Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases

Accepted Manuscript Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases Adam S. Cheifetz, MD, Robert Gianotti, MD, Raphael Luber, MD, Peter R. Gibson, MD PII: DOI: Reference:

S0016-5085(16)35193-9 10.1053/j.gastro.2016.10.004 YGAST 60762

To appear in: Gastroenterology Accepted Date: 6 October 2016 Please cite this article as: Cheifetz AS, Gianotti R, Luber R, Gibson PR, Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases, Gastroenterology (2016), doi: 10.1053/ j.gastro.2016.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Gastro 16-01543 Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases Adam S. Cheifetz, MD1, Robert Gianotti, MD1, Raphael Luber, MD2, Peter R, Gibson,

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MD2 1

Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA

2

Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne,

Australia

Corresponding author:

Professor Peter Gibson

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Note: All authors have made equivalent/equal contributions

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Department of Gastroenterology, Alfred Hospital, 99 Commercial Road, Melbourne, Victoria 3004, Australia. Tel +61 9076 3315; Fax +61 3 9076 2194; email: [email protected]

Grant Support:

none

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Abbreviations: CAM, complementary and alternative medicines; CB, cannabinoid; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; EPA, eicosapentaenoic acid; IBD, inflammatory bowel diseases; IL, interleukin; n-3 PUFAs, omega-3 polyunsaturated fatty acids; THC, delta-9-tetrahydrocannabinol; TNBS, trinitrobenzenesulfonic acid; TNF, tumor

Disclosures:

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necrosis factor; UCDAI, ulcerative colitis disease activity index; UC, ulcerative colitis.

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ASC: none related; consulting for Abbvie, Janssen, Takeda, Pfizer, Samsung; RG: none; RL: none; PRG: consulting for AbbVie, Ferring, Janssen, Merck, Nestle Health Science, Danone, Vital Foods, Allergan and Takeda. His institution has received speaking honoraria from AbbVie, Janssen, Ferring, Takeda, Fresenius Kabi, Mylan and Pfizer. He has received research grants for investigator-driven studies from AbbVie, Janssen, Falk Pharma, Danone and A2 Milk Company. His Department financially benefits from the sales of a digital application and booklets on the low FODMAP diet. He has published an educational/recipe book on diet.

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ACCEPTED MANUSCRIPT ABSTRACT Patients and physicians often have many questions regarding the role of complementary and alternative medicines (CAMs), or non-allopathic therapies, for inflammatory bowel diseases (IBD). CAMs of various forms are used by more than half of patients with IBD during some point in their disease course. We summarize the available evidence for the most commonly

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used and discussed CAMs. We discuss evidence for the effects of herbs (such as cannabis and curcumin), probiotics, acupuncture, exercise, and mind-body therapy. There have been few controlled studies of these therapies, which have been limited by their small sample sizes; most studies have been uncontrolled. In addition, there has been a lack of quality control for

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herbal preparations. It has been a challenge to design rigorous randomized placebo controlled trials, due in part to problems of adequate blinding for psychological interventions, acupuncture, and exercise. These barriers have limited the acceptance of CAM by physicians.

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However, such therapies might be used to supplement conventional therapies and help ease patient symptoms. We conclude that physicians should understand the nature of and evidence for CAMs for IBD, so that rational advice can be offered to patients who inquire about their use. CAMs have the potential to aid in treatment of IBD, but further research is needed to

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validate these approaches.

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Key words: herbal medicine, acupuncture, exercise, probiotics

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ACCEPTED MANUSCRIPT Complementary and alternative medicines (CAMs) are a group of diverse medical and healthcare systems, practices, and products that are not considered part of conventional medicine. Non-mainstream treatment approaches used together with conventional medicines are considered complementary, whereas non-mainstream tactics used in place of conventional medicines are called alternative. CAMs are diverse and can include herbal or phytotherapy,

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probiotics and prebiotic, and mind-body practices such as acupuncture and hypnosis. Though many of these practices have been used for centuries, particularly in traditional Chinese medicine, more recently these ways have taken a place on the fringe of Western medicine. CAMs are used commonly by patients with inflammatory bowel disease (IBD).1 Patients do

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not often divulge use of CAM to their physicians,2,3 although some will seek the advice of doctors for how and when to use these therapies. Physicians often have limited knowledge of

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CAMs and may be quick to discount their efficacy. This review aims to better equip gastroenterologists to engage patients in a discussion of CAMs and their role as a complement to conventional IBD therapies. Physicians are urged to explore the use of CAMs with their patients and ensure that they are used safely, and never as an alternative or replacement for

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accepted and well-studied medical therapies.

Use of CAMs

CAMs are used by 30%–50% of patients with IBD.1-6 Patients are often reluctant to mention CAMs with their treating physician and less than half divulge use of CAM to their provider.2,3

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Patients are afraid that their physician will have a negative response if they mention use of CAMs, and often feel more comfortable discussing their use with a nurse or non-physician.7 This discouraging reaction is likely garnered from our own lack of education and knowledge

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on the types and use of CAMs, as medical schools and residency programs often fail to include formal training on the topic.7-9 Despite patient perceptions, most gastroenterologists feel that CAMs can be used to supplement treatment of IBD, although a few have discussed the regulate use of CAMs.8,9 Some patients with IBD use CAMs, including vitamins and supplements, but do not recognize these as such and, therefore, do not report their use to physicians.10 Most patients are interested in learning more about CAMs10, and often cite side effects of standard medications and failure of prior therapies as their main reason. A search of Google for therapies claimed to have efficacy is shown in Supplementary Table 1. Most have little or no evidence.

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ACCEPTED MANUSCRIPT Predictors of CAM use include side effects of or dissatisfaction with conventional therapies4, female sex1,3,11,12, higher education1,6, use by friends or relatives4, long-term progression of disease13, and prolonged use of steroids14. Equal proportions of patients with Crohn’s disease (CD) vs ulcerative colitis (UC) appear to use CAMs1, although there is some discrepancy in the literature on these numbers6,

. The most commonly used CAMs among adult and

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include probiotics , herbs, vitamins, fish oil, and mind-body techniques

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pediatric patients

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12, 15

such as acupuncture1,6,11,17. Although there are conflicting data from different studies, CAM use may reduce adherence to conventional therapy2,5,17. There appears to be some geographic variation in CAM use, even within the US—patients with IBD in California are more likely to use nutritional supplements than patients in Texas, where spiritual therapies are twice as

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common18.

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Overall the data on CAM use vary and are based mainly on survey studies, which are prone to recall bias. However, findings from these types of studies indicate that patients are actively using CAM, often without a physician’s knowledge. We provide a roadmap of the available evidence for the most commonly used and discussed CAMs, with specific dosing strategies

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where appropriate.

Herbs and Dietary Supplements Cannabis/marijuana

Marijuana is derived from the flowering plant Cannabis sativa and has been used for its

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purported medicinal benefits for centuries. Marijuana is classified as a Schedule-1 drug by the US federal government, meaning that it has no medical use and a high potential for abuse. Despite this federal status, several states within the US have legalized the medical use of

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marijuana, decriminalized possession and allowed for legal recreational use19. As of 2016, 4 states (Alaska, Colorado, Oregon and Washington) and the District of Columbia have fully legalized the recreational use of marijuana. An additional 21 states now allow for the medical use of marijuana. Worldwide, marijuana laws are variable and several countries including Uruguay, the Netherlands and Columbia have laws allowing for legal use or cultivation.

The endocannabinoid system includes the cannabinoid receptor 1 (CNR1 or CB1) and cannabinoid receptor 2 (CNR2 or CB2), and their endogenous ligands, anandamide and 2arachidonoyl glycerol (2-AG). Cannabinoid receptors are expressed within the gut wall and enteric nervous system, and may have a role in intestinal motility.20 The major active 4

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in

marijuana

are

the

CBs

that

include

cannabinol

and

delta-9-

tetrahydrocannabinol (THC), the main component responsible for the psychoactive effects.

