586598

research-article2015

NCPXXX10.1177/0884533615586598Nutrition in Clinical PracticeParian et al

CAM Corner

Nutraceutical Supplements for Inflammatory Bowel Disease Alyssa M. Parian, MD1; Berkeley N. Limketkai, MD1,2; Neha D. Shah, MPH, RD, CNSC3; and Gerard E. Mullin, MD, CNSP1

Inflammatory bowel diseases (IBDs), specifically Crohn’s disease (CD) and ulcerative colitis (UC), are relapsing and remitting inflammatory diseases of the intestines. The etiology remains unknown; however, aberrations in genetics, imbalances in the gut microbiome, dietary and lifestyle factors such as cigarette smoking, medications, and environmental triggers are all believed to play a role in disease pathogenesis. A diet high in fiber and omega-3 fatty acids is protective for the development of IBD, whereas a diet high in refined sugars, complex carbohydrates, and omega-6 fatty acids (ie, red meat) increases the risk of acquiring IBD.1-5 The gut microbiome of patients with IBD is characterized by a reduced biodiversity compared with that of disease-free healthy controls.6,7 An aberrant mucosal immune system and irregular mucosal epithelium with increased permeability may permit the translocation of bacterial-derived toxins with resulting gut inflammation.8 This review aims to summarize the data behind complementary and nutrition therapies that directly influence the key steps in the pathogenesis of IBD and thus should be considered in the treatment of IBD.

Prebiotics Prebiotics are nondigestible fibrous products that selectively promote the growth or activity of commensal microorganisms that improve the well-being of the host.9 Prebiotics are carbohydrates that are not typically digestible by the human gastrointestinal tract; therefore, they are selectively fermented by commensal bacteria (ie, Bifidobacteria) and provide nutrients for their metabolism. There are multiple different prebiotics including inulin, fructo-oligosaccharides, galacto-oligosaccharides, soybean oligosaccharides, and complex polysaccharides. Fermentation of prebiotics produces short-chain fatty acids including butyrate, which has anti-inflammatory properties, promotes colonic epithelial integrity and healing, reduces neoplasia, and more.10-14 Inulin and oligofructoses promote the growth of lactobacilli and bifidobacteria, which may reduce inflammation. Prebiotics are not as well studied as probiotics for their influence in the natural history of IBD, with only small noncontrolled studies, typically including only patients with UC. Inulin was found to lower fecal calprotectin level, a marker of colonic

Nutrition in Clinical Practice Volume XX Number X Month 201X 1­–8 © 2015 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533615586598 ncp.sagepub.com hosted at online.sagepub.com

inflammation in patients with UC,15 and germinated barley foodstuff decreased UC clinical activity scores16 and maintained remission.17 Plantago ovata improved UC clinical symptoms and increased the health-promoting short-chain fatty acid butyrate in the stool, although the adverse effects of Plantago ovata, including constipation and flatulence, limit its use.18,19

Probiotics Probiotics are defined by the World Health Organization as “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host.”20 Probiotics aim to alter the microflora of the intestines to a more favorable subset of organisms that may have anti-inflammatory and gut healing properties. An increase in commensal bacteria and decrease in proinflammatory organisms such as Escherichia coli, Enterobacter aerogenes, Klebsiella pneumonia, Streptococcus viridans, Bacteriodes fragilis, Bacteriodes uniformis, and Clostridium ramosum can promote the production of shortchain fatty acids (SCFAs) such as butyrate. SCFAs lower the pH of the colon and therefore prohibit the growth of pathogenic organisms. In addition, probiotics may decrease intestinal permeability and improve the barrier function of the intestines.21 Probiotics also down regulate proinflammatory mediators and induce T regulatory cells to dampen damaging autoimmune responses.22-25 VSL#3 (Sigma-Tau Pharmaceuticals, Gaithersburg, MD) contains 3 genera of bacteria: Lactobacilli (L casei, L plantarum, L acidophilus, L delbrueckii), Bifidobacteria (B longum, B breve, B infantis), and Streptococcus (S salivarius). Multiple trials have found it to have an excellent safety profile. A From 1Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Palo Alto, California; and 3Digestive Health Center, Stanford Health Care, Palo Alto, California. Financial disclosure: None declared. Corresponding Author: Alyssa M. Parian, MD, Johns Hopkins Hospital, 4940 Eastern Avenue, A-Building, Suite 502, Baltimore, MD 21224, USA. Email: [email protected]

