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Supplements for Inflammatory Bowel Disease

By Gerard E. Mullin, MD; Laura K. Turnbull; S. Devi Rampertab, MD, Director of Integrative GI Nutrition Services; Johns Hopkins; Johns Hopkins University School of Nursing; Milton Hershey Penn State School of Medicine. 

Introduction
The use of nutraceutical supplements by patients with gastrointestinal disorders is widespread and growing. Most studies cite that 50% of patients with inflammatory bowel disease use nutraceutical supplements. There is an abundance of clinical trials demonstrating 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.  Thus the nutraceutical supplements that have been shown to have established efficacy for inflammatory bowel disease are reviewed.

Inflammatory Bowel Disease (IBD): The Gut on Fire
Inflammatory bowel disease is a chronic condition characterized by frequent relapses, hospitalizations, diminished quality of life (QOL), 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 that is oftentimes triggered by luminal bacteria [1].   Opportunities for natural product therapy include the modulation of mediators involved in the inflammatory process, altering luminal bacteria, modifying the immune response and rejuvenation of intestinal healing.

Usage of supplements for IBD
Surveys of complementary and alternative approaches by patients with gastrointestinal complaints have reported rates of utilization well over 50% [2-16]. Of all digestive disorders, usage appears to be most common in patients with IBD and IBS [16],[2],[9].  Table 1 summarizes the latest research on the utilization patterns of complementary and alternative medicine  (CAM) use in IBD.  Surveys have also addressed the reasons why patients used nutraceutical supplements for IBD and which ones they felt to be the most effective [23], [5] (Table 1).  Given their widespread usage, healthcare practitioners now need to be familiar with the potential benefits of nutraceutical supplements for IBD in an effort to offer superior care to their patients. 

Herbal Therapies

a. Aloe vera
A randomized, double-blind, controlled study showed that aloe vera gel, given for 4 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%) two (14%; P < 0.05), respectively, of 14 patients taking placebo (using a 2:1 A. vera: placebo randomization schedule). The Simple Clinical Colitis Activity Index and histological scores decreased during treatment with A. vera but not with placebo.

b. Wheat grass juice
In a randomized, double-blind, controlled trial, 23 patients with active distal UC were given oral wheat grass juice or placebo for 4 weeks [28].Treatment with wheat grass juice was associated with greater reductions in a composite clinical disease activity index, severity of rectal bleeding and physician’s global assessment than occurred in the placebo group. No side-effects were reported.

c. Germinated barley foodstuff
Two open-label Japanese trials suggested efficacy in UC for a germinated barley foodstuff (GBF), which consists mainly of dietary fiber and glutamine-rich protein.  The authors believe this substance acts primarily as a prebiotic [29-32].  In the first report, 11 patients given GBF for 4 weeks as 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-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 such patients [33].  GBF was well tolerated and appeared to be safe in all three reports.

d. Polyphenols
Polyphenols are phytochemicals that are found in food substances produced from plants.  Polyphenols are separated from essential micronutrients in that 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 (NFkB) 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 including: resveratrol, epigallocatechin, curcumin, quercetin and Boswellia.   Resveratrol, epigallocatechin, curcumin and quercetin have been demonstrated to display both prophylactic and therapeutic effects for colitis in animals; however quercetin was the least effective of the polyphenols studied.   In humans, clinical studies of polyphenols for the treatment of IBD are limited to Boswelia serrata and Curcuma longa. 

Boswellia serrata
Boswellia serrata (‘frankincense’) is a traditional Ayurvedic remedy and a component of incense. In India, the effect of the gum resin from B. 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 resulting in a 70% remission rate in 20 patients taking Boswellia for 6 weeks compared with 40% in 10 on sulfasalazine [36].  In a randomized, double-blind, controlled 8 week trial, the B. serrata extract, H15, was compared with mesalamine for active CD [37].  The study included 102 patients and was powered to show non-inferiority. The mean Crohn’s Disease Activity Index (CDAI) fell in both groups and H15 was well tolerated. This result was similar to those 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-inflammatory effects [40-43]. In a recent pilot study, curcumin, when given orally, was reported to benefit five patients with proctitis and five with Crohn’s disease [44]. Hanai and colleagues recently published the results of the first randomized, multicenter, double-blind, placebo-controlled trial from Japan to study the effect of Curcumin on maintenance of UC [45]. All of ninety-seven patients who enrolled and eighty-nine patients who completed the study took a standard dose of mesalamine or sulfasalazine and either 1 gm of Curcumin or placebo twice daily for 6 months and then were followed or another 6 months off study medications.  The relapse rate at 6 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 and Probiotics

a. 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 micro-organisms which, when consumed in adequate quantities, confer a health benefit on the host” [49-52]).  They have been used in the treatment of a number of 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 has shown mixed results regarding benefit as either an induction or maintenance adjunct to standard medical therapy.  In contrast, probiotics have been shown to benefit UC for both induction and for continued remission of disease. Table 2 [65-73].   

b. Prebiotics
As the intestinal microbiota has been linked to the pathogenesis of IBD, probiotic treatment is an avenue for therapeutic intervention. Another method is via the administration of prebiotics. Prebiotics are described 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, 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 then imparts 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.  Butyrate provides fuel for enterocytes, prevents pathogenic adherence and production of anti-bacterial substances, and decreases luminal pH [32, 78-81]. Based on these protective mechanisms, administration of SCFA enemas have been shown to be effective for left-sided UC that is refractory to medical therapy [78-81] [82]. 

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

Fish Oil
n–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 both through modulation of eicosanoid synthesis and through an eicosanoid-independent inhibitory effect on the proinflammatory cytokines. Thus, it has been proposed that supplemental n–3 fatty acids might be beneficial in treating or preventing relapse in chronic inflammatory diseases. 
For IBD, there are animal in vivo and in vitro studies which all show that n-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 for 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 n–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 n–3 fatty acids on steroid requirements suggest that n–3 fatty acids may reduce the need for or effective dose of corticosteroids among patients with IBD. Future studies should assess the effects of pharmaceutical grade enteric-coated n–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, as 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 certainly provides a rationale for further investigation of their potential in the treatment of IBD[107].

There is a further need for clinical trials evaluating the potential efficacy of natural approaches in combination with conventional therapy to achieve better outcomes in IBD. Continued education of health care practitioners about the potential benefits of nutraceutical supplements is essential since these therapies are being increasingly employed by patients with IBD. 


 
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