Animal models show that CB activation attenuates experimental colitis, whereas antagonists or knockouts increase inflammation. This effect is likely mediated through central and

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peripheral CB receptors, because activation at both locations significantly reduces colitis activity21. An experimental extract of Cannabis sativa, delivered into the colon, reduced intestinal inflammation and visceral pain in mice with colitis22. CB2 activation reduced reactive oxygen species produced by intestinal epithelium and decreased production of nitric

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oxide in macrophages23. Additionally, activation of the CB2 receptor attenuated chronic colitis in interlukin-10 knockout mice, which develop colitis, while inducing T-cell apoptosis and reducing mast cells, natural killer cells, and neutrophils in the lamina propria.24. Studies

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have shown dysregulation of the endogenous endocannabinoid system in colon tissues from patients with UC, characterized by increased expression of CB2 and altered levels of the endogenous CB ligand anandamide.25

Patients have long touted the effectiveness of marijuana in the relief of a variety of

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gastrointestinal symptoms including abdominal pain, nausea, and lack of appetite. A recent meta-analysis of 79 randomized trials of marijuana and its derivatives for therapy of various conditions showed that they may be beneficial for chronic cancer pain; chemotherapy-related

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nausea, vomiting, and neuropathic pain; and spasticity in patients with multiple sclerosis.26

Marijuana use is more common in patients with IBD than in the general population. An analysis of a large population-based cohort (NHANES) found that patients with IBD had an

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increased lifetime incidence of marijuana use (67% vs 60% of individuals without IBD), with 37% greater odds of use and an earlier age of first use than individuals without IBD. Marijuana use was particularly common by men over the age of 40.27 Approximately 10%– 15% of IBD patients report active marijuana use, often for relief of symptoms such as nausea, diarrhea, and abdominal pain and to increase appetite.28, 29 Predictors of use include previous abdominal surgery, use of pain medication, and use of other CAMs.29 One-third of patients said that marijuana relieved symptoms better than steroids and two-thirds said that they would quit driving to continue using cannabis. IBD activity is generally higher in patients who use marijuana.30

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ACCEPTED MANUSCRIPT Observational data indicate that marijuana use by patients with CD generally improves their overall perception of health, social function, and ability to work and reduces physical pain and depression, with an increase in weight and a reduction in Harvey-Bradshaw index (HBI) scores31 However, 1 study associated prolonged cannabis use with an increased risk of

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surgery 5-fold, comparable to cigarette smoking.30

One retrospective study of 30 patients with CD associated regular use of marijuana use with a reduction of HBI score, compared with pre-cannabis use score (from 14±6.7 to 7±4.7). Fewer patients required steroids and fewer surgeries were performed in the period of marijuana use,

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although the authors were cautious to ascribe any direct effect of marijuana to these factors without larger, controlled studies. No objective measurements of disease activity were

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reported.32

In the first and only published controlled trial of marijuana use by patients with CD, 21 patients with CD activity index (CDAI) scores above 200 were randomly assigned to groups given 2 marijuana cigarettes per day (115 mg THC) or a cannabis placebo (marijuana plant following extraction of THC). The primary endpoint was clinical remission, defined as a

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CDAI score below 150 after 8 weeks. The primary endpoint was not met though the study population was small and likely underpowered (45% [5/11] of patients receiving THCcontaining cigarettes vs 10% [1/11] of patients receiving placebo cigarettes).

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proportion of the group that received THC (90%) had a reduction in CDAI score of 100 points

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or more vs 40% in the placebo group. Importantly, there was no significant difference in levels of c-reactive protein, before vs after administration of the THC or placebo, between groups. Additionally, there was no objective measurement of inflammation by colonoscopy or

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image analysis. It is also important to consider that 19 of the 21 patients were able to tell what group they were in, essentially unblinding the study.33

Marijuana use does not come without risks, and its use continues to have important legal implications for patients and providers. A recent meta-analysis of marijuana efficacy across a spectrum of diseases demonstrated clear adverse events such as dizziness, nausea, fatigue, confusion, hallucination, and loss of balance26. Acute effects including anxiety and psychosis are also common.19,34 Cannabis use increases the risk of motor vehicle collision secondary to impaired motor skills and decreases attention. Long-term use may also be associated with cognitive impairments including deficits in learning, memory and attention, and in lower 6

ACCEPTED MANUSCRIPT educational achievement. The association with chronic lung disease and cancer is less clear, because epidemiology studies are often confounded by cigarette smoking.34 In addition, marijuana has an analgesic effect that may mask underlying disease progression and potentially increase the risk of complications such as perforation. As marijuana continues to be illegal at the federal level and in half of all states, access for many patients is difficult, if

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not, impossible. Although the federal government has backed away in recent years from prosecuting physicians and patients who are acting in accordance with state law, these rulings are subject to changes. Many physicians continue to be wary of engaging in discussion of medical marijuana, let alone writing prescriptions for fear of their license and DEA

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prescribing privileges being revoked.35,36

Although marijuana may reduce symptoms associated with IBD, there is little evidence to

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support an anti-inflammatory role outside of animal models, and there is no evidence that it positively alters the disease course. There is no way to control the dosing in routine clinical practice and, with the unpredictable psychoactive effects, we cannot recommend its use to treat IBD or offer dosing strategies for patients with IBD until more data are available from

Turmeric and Curcumin

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clinical trials.

Turmeric (Curcuma longa), a rhizomatous plant from the ginger family (Zingiberaceae), is a staple spice in Asian cuisine. Curcumin is a major active ingredient of turmeric that gives the

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root its characteristic yellow color. It has been used for thousands of years, principally as a dye and also for its purported medicinal properties. Curcumin has gained attention for its antiinflammatory properties and usefulness in treatment of gastrointestinal disease; it is among

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the best studied herbs for patients with IBD.

The beneficial effects of curcumin have been shown in mice with colitis. Colonic mucosa from mice with colitis induced by trinitrobenzenesulfonic acid (TNBS) and given curcumin at the time of induction have reduced infiltration by CD4+ T cells and inhibition of nuclear factor (NF)-κB, compared with mice not given curcumin, with reductions in wasting and histologic features of inflammation.37 NCB-02 (a standardized curcuminoid preparation with 70% curcumin) decreases levels of NF-kB and inducible nitric oxide synthase in rats with colitis, and also reduces histologic features of inflammation and myeloperoxidase activity (a

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ACCEPTED MANUSCRIPT marker of neutrophil activity).38 Curcumin has also been shown to block endothelial cell angiogenesis via inhibition of cyclo-oxygenase-2 and prostaglandin E-2.39

In a large pilot study, 50 patients with mild to moderate UC with incomplete response to maximum doses of mesalamine (4 g oral plus topical) were randomly assigned to groups

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given curcumin (3 g/day) or placebo, for 4 weeks, with a primary endpoint of clinical remission.40 Curcumin induced clinical remission in 54% of patients, whereas none of the patients in the placebo group were in clinical remission. A higher proportion of patients in the curcumin group achieved endoscopic remission (partial Mayo score of 1 or less, 38%) than in

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the placebo group (none of the patients). However, unblinding of the curcumin group, based on stool color, might have affected the results of the study.

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Curcumin may also have a role in maintenance of remission in patients with UC. In one study, 89 patients with UC in clinical remission were randomly assigned to groups given sulfasalazine and mesalamine, along with curcumin (1 g of 50% curcumin, twice daily) or placebo for 6 months. Only 5% of patients given curcumin, compared with 21% of patients given placebo, relapsed over the 6 months. Curcumin was also associated with significantly improved clinical activity index and endoscopic scores. Side effects of curcumin were mild,

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and included bloating and nausea.41 Inadequate blinding and insufficient reporting of mesalamine dose may have introduced bias in this study.42 Overall, there are few significant adverse events that limit the use of curcumin. Dose-ranging studies in pediatric patients with

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IBD found only an increase in gassiness with dose increases up to 4 g daily.43

A recent study evaluated NCB-02 enema in the induction of remission in patients with mild to

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moderate distal UC receiving stable doses of oral mesalamine, immune modulators, or steroids. The primary endpoint was a reduction in UC disease activity index by more than 3 points at 8 weeks of therapy. Likely due to a small sample size and a high rate of patients lost to follow up, the intention-to-treat analysis did not show statistically significant difference between groups (57% for the NCB-02 group vs 36% for the placebo group). However, perprotocol analysis did show a significant improvement in response, remission, and endoscopic score in the curcumin enema vs placebo groups.44

Based on the available evidence of efficacy and safety, curcumin can be considered for induction therapy in patients with UC and mild to moderate symptoms, without a complete 8

ACCEPTED MANUSCRIPT response to optimized mesalamine (oral and topical), who do not warrant or want doseescalation to immune modulators or biologics. Curcumin can also be considered as supplementary therapy for patients currently in remission on optimized mesalamine. The

Fish oil

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exact dose is unclear, but, based on the available data should be between 1 and 3 g daily.

Fish oil is found predominantly in oily fish (tuna, salmon, mackerel, herring, sardine) or commercially produced fish-oil capsules.

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The principal components of fish oil are the omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid. These inhibit the

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metabolism of arachidonic acid to the inflammatory eicosanoids.45 As such, they are thought to have anti-inflammatory effects in multiple disorders. The effects of n-3 PUFAs or their derivatives in mice or rats with colitis have been mixed, with some showing benefit in reducing the expression of inflammatory mediators and alleviating colitis,46-50 whereas others showed no benefit51,52 or even increases in some inflammatory mediators.52 In human studies, the effects of fish oils on pathophysiological events have been extensively reviewed and will 53

). The results are unconvincing for consistent effects with

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not be outlined in detail (see positive or no changes51,52,54-58.

