight exposure is lower in areas where IBD occurs most often, which means IBD is most prevalent in northern climates, such as North America and Northern Europe.102,103 Vitamin D deficiency is common in patients with IBD, even when the disease is in remission.104 Several observations in animal models of colitis provide strong evidence that establishes vitamin D and vitamin D receptor (VDR) as a physiologic regulator of intestinal inflammation in IBD.105

It is unclear why vitamin D deficiency occurs more frequently in both forms of IBD. It is probably due to the combined effects of low vitamin D intake, malabsorption of many nutrients (including vitamin D), and decreased outdoor activities in climates that are not optimal for vitamin D synthesis in the skin.

Since the risk of osteoporosis and vitamin D deficiency is higher in IBD, every patient should be tested for 25-OH vitamin D3 levels.106 The accumulating evidence for the immunomodulatory effects of VDR ligands provides a rationale for further investigation of their potential in IBD treatment.107

There is a further need for clinical trials of the potential efficacy of natural approaches in combination with conventional therapy to achieve better outcomes in IBD. Continued education of physicians and other healthcare practitioners on the potential benefits of nutraceutical supplements is essential if we are to give well-informed advice to patients such as Mary and George who are considering or already using alternative therapies for IBD.

— Gerard E. Mullin, MD, MHS, FACN, CNSP, CNS, AGAF, is director of integrative gastrointestinal nutrition services at Johns Hopkins Hospital.

— Kathie M. Swift, MS, RD, LDN, is nutrition director at the UltraWellness Center in Lenox, Mass.

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