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randomized, placebo-controlled trial found that UC patients with pouchitis treated with VSL#3 had an 85% decrease in the rate of relapse.26 A 30% decreased rate of pouchitis was found when using VSL#3 as the primary prevention of pouchitis in patients with UC.27 Current guidelines for the management of pouchitis suggest that VSL#3 be used for prevention of recurrent pouchitis in patients with UC, but there are not enough data to recommend it for the treatment of acute pouchitis.28 Multiple small studies have found positive results for the use of VSL#3 in the induction and maintenance of remission of UC.29-34 A meta-analysis by Jonkers et al35 showed that higher doses of VSL#3 (3600 billion bacteria daily) induced remission in active UC 70% more frequently than placebo.29 Studies of VSL#3 in patients with CD are more limited and less appealing.36-39 A prospective, placebo-controlled trial found that VSL#3 started within 30 days of ileal resection and re-anastomosis trended toward a decreased endoscopic recurrence (9.3% vs 15.7%, P = .19). In addition, compared with placebo, those who received VSL#3 had a decrease in proinflammatory mucosal cytokine expression. The timing seemed to make a difference, as those who were started on the probiotic > 90 days after surgery did not have any less severe recurrence or alteration in cytokine production than placebo.40 E coli Nissle 1917 has been found in several studies to induce and maintain remission in patients with UC and is equally as effective as mesalamine therapy.41-44 Bifidobacteriafermented milk (BFM) containing Bifidobacterium breve, B bifidum, and Lactobacillus acidophilus is effective in inducing and maintaining remission of UC, preventing flares, and increasing the stool concentration of butyrate and short-chain fatty acids.45,46 BIO-THREE probiotic, containing 3 genera of “good” bacteria, was found to induce remission in 45% of patients with UC with mild to moderate distal colitis and increase the levels of Bifidobacteria in the stool and had no significant adverse events.47 Lactobacillus rhamnosus GG (LGG) did not improve active pouchitis symptoms or inflammation in patients with UC despite a proven change in the microbiome.48 LGG has also been studied in active and postoperative CD with negative results.49-51 Another Lactobacillus strain, johnsonii, has been studied in the prevention of postoperative recurrence in CD without a difference clinically or endoscopically compared with placebo.52,53 A small study found that adding Saccharomyces boulardii to standard medical therapy was helpful in maintaining remission in CD.54 However, a recent meta-analysis showed that there was no benefit of Saccharomyces for the treatment of CD.55 A pilot study in patients with active UC found positive results using Saccharomyces boulardii in combination with mesalamine therapy.56 Two meta-analyses found some benefit in probiotics in inducing remission in UC, especially when combined with conventional therapy.57,58 The meta-analyses also demonstrated a benefit in maintaining remission in UC.57,58 Several Cochrane reviews and meta-analyses in patients with CD did

not find a significant benefit of probiotics in decreasing relapse rates,38 preventing postoperative recurrences,36 or maintaining remission.37,39 The small size of the studies, the heterogeneous methodology, and the varied measured outcomes limit these studies. Larger trials are needed to better evaluate probiotics in the treatment of IBD.

Synbiotics Synbiotics are combinations of prebiotics and probiotics that are felt to exert a synergistic effect on the gastrointestinal tract. Two studies of different synbiotics in active CD found promising results with improved clinical symptoms, a decrease in tumor necrosis factor (TNF)-α, and an increase in fecal Bifidobacteria.59,60 In a trial of 30 patients with CD treated with Synbiotic 2000 (combination of 4 probiotics and 4 prebiotics), there was no effect on postoperative recurrence.61 Bifidobacterium longum/Synergy 1 was given to 18 patients with active UC for 1 month and they were found to have improvement in endoscopic inflammation and significantly decreased levels of inflammatory cytokines including TNF-α and interleukin (IL) 1-α. A study of 41 patients with mild to moderate UC randomized to synbiotics (Bifidobacterium breve strain and galactooligosaccharide) or placebo showed more improvement in endoscopic score and lower levels of the myeloperoxidase inflammatory marker.62 A larger study of 120 patients with UC randomized to probiotic, prebiotic, or synbiotic therapy similarly found synbiotics to have greater improvements in symptom scores and C-reactive protein levels.63

Fish Oil Essential fatty acids (EFAs) consist of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). EFAs are not endogenously produced and can be acquired only through dietary intake. Omega-3 EFAs have been shown to have anti-inflammatory properties, whereas omega-6 EFAs are believed to have proinflammatory effects. Fish oil is a valuable source of omega-3 and has been shown to affect the gut immune system by suppressing T cell signaling, inhibiting proinflammatory cytokine synthesis, reducing inflammatory cell recruitment, decreasing the key proinflammatory transcription factor NF-kB, and enhancing epithelial barrier function. There have been 6 individual studies showing benefit from fish oil for the treatment of chemical-induced colitis in animal models.64-69