Several studies have reported results, presented in Supplementary Table 2. The most rigorous

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trials assessing n-3 PUFAs in patients with CD were EPIC-1 and EPIC-259, which included 363 and 375 patients, respectively, in their modified intention-to-treat analyses. Each study

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found no differences, compared to placebo, in rate of relapse. In EPIC-1, patients received no other therapies, whereas in EPIC-2, patients underwent an 8-week wean from steroids, initially. These results support negative findings from study of 133 patients, that fish oil did not prevent relapse in patients in steroid-induced remission60. In a much smaller cohort of 78 patients, fish oil prevented relapse in patients receiving no other therapy.61

Results from studies of patients with UC have been mostly disappointing. The largest studies assessing patients in remission showed no statistically significant differences in rates of relapse or in macroscopic or histologic appearance with treatment.62,63 Similarly, a subgroup analysis of 34 patients with UC in remission when they began taking EPA confirmed no 9

ACCEPTED MANUSCRIPT statistically significant difference in relapse rate over 1 year (EPA 42% vs placebo 48%).64 However, patients receiving steroids when they were assigned to groups had reduced median corticosteroid requirements in the first 2 months; there was a trend toward a significant difference in proportions of patients who achieved steroid-free remission with EPA vs placebo. Other studies reported potential clinical benefits from fish oil components for

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patients with UC56,57,65,66, but these all involved fewer than 20 patients. Although no safety concerns have arisen57,59,62, a common theme has been patient complaints regarding fishy breath odor60 65,67. So, although there are biologic mechanisms by which fish

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oil could reduce inflammation and positive results from animal studies, there have been insufficient findings from large studies of patients that fish oil maintains remission in patients with CD or UC. At best, fish oil could be regarded as a supplement that at least does no harm.

received little or no attention.

Other herbal preparations

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It is important to note that its interaction with immunomodulatory and biologic therapies have

There are several other herbal preparations that have been studied in some randomized

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controlled trials of patients with IBD (see Table 2). Most have evidence of anti-inflammatory activity from mice or rats with colitis and some indication of efficacy in patients with IBD. However, the magnitude of the effects observed seem small for most of these agents, and many have concerning side effects. For example, wheat grass had promising effects in 23

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patients with active UC, but 1 in every 3 patients developed nausea.68 Promising herbs include aloe vera, which was found 12 years ago to provide convincing benefits, without side effects, to patients with active UC in a study of good quality.69 Wormwood had steroid-sparing and

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remission-inducing effects in 2 small studies (n=40 and 20) performed by 1 group of researchers in patients with CD; it had no documented side effects and was effective in resolving depression.70,71 An extract of Andrographis panniculata (HMPL-004) produced similar responses and rates of mucosal healing, compared with mesalazine, and superior rates of clinical response, compared with placebo, in patients with mild-to-moderate UC in 2 welldesigned studies (n=108 and 224), with minimal side effects.72,73 However, adverse reactions at similar doses led to trial interruption during a phase 1 study of patients with HIV infection.74 Although none of these herbs carry recommendations for clinical practice, some deserve further study.

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ACCEPTED MANUSCRIPT Probiotics Probiotics, in the form of single or multiple cultures of organisms, most commonly bacteria and/or yeast, are ubiquitous in today’s gastroenterology practice and are often the most-used complementary therapy by patients with IBD.17 Most surgeons and gastroenterologists recommend probiotics to their patients in the form of yogurt or over the counter

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preparations.75

Little is known about the mechanisms of beneficial effects of probiotics, but these are likely to be immunomodulatory and anti-inflammatory, such as down-regulation of inflammatory cytokines76 and expression of toll-like receptors.77 Intestinal tissues from mice with colitis

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have increased expression of epithelial tight-junction proteins and reductions in apoptosis.78 Intact bacteria may not be needed to reduce colitis; these severity of colitis in mice can be

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reduced by injection of DNA extracts from VSL#3, a multi-organism combination. This reduction appears to be mediated by toll-like receptor-9 signaling.79 Up-regulation of the antiinflammatory cytokine interleukin 10 (IL10) has also been demonstrated in patients given VSL#3.80

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Effectiveness

There are few data on the effects of probiotics for induction or maintenance of remission in patients with CD, although a recent meta-analysis found that that probiotics provide no significant benefit81. However, several small trials reported reductions in mucosal tumor

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necrosis factor (TNF) activity82 and variable clinical response.83,84 Probiotics, including lactobacillus and VSL#3, appear ineffective in preventing post-operative recurrence of CD.85,86 In a recent study of 119 patients who underwent surgery, those receiving VSL#3 and

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placebo had similar rates of recurrence of severe endoscopic disease (Rutgeerts scores of 3–4) over 12 months, although those receiving VSL#3 had significantly reduced levels of mucosal cytokines at day 90.86

Probiotics, especially VSL#3, might induce remission in patients with mild to moderate UC. In 144 patients, more attained a 50% reduction in the ulcerative colitis disease activity index (UCDAI) score with VSL#3 than with placebo after 8 weeks of treatment (63% vs 41%), but there no differences for clinical remission (UCDAI score less than 2) or in endoscopic score.87 Another study reported clinical remission (UCDAI score below 2) at 12 weeks in a significantly greater proportion of patients receiving VSL#3 (43%) than placebo (16%).88 11

ACCEPTED MANUSCRIPT VSL#3 also appears to increase remission rates when combined with standard therapy in pediatric patients with improved endoscopic severity scores.89 Open-label studies showed that VSL#3 induced clinical remission in 56%–77% of patients when combined with standard therapy, and reduced endoscopic severity.90,91 The addition of VSL#3 to low-dose balsalazide was modestly superior to balsalazide alone in the induction of remission in patients with mild

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to moderate UC.92

Non-pathogenic strains of Escherichia coli (Nissle 1917) appear to be as effective as mesalamine in maintaining remission in patients with UC.93,94 Two large meta-analyses found

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that this bacterial strain provided a small benefit to probiotics. However, this study had limited data and was at risk for bias; the effect appeared to be largely mediated by VSL#3. The recently published Toronto consensus guidelines do not recommend the routine use of

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probiotics to induce or maintain UC outside of a clinical trial.81,95,96

Pouchitis is an inflammatory condition of the ileo-anal pouch likely to be caused by an aberrant immune response and bacterial dysbiosis in genetically susceptible patients. The rationale for probiotic therapy for patients with pouchitis is based on this proposed dysbiosis

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and the ability of probiotics to alter the intestinal flora and modulate the immune response.81 In a randomized study of 40 patients with recurrent pouchitis in clinical and endoscopic remission after 1 month treatment with ciprofloxacin and rifaximin, all of the patients who received placebo relapsed by 9 months, whereas only 15% of the patients given VSL#3

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relapsed during this period.80 VSL#3 given as a once-daily dose also prevented recurrent pouchitis in a study of 36 patients, with 85% achieving remission compared with 6% in the placebo group over 1 year.97 In contrast, real-world experiences have not matched results

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from clinical trials; 80% of 31 patients from the Cleveland Clinic stopped taking VSL#3 due to recurrence of pouchitis or adverse effects (occurred in 2 patients). Only 6 of 31 patients were able to continue taking VSL#3 and remained remission for 8 months; at the end of the study period, none had significant improvements in pouch endoscopy scores.98

VSL#3 was reported to prevent a first episode of pouchitis, when given once daily (900 billion bacteria) to 40 patients: only 10% of patients receiving VSL#3 vs 40% given placebo developed a first episode of acute pouchitis within the first year after pouch formation.99 Higher doses of VSL #3 might be used to treat mild pouchitis. In an open-label nonrandomized study in Italy, 69% of 23 consecutive patients with mild pouchitis given VSL#3 12

ACCEPTED MANUSCRIPT twice per day (3600 billion bacteria daily) were in remission at 4 weeks and maintained that remission over 6 months at a reduced dose (1800 billion bacteria) twice daily.100 However, this study was open-label and would need to be confirmed in a randomized-placebo controlled study.

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Some probiotics may have an adjunct role in patients with UC, but not CD. The largest effects have been observed in patients given VSL#3 for recurrent antibiotic-responsive pouchitis. VSL#3 was given in an attempt to prevent recurrence or prevent a first episode of pouchitis,99 particularly for patients with an increased risk of chronic pouchitis: those who are positive for the anti-neutrophil cytoplasmic antibody101, have pancolitis or have a shorter disease duration

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before surgery.102 Although VSL#3 provides a safe option (side effects mostly limited to

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bloating91,95), its barriers to use include high cost and lack of insurance coverage.

Other Therapies Trichuris suis

In regions with a low incidence of IBD, parasitic infections are endemic. This observation, along with the hygiene hypothesis, lead to the concept that parasitic infections might protect

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against or even be used to treat IBD.103-105 Helminths typically induce T-helper 2 (Th2) and Tregulator (Treg) cell responses, and reduce the Th1 response, to promote worm survival. Induction of Th2 cells has been observed in patients infected with T suis or pig whipworm,106109

a porcine nematode that colonizes humans but does not cause disease.110 In this model, a

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harmless helminthic infection can modulate the immune response to reduce intestinal inflammation in patients with IBD. Animals with parasitic infections have evidence for reduced colitis.111,112 Infection with the hookworm Necator americanus can reduced the

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immune responses and duodenal damage to wheat challenge in patients with celiac disease.113

Small open-label studies of patients with CD or UC reported a response or remission following administration of eggs of T suis,110,114 and randomized controlled trials have been performed for patients with these IBDs. In a study of 54 patients with active UC, 43% responded and 10% reached remission when patients were given T suis every 2 weeks for 12 weeks; this is in comparison to 17% and 4% for patients who received placebo, respectively (P=.04 for response and not significant for remission).115 A large placebo-controlled trial of patients with CD has been completed and the results are eagerly awaited. Treatment-related side effects have been most commonly gastrointestinal, but do not differ in incidence from the 13

ACCEPTED MANUSCRIPT placebo groups. T suis appears to be well tolerated and may have some efficacy in patients with IBD. Further data are required before this should be rolled out into clinical practice.

Acupuncture and moxibustion Acupuncture and moxibustion are Chinese therapies used for more than 4000 years.

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Acupuncture involves the placement of thin needles into the skin at pre-defined ‘acupoints’ to achieve a desired benefit Moxibustion can either be ‘mild-warm’ or ‘herb-partitioned’. Mildwarm moxibustion is where an ignited moxa stick is held over a patient’s skin. Herbpartitioned moxibustion is where ignited moxa cones are placed onto a herbal cake over

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patients’ acupoints.

Multiple studies of rats with colitis, induced by different methods, have provided some insight

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into the mechanisms of acupuncture and moxibustion. Interpretation of results, however, has been challenged by heterogeneity in methods of colitis induction, control groups, acupuncture sites, methods, and outcomes (see supplementary text). Findings from small pathophysiology studies in humans have some concordance with findings from rat studies. The combination of herb-partitioned moxibustion and acupuncture improved intestinal morphology similar to mesalazine in patients with mild to moderate CD, with increases in the expression of tight

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junction proteins116. A small single-blind randomized controlled trial of herb-partitioned moxibustion and acupuncture showed some reductions in CDAI scores, with associated reductions in levels of IL17 and increases in numbers of circulating Treg cells compared to

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controls117. A separate study reported reductions in the inflammatory cytokine IL8 and intercellular adhesion molecule 1 (ICAM1) in patients with UC exposed to herb-partitioned

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moxibustion, compared with control patients exposed to bran-partitioned moxibustion 118.

A meta-analysis of English and foreign language studies examined 10 reports of the effects of acupuncture and moxibustion, combined or alone, vs mesalamine in patients with UC. Although heterogeneity among the studies was low, so was method quality. However, efficacy of both treatments were significantly (more than 5-fold) greater than that of oral mesalamine 1 19.

Six studies have been published in the English language (Table 2) that report positive results in patients with UC or CD. Five tested a combination of acupuncture with 1 form of moxibustion, and 1 tested only moxibustion. The strength of the blinding in acupuncture 14

ACCEPTED MANUSCRIPT studies has been debated—patients who receive placebo are exposed to possible bias from interactions with the non-blinded practitioner. Some of the studies did not provide a moxibustion placebo control120,121. The endpoints measured have varied from clinical disease activity scores to objective measures, but some have used poorly validated measures. Few have reported adverse events; 1 study reported a subcutaneous hematoma from acupuncture

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and a mild burn from sham moxibustion122.

Although results from human studies are impressively positive, they carry multiple limitations. Furthermore, with patients on immune modulator or biologic therapies excluded,

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it is difficult to establish any recommendations regarding the treatments’ role within current therapeutic algorithms. Evidence-based clinical application should therefore be restricted to patients receiving no other therapy, who are unwilling or unable to be treated with

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conventional agents.

Mind-body therapies

Psychologic stress and IBD are intricately related. Patients with IBD have higher rates of anxiety and depression123,124 and lower quality of life;124 there are links between psychologic

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stress and IBD flares.125-127 The mechanisms are poorly understood, but cognitive, physical and autonomic-targeting therapies have been proposed.

The physiological response to stress involves interactions among the hypothalamus, pituitary,

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adrenal glands, the autonomic nervous system, and likely other pathways.125 The vagus nerve appears to regulate anti-inflammatory effects; activation of its afferent fibers stimulates interactions among the hypothalamus, pituitary, and adrenal glands;128,

129

release of

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acetylcholine from its efferent fibers inhibits release by macrophages of inflammatory cytokines such as TNF, through interaction with the α7 subunit of the nicotinic acetylcholine receptor on the macrophage surface.128-130 In patients with CD, there is an inverse association between vagal tone and circulating TNF131; patients with CD have lower vagal tone than controls.132 Vagal stimulation reduced inflammation in rats with colitis induced by TNBS.133

A heterogeneous group of cognitive therapies including relaxation programs, psychodynamic therapies, hypnosis, yoga and comprehensive mind-body programs have been tested with varying rigor against assorted endpoints in patients with IBD (Table 2). Although nearly all findings (except for those from psychodynamic therapies) indicate that these increase quality 15

ACCEPTED MANUSCRIPT of life, psychological status and, in some cases, reduce symptoms such as pain in patients with UC or CD, the strategies have few effects on disease activity itself. The only exceptions were gut-directed hypnotherapy134,135 and, in 1 study, a relaxation program136, although none of the data for reductions in disease activity were of strong quality. Chronic vagal stimulation via an implantable device in an open-label study of 7 patients with refractory CD showed promise; 4

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patients entered remission and 1 responded to treatment, although 2 patients exited the trial due to clinical decline128.

Cognitive techniques are therefore safe, adjunct approaches that improve psychological status

Direct neuromodulation requires further exploration.

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Exercise

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and quality of life in patients with IBD, but may not directly affect inflammatory activity.

There is a strong link between exercise and IBD (see Table 3). Results have not been reported from direct studies of the effects of exercise on varying types and degrees of intestinal inflammation in patients. However, the safety and effects on clinical disease activity have been examined in several studies.137,138 Mild-to-moderate intensity running, 3 times per week over 10 weeks, was well tolerated by 30 patients with mildly active IBD without changes to

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disease activity and with some improvement in wellbeing.139 Likewise, walking 3 times weekly for 12 weeks had no detrimental effects on disease activity in studies of 32 and 12 patients with largely quiescent CD and improved psychological, physiologic, and quality of

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life indices.140,141 A 12-month low-impact exercise program also increased bone mineral density in a randomized controlled trial of 117 patients with CD.142 A regular exercise program would be likely to increase quality of life and general well-being, based on studies of

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other diseases.143 Its implementation may have limitations; for example, in a study of 227 patients with IBD, 44% described multiple barriers to exercise, such as fatigue and joint pain.144

It is likely that mild to moderate exercise programs provide multiple benefits to patients with IBD with at least mild inflammation. Exercise does not appear to have detrimental effects on disease activity, although reductions in intestinal inflammation have not been demonstrated. In contrast, excessive and strenuous exercise might be, at least theoretically, hazardous. In prescribing exercise, physicians should take into account the risk of exercise addiction, which can be associated with excessively strenuous exercise.145 16

ACCEPTED MANUSCRIPT Future Directions Patients with IBD frequently use CAMs. Physicians should be aware of the various types of CAMs, as they are diverse and range from herbs to exercise and psychological therapies. Patients and physicians alike often have many questions regarding the role of CAMs in

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disease management. Few studies have evaluated these therapies, and many had small sample sizes or were uncontrolled. In addition, there is a lack of quality control for herbal preparations and difficulties with design of rigorous randomized placebo controlled trials due, in part, to problems of adequate blinding for psychological interventions, acupuncture, and

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exercise. These barriers have limited the acceptance of CAMs by physicians, who value evidence-based medicine. Regardless, physicians should understand the nature and evidence behind the various CAMs so that rational advice can be offered to patients enquiring about or

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using them. Though CAMs could be used to supplement conventional IBD therapy, further

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research is needed to validate these approaches.