Induction There are no randomized trials that specifically investigated the use of oral n-3 PUFA for induction of remission in active CD. Several small initial studies showed positive results in the treatment of active UC with fish oil,70-73 including 3

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randomized, placebo-controlled studies showing significant results.70,71,74 One of the randomized, placebo-controlled trials with 18 patients found an improvement in clinical, endoscopic, and histologic scores.74 A larger randomized trial of 121 patients with active UC compared a nutritionally balanced oral supplement enriched with fish oil fructo-oligosaccharides, gum arabic, vitamin E, vitamin C, and selenium with a carbohydrate-based placebo formula for 6 months. No difference in clinical, endoscopic, and histologic scores was seen, but there was a more rapid reduction in prednisone dose in those who received the nutrition supplement.75 A small crossover trial that compared fish oil 5.4 grams per day with sulfasalazine 2 grams per day in 10 patients with mild to moderate active UC found significantly increased inflammatory markers (ie, C-reactive protein, erythrocyte sedimentation rate, and platelets) in the fish oil arm.76 Despite lower sigmoidoscopy scores, there was no difference in histologic scores. The study investigators therefore concluded that sulfasalazine was superior to fish oil in the treatment of mild to moderate active UC.

Maintenance The Epanova Program in Crohn’s Study 1 (EPIC-1) and 2 (EPIC-2) were 2 randomized controlled trials that recruited patients with quiescent CD from 98 centers in the United States, Canada, Europe, and Israel.77 The participants were randomized to commercial omega-3 fatty acid capsules (50%60% EPA, 15%-25% docosahexaenoic acid) or placebo. Relapse rates were similar in both treatment arms. A recent meta-analysis by the Cochrane Collaboration evaluated the efficacy of n-3 PUFA for the maintenance of remission in CD.78 The pooled analysis included 6 studies with 1039 participants and showed a marginal benefit of n-3 PUFA compared with placebo (relative risk [RR] = 0.77; 95% confidence interval [CI], 0.61-0.98). However, there was unexplained heterogeneity (I2 = 58%) and 4 studies were graded as having high or unknown risk of bias.79-82 The remaining 2 studies considered to have no significant heterogeneity and low risk of bias were the EPIC-1 and EPIC-2 studies. The protective effect of n-3 PUFA was no longer statistical significant (RR = 0.88; 95% CI, 0.74-1.05) with these 2 combined studies. The efficacy of fish oil seems to be improved when combined with mesalamine therapy80 and when used for Crohn’s colitis rather than small bowel enteritis.79 A systematic review is difficult to perform on this topic due to variation in fish oil formulations, differences in disease location, and severity. Fish oil may have its greatest effects in patients with IBD with proven essential fatty acid deficiency, and once levels are replete, there may be no further benefit.83 For the maintenance of remission in UC, the 3 randomized trials that compared fish oil with placebo in 138 patients did not detect a difference in 1- to 2-year relapse rate.84-86

Curcumin Curcumin is a naturally occurring substance from the plant Curcuma longa and has been used successfully in Ayurvedic medicine for hundreds of years. Curcumin has natural antiinflammatory properties acting on the arachidonic acid cascade and inhibiting NF-kB as well as immunosuppressive effects by inhibiting IL-2 synthesis and TNF-α.87,88 Multiple animal studies found that curcumin was able to treat as well as prevent chemically induced colitis.89-91 In a human pilot study, 10 patients (5 CD, 5 UC) were treated with curcumin and 90% improved symptomatically and serologically. Four of the 5 patients with UC were able to decrease or stop concurrent colitis medication.92 A larger, randomized, double-blind, placebocontrolled trial of 89 patients with quiescent UC on baseline mesalamine therapy found that the addition of curcumin 1 gram orally twice daily resulted in symptomatic and endoscopic improvement as well as a significantly lower relapse rate.93 Curcumin has been shown to have an excellent safety profile and is well tolerated.94,95 Due to its chemopreventive activity against colon cancer,96 curcumin may be an ideal adjunctive therapy for colitis patients due to their increased risk of colorectal cancer. A Cochrane review was performed to evaluate the efficacy and safety of curcumin for maintenance of remission in patients with UC.97 Only 1 study by Hanai et al,93 mentioned above, met the inclusion criteria, and the Cochrane analysis concluded that curcumin may be a safe and effective adjunctive therapy when coupled with mesalamine for maintenance of remission, but further studies are needed.