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108. Hoeksema MA, Laan LC, Postma JJ, et al. Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling. Faseb j 2016. 109. Ottow MK, Klaver EJ, van der Pouw Kraan TC, et al. The helminth Trichuris suis suppresses TLR4-induced inflammatory responses in human macrophages. Genes Immun 2014;15:477-86. 110. Summers RW, Elliott DE, Qadir K, et al. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol 2003;98:2034-41. 111. Khan WI, Blennerhasset PA, Varghese AK, et al. Intestinal nematode infection ameliorates experimental colitis in mice. Infect Immun 2002;70:5931-7. 112. Reardon C, Sanchez A, Hogaboam CM, et al. Tapeworm infection reduces epithelial ion transport abnormalities in murine dextran sulfate sodium-induced colitis. Infect Immun 2001;69:4417-23. 113. Daveson AJ, Jones DM, Gaze S, et al. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One 2011;6:e17366. 114. Summers RW, Elliott DE, Urban JF, Jr., et al. Trichuris suis therapy in Crohn's disease. Gut 2005;54:87-90. 115. Summers RW, Elliott DE, Urban JF, Jr., et al. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 2005;128:825-32. 116. Shang HX, Wang AQ, Bao CH, et al. Moxibustion combined with acupuncture increases tight junction protein expression in Crohn's disease patients. World J Gastroenterol 2015;21:4986-96. 117. Zhao C, Bao C, Li J, et al. Moxibustion and Acupuncture Ameliorate Crohn's Disease by Regulating the Balance between Th17 and Treg Cells in the Intestinal Mucosa. Evid Based Complement Alternat Med 2015;2015:938054. 118. Zhou EH, Liu HR, Wu HG, et al. Down-regulation of protein and mRNA expression of IL-8 and ICAM-1 in colon tissue of ulcerative colitis patients by partition-herb moxibustion. Dig Dis Sci 2009;54:2198-206. 119. Ji J, Lu Y, Liu H, et al. Acupuncture and moxibustion for inflammatory bowel diseases: a systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med 2013;2013:158352. 120. Joos S, Brinkhaus B, Maluche C, et al. Acupuncture and moxibustion in the treatment of active Crohn's disease: a randomized controlled study. Digestion 2004;69:131-9. 121. Joos S, Wildau N, Kohnen R, et al. Acupuncture and moxibustion in the treatment of ulcerative colitis: a randomized controlled study. Scand J Gastroenterol 2006;41:1056-63. 122. Bao CH, Zhao JM, Liu HR, et al. Randomized controlled trial: moxibustion and acupuncture for the treatment of Crohn's disease. World J Gastroenterol 2014;20:11000-11. 123. Kurina LM, Goldacre MJ, Yeates D, et al. Depression and anxiety in people with inflammatory bowel disease. J Epidemiol Community Health 2001;55:716-20. 124. Mizrahi MC, Reicher-Atir R, Levy S, et al. Effects of guided imagery with relaxation training on anxiety and quality of life among patients with inflammatory bowel disease. Psychol Health 2012;27:1463-79. 125. Bernstein CN, Singh S, Graff LA, et al. A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol 2010;105:1994-2002. 126. Maunder RG. Evidence that stress contributes to inflammatory bowel disease: evaluation, synthesis, and future directions. Inflamm Bowel Dis 2005;11:600-8. 127. Levenstein S, Prantera C, Varvo V, et al. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 2000;95:1213-20. 128. Bonaz B, Sinniger V, Hoffmann D, et al. Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study. Neurogastroenterol Motil 2016;28:948-53.

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129. Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol 2016. 130. Pavlov VA, Wang H, Czura CJ, et al. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 2003;9:125-34. 131. Pellissier S, Dantzer C, Mondillon L, et al. Relationship between vagal tone, cortisol, TNFalpha, epinephrine and negative affects in Crohn's disease and irritable bowel syndrome. PLoS One 2014;9:e105328. 132. Rubio A, Pellissier S, Picot A, et al. The link between negative affect, vagal tone, and visceral sensitivity in quiescent Crohn's disease. Neurogastroenterol Motil 2014;26:1200-3. 133. Meregnani J, Clarencon D, Vivier M, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci 2011;160:82-9. 134. Keefer L, Taft TH, Kiebles JL, et al. Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis. Aliment Pharmacol Ther 2013;38:761-71. 135. Miller V, Whorwell PJ. Treatment of inflammatory bowel disease: a role for hypnotherapy? Int J Clin Exp Hypn 2008;56:306-17. 136. Milne B, Joachim G, Niedhardt J. A stress management programme for inflammatory bowel disease patients. J Adv Nurs 1986;11:561-7. 137. Narula N, Fedorak RN. Exercise and inflammatory bowel disease. Can J Gastroenterol 2008;22:497-504. 138. Shephard RJ. The Case for Increased Physical Activity in Chronic Inflammatory Bowel Disease: A Brief Review. Int J Sports Med 2016. 139. Klare P, Nigg J, Nold J, et al. The impact of a ten-week physical exercise program on healthrelated quality of life in patients with inflammatory bowel disease: a prospective randomized controlled trial. Digestion 2015;91:239-47. 140. Ng V, Millard W, Lebrun C, et al. Low-intensity exercise improves quality of life in patients with Crohn's disease. Clin J Sport Med 2007;17:384-8. 141. Loudon CP, Corroll V, Butcher J, et al. The effects of physical exercise on patients with Crohn's disease. Am J Gastroenterol 1999;94:697-703. 142. Robinson RJ, Krzywicki T, Almond L, et al. Effect of a low-impact exercise program on bone mineral density in Crohn's disease: a randomized controlled trial. Gastroenterology 1998;115:36-41. 143. Poitras VJ, Gray CE, Borghese MM, et al. Systematic review of the relationships between objectively measured physical activity and health indicators in school-aged children and youth. Appl Physiol Nutr Metab 2016;41:S197-239. 144. DeFilippis EM, Tabani S, Warren RU, et al. Exercise and Self-Reported Limitations in Patients with Inflammatory Bowel Disease. Dig Dis Sci 2016;61:215-20. 145. Jee YS. Exercise addiction and rehabilitation. J Exerc Rehabil 2016;12:67-8. 146. Korkina L, Suprun M, Petrova A, et al. The protective and healing effects of a natural antioxidant formulation based on ubiquinol and Aloe vera against dextran sulfate-induced ulcerative colitis in rats. Biofactors 2003;18:255-64. 147. Park MY, Kwon HJ, Sung MK. Dietary aloin, aloesin, or aloe-gel exerts anti-inflammatory activity in a rat colitis model. Life Sci 2011;88:486-92. 148. Langmead L, Makins RJ, Rampton DS. Anti-inflammatory effects of aloe vera gel in human colorectal mucosa in vitro. Aliment Pharmacol Ther 2004;19:521-7. 149. Anthoni C, Laukoetter MG, Rijcken E, et al. Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis. Am J Physiol Gastrointest Liver Physiol 2006;290:G1131-7. 150. Catanzaro D, Rancan S, Orso G, et al. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage. PLoS One 2015;10:e0125375.

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151. Krieglstein CF, Anthoni C, Rijcken EJ, et al. Acetyl-11-keto-beta-boswellic acid, a constituent of a herbal medicine from Boswellia serrata resin, attenuates experimental ileitis. Int J Colorectal Dis 2001;16:88-95. 152. Hartmann RM, Fillmann HS, Martins MI, et al. Boswellia serrata has beneficial antiinflammatory and antioxidant properties in a model of experimental colitis. Phytother Res 2014;28:1392-8. 153. Hartmann RM, Morgan Martins MI, Tieppo J, et al. Effect of Boswellia serrata on antioxidant status in an experimental model of colitis rats induced by acetic acid. Dig Dis Sci 2012;57:2038-44. 154. Kiela PR, Midura AJ, Kuscuoglu N, et al. Effects of Boswellia serrata in mouse models of chemically induced colitis. Am J Physiol Gastrointest Liver Physiol 2005;288:G798-808. 155. Latella G, Sferra R, Vetuschi A, et al. Prevention of colonic fibrosis by Boswellia and Scutellaria extracts in rats with colitis induced by 2,4,5-trinitrobenzene sulphonic acid. Eur J Clin Invest 2008;38:410-20. 156. Holtmeier W, Zeuzem S, Preiss J, et al. Randomized, placebo-controlled, double-blind trial of Boswellia serrata in maintaining remission of Crohn's disease: good safety profile but lack of efficacy. Inflamm Bowel Dis 2011;17:573-82. 157. Gupta I, Parihar A, Malhotra P, et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res 1997;2:37-43. 158. Gupta I, Parihar A, Malhotra P, et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med 2001;67:391-5. 159. Liu Z, Wilson-Welder JH, Hostetter JM, et al. Prophylactic treatment with Hypoxis hemerocallidea corm (African potato) methanolic extract ameliorates Brachyspira hyodysenteriaeinduced murine typhlocolitis. Exp Biol Med (Maywood) 2010;235:222-30. 160. Wei X, Gong J, Zhu J, et al. Therapeutic effects of triptolide on interleukin-10 gene-deficient mice with colitis. Int Immunopharmacol 2008;8:1808-12. 161. Yu C, Shan T, Feng A, et al. Triptolide ameliorates Crohn's colitis is associated with inhibition of TLRs/NF-kappaB signaling pathway. Fitoterapia 2011;82:709-15. 162. Sun J, Shen X, Dong J, et al. Tripterygium wilfordii Hook F as Maintenance Treatment for Crohn's Disease. Am J Med Sci 2015;350:345-51. 163. Ren J, Wu X, Liao N, et al. Prevention of postoperative recurrence of Crohn's disease: Tripterygium wilfordii polyglycoside versus mesalazine. J Int Med Res 2013;41:176-87. 164. Zhu W, Li Y, Gong J, et al. Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn's disease: a randomized clinical trial. Dig Liver Dis 2015;47:14-9. 165. Qian SZ. Tripterygium wilfordii, a Chinese herb effective in male fertility regulation. Contraception 1987;36:335-45. 166. Ren J, Tao Q, Wang X, et al. Efficacy of T2 in active Crohn's disease: a prospective study report. Dig Dis Sci 2007;52:1790-7. 167. Chung KS, Choi HE, Shin JS, et al. Chemopreventive effects of standardized ethanol extract from the aerial parts of Artemisia princeps Pampanini cv. Sajabal via NF-kappaB inactivation on colitis-associated colon tumorigenesis in mice. Food Chem Toxicol 2015;75:14-23. 168. Ahn BO, Ko KH, Oh TY, et al. Efficacy of use of colonoscopy in dextran sulfate sodium induced ulcerative colitis in rats: the evaluation of the effects of antioxidant by colonoscopy. Int J Colorectal Dis 2001;16:174-81. 169. Wendel GH, Maria AO, Mohamed F, et al. Effect of dehydroleucodine in experimental colitis in rats and mice. Pharmacol Res 1999;40:339-44. 170. Yang Z, Ding J, Yang C, et al. Immunomodulatory and anti-inflammatory properties of artesunate in experimental colitis. Curr Med Chem 2012;19:4541-51.