Boswellia Boswellia serrata is another frequently used Ayurvedic herb to treat inflammatory conditions by also acting on the arachidonic acid cascade and inhibiting leukotrienes, leading to a decrease in proinflammatory cytokines.98 A study by Gupta et al99 found that B serrata (350 mg 3 times a day) was as effective as sulfasalazine therapy in reducing symptoms in patients with UC. A randomized, double-blind controlled trial by Gerhardt et al100 showed a Boswellia extract (H15) to be equivalent to mesalamine in the treatment of CD. A double-blind randomized controlled trial of 108 patients confirmed the safety and patient tolerability of B serrata.101

Other Herbal Therapies Aloe vera is well-known in traditional medicine to promote gut epithelial healing and has been shown to be an antioxidant with possible anti-inflammatory properties and found to decrease reactive oxygen metabolite production in a dose-dependent manner in in vitro studies.102 The studies on aloe vera are limited to mostly case reports showing improved colitis with oral therapy.102-109 One placebo-controlled trial in patients with UC

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did find aloe vera efficacious in achieving clinical and microscopic improvement and with minimal side effects.108 Wheat grass juice (triticum aestivum) is also believed to have antioxidant properties110 and has been used for the treatment of thalassemias, intestinal diseases, and IBD. Pigenin, the major component of wheat grass, blocks production of proinflammatory cytokines IL-1β, IL-8, and TNF through inactivation of NF-κB.111 A randomized, placebo-controlled trial in patients with active UC found that 100 mL of wheat grass juice was associated with decreased disease activity and rectal bleeding.112 An herbal treatment consisting of myrrh, dry extract of chamomile flowers, and coffee charcoal has been shown to have anti-inflammatory and antidiarrheal properties. A study of this herbal preparation found it noninferior to low-dose mesalamine treatment in the maintenance of remission of UC.113

Vitamin D Vitamin D regulates cell growth and is an important cofactor for the immune system. Deficiencies in vitamin D have been linked to several inflammatory conditions.114-116 Along with calcium, vitamin D is essential for bone health, which is prudent in patients with IBD who have many risk factors for poor bone health, including chronic inflammation and steroid use. Vitamin D supplementation has been shown to restore immunoreactivity and decrease monocyte production of IL-6 and TNF-α.117-120 Endogenous production of vitamin D in the skin during exposure to UVB sun rays is the major source. Fatty fishes, cod liver oil, beef liver, egg yolks, and fortified milk contain high levels of vitamin D.121 Levels of vitamin D < 20 ng/mL are considered deficient, whereas levels between 20 and 30 ng/mL are considered insufficient.121 Patients with IBD are frequently deficient in vitamin D due to sun avoidance in those on thiopurines, small bowel inflammation affecting absorption, ileal resection affecting bile salt resorption, increased excretion in the stool, and higher requirements.121-125 Vitamin D deficiency may be a risk factor for the development of IBD supported by higher rates of IBD in northern latitudes and an increased number of flares during winter (low sunlight) months.126-128 In the Nurses’ Health Study, a lower risk of CD was seen in participants with higher vitamin D levels. In addition, those taking vitamin D supplements had a lower risk of the development of UC.129 Ananthakrishnan et al130 found in a prospective study that patients with CD who normalized their vitamin D level through supplementation had a lower rate of hospitalization and surgery. Smaller studies in patients with CD taking vitamin D supplementations have shown a trend toward a decrease in relapse rates and a lower disease activity score.131,132

Conclusion Several nutraceuticals show promising results for the treatment of inflammatory bowel disease with minimal to no side effects

Table 1.  Therapeutic Modalities in the Treatment of Inflammatory Bowel Diseases. Therapy Probiotics Fish oil Curcumin Boswellia Butyrate enemas Aminosalicylates Corticosteroids Azathioprine Infliximab

Level of Evidencea

Level of Risk

A B B B B A A B A

Low Low NA Low NA Moderate High High High

NA, not available. a Level of evidence is based on Strength of Recommendation Taxonomy (SORT). Grade A is based on consistent, good-quality, patient-oriented evidence such as systematic reviews or meta-analyses, or high-quality patient-oriented randomized controlled trial. Grade B is based on inconsistent or limited-quality patient-oriented evidence. Grade C is based on consensus, usual practice, opinion, or disease-oriented evidence.

(Table 1). Prebiotics and probiotics appear to alter the gut microbiome by increasing biodiversity and increasing the production of butyrate, an anti-inflammatory and antineoplastic agent of the gut. Fish oil acts as a direct anti-inflammatory agent as well as an immune regulator. Curcumin and Boswellia both are anti-inflammatory agents that act on a variety of receptors, and vitamin D affects cell growth and immune system regulation. As per President Obama, we are at the dawn of the age of personalized medicine and the U.S. federal government will be further investing to bring this to fruition. Thus, in the future we may be able to predict response to these natural therapies based on gut microbiome analyses, serological markers, and more. Continued trials are needed to determine the subset of patients with IBD who would respond best to each nutraceutical and how to best combine natural medicines with conventional pharmaceuticals.

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