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171. Keefer L, Kiebles JL, Kwiatek MA, et al. The potential role of a self-management intervention for ulcerative colitis: a brief report from the ulcerative colitis hypnotherapy trial. Biol Res Nurs 2012;14:71-7. 172. Keller W, Pritsch M, Von Wietersheim J, et al. Effect of psychotherapy and relaxation on the psychosocial and somatic course of Crohn's disease: main results of the German Prospective Multicenter Psychotherapy Treatment study on Crohn's Disease. J Psychosom Res 2004;56:687-96. 173. Shaw L, Ehrlich A. Relaxation training as a treatment for chronic pain caused by ulcerative colitis. Pain 1987;29:287-93. 174. Jedel S, Hoffman A, Merriman P, et al. A randomized controlled trial of mindfulness-based stress reduction to prevent flare-up in patients with inactive ulcerative colitis. Digestion 2014;89:142-55. 175. Elsenbruch S, Langhorst J, Popkirowa K, et al. Effects of mind-body therapy on quality of life and neuroendocrine and cellular immune functions in patients with ulcerative colitis. Psychother Psychosom 2005;74:277-87. 176. Sharma P, Poojary G, Velez DM, et al. Effect of Yoga-Based Intervention in Patients with Inflammatory Bowel Disease. Int J Yoga Therap 2015;25:101-12.

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Table 1. CAMs Tested in Randomized Controlled Trials of Patients With IBD Synonyms

Description

Animal/pre-clinical evidence

Marijuana

Murine models: cannabinoid Possible therapeutic potential in

Cognitive and

derived from the

activation attenuates colitis,

CD, reduction in CDAI scores

motor

Cannabis sativa plant

specifically in IL10-

symptom driven, no evidence for impairment,

Yellow spice or

In mice and rats with colitis,

TE D

Turmeric

M AN U

knockout mice 24

Curcumin

Adverse effects

Multiple preparations

SC

Cannabis

Results from human trials

RI PT

CAM

mucosal healing33

anxiety, dizziness, loss of balance, nausea, psychosis

UC induction: 50% increased

Rare nausea and

supplement derived

reduces makers and

response vs placebo 40

diarrhea, yellow

from the Curcuma

histologic features of

UC remission: 15% relapse

stools

inflammation, blocks NF-

reduction vs placebo41**

EP

longa plant

VSL#3

Probiotic

AC C

KB and inducible nitric

8 strains of bacteria

oxide synthase 38 Murine models: variable

UC: possible increase in clinical 81

including

including toll-like receptor

remission

bifidobacteria and

modulation, increased tight

Pouchitis: Prevention and

lactobacillus

junction integrity, and

reduction in relapse99, 100*

increase in IL10 levels76, 77

Rare bloating and diarrhea

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Succulent of lily

In mice with colitis, reduces

Mild to moderately active UC

family

intestinal inflammation and

(n=34): higher rates of clinical

oxidative stress, increases

remission with aloe vera (37%

motility 146, 147

vs 7%, P=.09); improvement in

Nil

RI PT

nil

Complex anti-oxidant and

clinical response (47% vs 14%,

anti-inflammatory

P=.048)69

SC

Aloe vera

properties in human colonic

M AN U

biopsies148 green

annual herbaceous

In mice, reduced

Mild to moderately active UC:

Mild skin rashes

is

chirayta,

plant in the family

inflammation and

1.2 g/d similar efficacy to

(8%)

paniculata

creat, king of

Acanthaceae

production of inflammatory

mesalazine 4.5 g/d (n=108)73.

Safety concerns

bitters, India

Ethanol extract

cytokines, higher proportion

1.8 g/d superior to placebo in

in unrelated

Echinacea

(HMPL-004)

of naive lamina CD4+ T

producing a clinical response but study in HIV

and chuan

evaluated

cells in lamina propria

not remission (n=224)72

Frankincense, derived from the resin

Contrasting effects in mice

No benefit maintaining

epigastric pain,

Salai Guggal,

and rats with colitis, and in

remission in patients with CD

retrosternal

cell lines: Anti-

receiving no other therapy

burning, nausea

Shallaki

of Boswellia trees

AC C

Boswellia

EP

xin lian

TE D

Andrograph

inflammatory effects

149-153

increased severity of 154

colitis , and no effect

155

,

(n=82, 60% vs 55%)

156

and anorexia in

In non-randomized studies,

uncontrolled

produced similar rates of

study

remission to sulfasalazine in

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UC157 and in chronic colitis158 lei gong teng,

vine-like plant that

Triptolide suppressed

More effective than mesalazine

Reversible

m wilfordii

thunder god

grows in southern

severity of spontaneous

in preventing relapse in patients

suppression of

Hook F

vine

China

colitis in IL10-deficient

with CD for 12 months after

male fertility165

Extracts used (e.g.,

mice 159-161

medically induced remission

Leucopenia,

(n=198)162 or curative resection

hepatic dysfunction162

Inferior to azathioprine in

Abdominal pain,

preventing endoscopic lesions

diarrhea166

after curative resection (n=90)164.

Anti-oxidant and anti-cancer In patients with active distal UC

wheat plant Triticum

effects in human cell lines

(n=23), 91% reduction in disease

aestivum

and animal studies, but no

activity index vs 42% with

effect in patients with IBD

placebo (P=.031); trend towards

AC C

Wormwood

(n=36)163.

young grass of the

TE D

-

EP

Wheat grass

M AN U

SC

triptolide)

RI PT

Tripterygiu

endoscopic improvement (78% vs 30% improving, P=.13)68

Artemisia

subtype of the

Various Artemisia species

10 weeks of therapy for 40

absinthium,

Artemisia plant

(not tested in humans)

patients with CD in clinical

reduce inflammation (and

remission ≤40 mg/d

absinthe

carcinogenesis in one) in

prednisolone: CDAI reduced by

wormwood

mice or rats with colitis167-

≥70 in 65% of patients given

absinthe,

Nausea in 33%

Nil reported

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170

wormwood vs none given placebo (P=.01); steroid

RI PT

weaning in 90% vs 45% (P=non-significant); Resolution of depression in 70% vs 0%70.

SC

6 weeks of therapy in 20 patients with active CD: reduction in

M AN U

CDAI score and TNF levels in wormwood group only; Clinical remission in 6 of 10 vs 0 of 1071.

TE D

*UC Induction: 3600 billion bacteria per day (2 double strength packets twice daily88; Pouchitis Induction: 3600 billion bacteria per day (2 double strength packets twice daily)100 – treatment dose 900 billion bacteria daily – prevention dose; Pouchitis maintenance: 1800 billion bacteria daily (6g daily)80, 97

EP

OR

AC C

900 billion bacteria per day (3g daily)99. One double strength sachet of VSL #3 contains 3g or 900 billion bacteria. ** The dose of curcumin in commercially available turmeric preparations is highly variable and can range from 50 to 500 mg. Induction dose in UC 3 g; Maintenance dose in UC 1 g. Table 2. Controlled Trials of Acupuncture and/or Moxibustion, or Cognitive and Autonomic Therapies, for Patients With IBD Interventi

Study Design

Patients

Primary End points

Secondary Endpoints

Quali

Re

ACCEPTED MANUSCRIPT

on

ty

f

Score

RI PT

Acupuncture and/or moxibustion 51 patients with

Decrease in mean CDAI

Treatment was superior to

re and

study of Acupuncture and

mild to moderate

score from 250±51 to

placebo regarding general

moxibusti

moxibustion vs sham

CD

163±56, compared to 220±42

well-being (n=0.045), with

on

acupuncture (without

Treatment (n=27), to 181±46 for placebo group

similarly improved quality of

moxibustion)

placebo (n=24)

life.

12 weeks of follow up

M AN U

10 sessions over 4 weeks,

(P=.003)

SC

Acupunctu Randomized, single-blind

Decrease in mean colitis

Acupuncture and

mild to moderate

activity index score from 8.0

moxibustion each increased

moxibustion vs sham

UC

(±3.7) to 4.2 (±2.4) vs to

general well-being and

acupuncture (without

Treatment (n=15), control from 6.5 (±3.4) to 4.8

quality of life, with no

moxibustion)

control (n=14)

(±3.9) (P=.048)

relative differences

121

1

117

AC C

EP

TE D

study of acupuncture and

Acupunctu Randomized, single-blind

20 patients with

Decrease in CDAI score in

Reduced Th17-associated

re and

study of acupuncture and

mild to moderate

HPM vs control by 111±55

factors and increased Treg-

herb-

HPM vs wheat-bran-

CD

(P=.002).

cell factors in treatment group

partitioned partitioned moxibustion

Treatment (n=10), Reduced histologic markers

compared with controls (all

moxibusti

control (n=10)

P<.01)

and superficial

3

reactive protein

29 patients with

16 weeks of follow up

120

No difference in level of c-

Randomized, single-blind

10 sessions over 5 weeks,

2

of inflammation

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acupuncture; 36 sessions over 12 weeks. 60 patients with

Similar reductions in

Increased expression of tight

control Acupuncture and

mild to moderate

histologic features of CD

junction protein or mRNA of

HPM 6 times per week vs

CD

between groups

ZO1, occluding, and claudin-

mesalazine 4g daily for 12

Acupuncture and

weeks

HPM (n=30),

RI PT

Non-randomized, parallel-

SC M AN U

(n=30)

5

122

protein and mRNA of ZO1 in intestinal tissue samples from patients receiving acupuncture and HPM vs mesalazine

Decrease in CDAI score with

study of acupuncture and

mild or moderate

treatment compared to control hemoglobin, c-reactive

HPM vs superficial

CD

(mean reduction of 108±60 vs proteins, inflammatory bowel

acupuncture and wheat

Treatment (n=40), mean reduction of 32±46)

disease quality-of-life

bran-partitioned

control (n=37)

questionnaire and CD

TE D

77 patients with

EP

116

both groups. Higher levels of

Randomized, double-blind

moxibustion

0

1 compared to baseline for

Mesalazine

AC C

on (HPM)

(P<.0001)

Reduced levels of

endoscopic index of severity

3 times per week for 12

scores with treatment

weeks, 24 weeks of follow

compared to control.

up

(P<.05 for each) Safety: 1 subcutaneous

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hematoma during acupuncture,

RI PT

and 1 mild burn from control moxibustion

109 patients with

Improved clinical state (scale

Similar histological

partitioned of HPM vs bran-

mild to moderate

of much improved, vs

improvement

moxibusti

partitioned moxibustion,

UC

improved or ineffective) in

Down regulation of IL8 and

on alone

72 sessions over 13 weeks

HPM (n=61),

HPM group.

ICAM1 with HPM compared

control (n=48) Mind-body therapies Open-label pilot study,

7 patients with

vagal

6 months in duration

ileocolonic CD

nerve

and CDAI scores

2/3 with level of c-reactive

remission (CDAI score below

protein greater than 5 mg/L

stimulatio

from 220 to 450

EP

n

150)

2

118

0

128

2

171

to control.

4/7 patients achieved clinical

TE D

Chronic

SC

Randomized, blinded stud

M AN U

Herb-

lowered level to below 5 mg/L 2/3 with fecal calprotectin level above 100 µg/g

AC C

achieved levels below 20 µg/g. 5/7 patients in endoscopic remission

Gut-

Randomized controlled

36 patients with

Improvements in IBD

directed

study of hypnotherapy vs

UC, in remission

questionnaire scores and

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hypnother

active attention control,

Treatment (n=19)

overall health-related quality

apy

7 weekly sessions and

Control (n=17)

of life (short-form 12 Health survey version 2) (P<.05 for

1 year of follow up

both)

RI PT

biweekly home practice,

Remission at 1 year in 68%

UC, in remission

vs 40% of controls (P=.04).

Hypnotherapy

Greater time to first relapse

(n=26)

(78 days, P=.03)

M AN U

Control (n=29)

1

134

0

135

2

136

SC

54 patients with

Case series study of

15 patients with

2 (13%) required surgery,

12 sessions in addition to

IBD (UC or CD)

usual treatment, mean

of severe to very

follow-up time of 5.4

severe activity,

1 (7%) moderate-severe,

years

despite steroids

9 (60%) completely weaned

Increased quality of life

4 (27%) complete remission,

TE D

8 (53%) had mild severity,

from steroids

manageme controlled trial of nt classes

6 classes vs none, 1 year follow up

80 patients with

Decreased CDAI score and

CD or UC

IBD stress index at 4 months

EP

Single-blind, randomized

AC C

Stress

Treatment (n=40)

(P<.05), but not control (P

Control (n=40)

value nonsignificant), Sustained for 1 year

ACCEPTED MANUSCRIPT

Psychodyn Single-blind, randomized,

81 patients with

No difference in clinical

controlled, multi-center

CD

course, depression, anxiety,

therapy

study of the effects of 10

Psychotherapy

quality of life, or

and

or more verbal and

(n=52)

psychological and socio-

relaxation

relaxation sessions over

Control (n=29)

communicative function

additional treatment,

M AN U

2 years follow up. Progressiv

Open randomized

40 patients with

e

controlled study of

UC

relaxation

progressive relaxation vs

Relaxation (n=20) inflammatory drugs (P<.03).

waiting list control,

Control (n=20)

12 weeks of follow up

Reduction in multiple pain

39 patients with

Improvements in state-trait

training

active CD or UC

anxiety inventory score, IBD

Treatment (n=18)

questionnaire results, reduced

controlled study of

AC C

and guided 3 treatment sessions and

EP

Relaxation Open, randomized

audio disc vs waiting list, 5 weeks in duration

173

2

124

measures and use of anti-

TE D

6 sessions over 6 weeks,

imagery

1

SC

maximum 1 year vs no

172

RI PT

amic

2

Control (n=21).

pain and stress, and better mood (P<.01 for all), and reduced intestinal symptoms (P<.05), No difference in number of

ACCEPTED MANUSCRIPT

bowel movements.

Randomized controlled

44 patients with

Reduced depression, trait

High drop-out rate (44% in

ss-based

pilot study at 2 centers,

CD or UC

anxiety, and dispositional

treatment group)

cognitive

comparing mindfulness-

Treatment (n=22)

mindfulness (P<.05 for all),

therapy

based cognitive therapy in

Control (n=22)

No difference in disease

activity or modified IBD

weeks vs wait-list control,

questionnaire results.

Double-blind, randomized

55 patients with

ss

controlled study

UC in remission

Mindfulness-based stress

Treatment (n=27)

reduction sessions vs

Control (n=28)

12 months follow up

AC C

8 weekly sessions,

EP

time/attention control,

No difference in rate of, time

Improved IBD questionnaire

to, or severity of flare

scores and lower levels of

TE D

Mindfulne

M AN U

group training over 8

6 months of follow up

3

SC

RI PT

Mindfulne

ACTH in patients with flare receiving treatment vs control (P<.01). No clinically significant differences in fecal level of calprotectin, serum levels of cytokines or c-reactive protein

3

174

ACCEPTED MANUSCRIPT

Randomized, controlled

30 patients with

Improvement in short-form

No difference in TNF levels,

body

study of a mind-body

UC in remission

36 mental health scores

lymphocyte subsets or

program

program (60 hrs training

or low disease

(P<.01), psychological health

endocrine markers

over 10 weeks) vs waiting

activity

sum score (P<.05), and IBD

list control,

Treatment (n=15)

questionnaire bowel scales

8 months of follow up.

Control (n=15)

component (P<.01), but not

0

175

1

176

SC

RI PT

Mind-

other components,

M AN U

No difference in disease activity

Single-blind, randomized

87 patients with

controlled study of yoga (1 CD or UC in

Reduced anxiety (P<.01) in

No differences in markers of

patients with UC but not CD,

autonomic activity or immune

Increase in intestinal colicky

response (soluble IL2R,

remission

additional treatment

Yoga (n=44)

pain in control group (P<.05)

serum eosinophilic cationic

(control)

Control (n=43)

but not yoga group (between-

protein)

TE D

hr/day for 8 weeks) v. no

EP

group difference, P<.05),

AC C

Yoga

No difference in other symptoms

ACCEPTED MANUSCRIPT

Table 3. The link between exercise and inflammatory bowel disease (IBD)

Key evidence

RI PT

Principle

Prospective long-term study of Swedish men presenting for military conscription medical

adolescents and young adults is predictive of

assessments: the least active quintile had a Hazard Ratio of 1.32 (95% CI 1.05-1.66) relative to

subsequent development of IBD

those in the most active quintile24

SC

The degree of exercise undertaken by healthy

Women in the Nurses’ study: the most physically active quintile had a HR of 0.64 (0.44-0.94)

M AN U

compared with those in the least active quintile25. Levels of physical activity in patients with

Chance of self-reported relapse over a 6-month period after measuring exercise levels via a

quiescent disease predict risk of subsequent

validated leisure-time activity index one-third lower in 1308 patients with CD who engaged in

relapse

higher exercise levels (adjusted RR 0.72 (95% CI 0.55-0.94). Risk of disease flares in UC or

TE D

indeterminant colitis (N=549) one-quarter lower in those with the greatest exercise levels (adjusted RR 0.78 (95% CI 0.54-1.13)26. Voluntary exercise reduces inflammation in murine models of chemically-induced colitis 27.

Biological plausibility in the defined or

Mechanisms by which regular exercise has anti-inflammatory effects:

EP

Experimental animal evidence

•

Release from muscles of an array of soluble factors27.

intestinal inflammation

•

Possibly by altering microbiota28.

AC C

postulated mechanisms between exercise and

Mechanisms by which higher intensity exercise can be pro-inflammatory: •

Patients with ileal CD (N=6): one-hour’s moderate aerobic exercise (maximum 60% oxygen consumption) induced neutrophil activation, increased oxidative stress and zinc loss in the urine29.

•

Extreme exercise can result in intestinal ischemia30.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Supplementary Table 1. Therapeutic substances (not including diets, prebiotics or probiotics) claimed to be efficacious in patients with IBD according to Google search (accessed 8-11-16)a Proposed Mechanism(s)

http://www.mayoclinic.org/diseases-conditions/inflammatory-boweldisease/basics/alternative-medicine/con-20034908 http://www.healthline.com/health/crohns-disease/alternativetreatments#Fishoil4

RI PT

Website

Anti-inflammatory

SC

Substance Oral supplements Fish oil

M AN U

http://www.ccfa.org/resources/complementary-alternative.html

http://www.totalhealthmagazine.com/Digestion/Natural-Treatment-ForInflammatory-Bowel-Diseases.html http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#10

(Oral or enema)

http://www.mayoclinic.org/diseases-conditions/inflammatory-boweldisease/basics/alternative-medicine/con-20034908

Anti-inflammatory

EP

Aloe vera

TE D

http://www.drweil.com/drw/u/ART03123/Ulcerative-Colitis-InflammatoryBowel-Disease.html

AC C

http://www.listentoyourgut.com/symptoms/14/crohn-s-disease.html http://www.raysahelian.com/inflammatoryboweldisease.html http://www.naturaldigestivehealing.com/blog/2010/11/11/all-about-aloe/ http://www.compleatmother.com/womens-health/crohns-disease/crohnsdisease.shtml Tumeric/curcumin

http://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-

Anti-inflammatory

ACCEPTED MANUSCRIPT

disease/basics/alternative-medicine/con-20034908

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/

SC

Boswellin

RI PT

http://www.drweil.com/drw/u/ART03123/Ulcerative-Colitis-InflammatoryBowel-Disease.html

Anti-inflammatory, through inhibition of 5lipoxygenase, a key enzyme in the biosynthesis of leukotrienes

M AN U

http://www.totalhealthmagazine.com/Digestion/Natural-Treatment-ForInflammatory-Bowel-Diseases.html

http://www.naturalhealth365.com/crohns-disease-probiotics-zinc-1055.html/

TE D

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

http://www.positivehealth.com/article/colon-health/herbal-treatment-ofirritable-bowel-syndrome-and-inflammatory-bowel-disease

EP

http://www.integrativepractitioner.com/topics/digestive-health/supplementsfor-inflammatory-bowel-disease/ http://www.integrativepractitioner.com/topics/digestive-health/supplementsfor-inflammatory-bowel-disease/

Arsenicum album

http://vitalitymagazine.com/article/nutrition-homeopathy-for-inflammatorybowel-disease/

Anti-diarrheal

Barley Grass Juice Powder

http://www.regenerativenutrition.com/natural-supplements-cure-crohnsdisease.asp

For deep “bowel restoration” and provision of valuable nutrients deficient in Crohn’s disease

AC C

Wheat Grass Juice

ACCEPTED MANUSCRIPT

http://www.regenerativenutrition.com/shop-product.asp?prod=70 http://www.hoffmancenter.com/page.cfm/249

For control of intestinal pain and inflammation

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

Capsaicin

http://www.ecologyhealthcenter.net/node/181

Cayenne Pepper

http://www.emaxhealth.com/1020/natural-ways-might-stop-diarrhea-crohnsdisease

Contains proteolytic enzymes, and displays in vitro reduction in pro-inflammatory cytokines in active IBD colonic biopsies 1 For symptomatic relief of pain, cramps, bloating, and diarrhea Anti-inflammatory

SC

RI PT

Bastyr (Robert’s) Formula B Bromelain (extract from pineapple plant)

(oral or enema)

Clay

http://www.paddingtonclinic.com.au/treating-inflammatory-bowel-diseasenaturally/ http://drsircus.com/medicine/crohns-disease-real-causes-natural-treatments/

TE D

Chamomile

M AN U

http://www.compleatmother.com/womens-health/crohns-disease/crohnsdisease.shtml

“Calming effect” on the gut Acts as a stool bulking agent, absorbs toxins, and stimulates peristalsis

http://www.blissful-wisdom.com/treating-crohns-disease-constipation-anddiverticulitis.html http://www.thesuperfoods.net/coconut/coconut-oil-for-crohns-disease

Anti-inflammatory, anti-microbial

EP

Coconut oil

AC C

http://www.thecocohut.com.au/27/How-Coconut-Oil-Coconut-Water-HaveHelped-My-Crohn-s-Disease Conjugated linoleic acid

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/

Devils claw (Harpagophytum procumbens) Digestive enzyme supplementation

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

Antioxidant, analgesic

http://drsircus.com/medicine/crohns-disease-real-causes-natural-treatments/

Reduces pancreatic workload and hydrochloric acid requirements

ACCEPTED MANUSCRIPT

Fish peptides derived from hydrolysed white fish

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/

Symptomatic reduction through restoring gut integrity

RI PT

http://www.hoffmancenter.com/page.cfm/1233 http://www.raysahelian.com/inflammatoryboweldisease.html

(oral or enema)

http://www.compleatmother.com/womens-health/crohns-disease/crohnsdisease.shtml

Gamma-linoleic acid

http://vitalitymagazine.com/article/nutrition-homeopathy-for-inflammatorybowel-disease/

Ginger

http://www.ion.ac.uk/information/onarchives/crohnsdisease

Anti-inflammatory

http://www.paddingtonclinic.com.au/treating-inflammatory-bowel-diseasenaturally/ http://vitalitymagazine.com/article/nutrition-homeopathy-for-inflammatorybowel-disease/

Enhances repair of the small intestinal lining, aiding nutrient absorption

M AN U

http://www.listentoyourgut.com/symptoms/14/crohn-s-disease.html http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Anti-inflammatory

Anti-inflammatory

EP

Green Tea

TE D

L-Glutamine

Bactericidal

SC

Garlic

AC C

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/ Licorice Root

http://www.positivehealth.com/article/colon-health/herbal-treatment-ofirritable-bowel-syndrome-and-inflammatory-bowel-disease

Jini’s Wild Oregano Oil Protocol Magnesium supplementation Manuka Honey

http://www.listentoyourgut.com/symptoms/14/crohn-s-disease.html

Anti-inflammatory, through inhibition of phospholipase A2 and augmentation of effects of cortisol Anti-bacterial

http://drsircus.com/medicine/crohns-disease-real-causes-natural-treatments/

Anti-inflammatory

http://www.ion.ac.uk/information/onarchives/crohnsdisease

Anti-inflammatory, Anti-bacterial

ACCEPTED MANUSCRIPT

http://lizzycrohnspage.blogspot.com.au/2011/04/powers-of-manuka-honey.html http://umm.edu/health/medical/altmed/herb/marshmallow

Anti-inflammatory, and improves gut epithelial integrity

RI PT

Marshmallow Root

https://draxe.com/marshmallow-root/

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/

Mucopolysaccharides

https://beamingwithhealth.com.au/resources/conditions/inflammatory-boweldisease

Improves healing and regeneration of gut lining

N-acetyl glucosamine

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/

Improves repair of gut damage, and protects uninflamed sections of gut

SC

Melatonin and enteric-coated propionyl-L-carnitine Mercurius solubus

Anti-diarrheal

TE D

M AN U

http://vitalitymagazine.com/article/nutrition-homeopathy-for-inflammatorybowel-disease/

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

EP

http://www.progressivehealth.com/learn-how-n-acetylglucosamine-can-helpcrohns.htm http://www.ecologyhealthcenter.net/node/181 http://www.encognitive.com/node/5100

Phellodendron root

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Phosphatidylcholine

http://drhoffman.com/article/natural-treatment-options-for-inflammatorybowel-disease/

Poria mushroom

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-disease-

AC C

Peppermint oil

Symptomatic treatment through reduction in abdominal pain, bloating and bowel movement frequency Anti-inflammatory

Aids digestion

ACCEPTED MANUSCRIPT

crohns-ulcerative-colitis.html http://www.blissful-wisdom.com/treating-crohns-disease-constipation-anddiverticulitis.html

Absorbs toxins and undigested matter

Salvia root

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Analgesic, through improving “blood congestion”

Scute root

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Anti-inflammatory

Slippery Elm (Oral or enema)

http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#04

Anti-inflammatory

M AN U

SC

RI PT

Psyllium Husk

http://www.drweil.com/drw/u/ART03123/Ulcerative-Colitis-InflammatoryBowel-Disease.html

TE D

http://www.compleatmother.com/womens-health/crohns-disease/crohnsdisease.shtml http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#05

Anti-inflammatory

Thyroplex

http://www.listentoyourgut.com/symptoms/14/crohn-s-disease.html

Rebalances hormones

Tormentil (Potentilla tormentilla)

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

Antioxidant

Vilwa Fruit

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Anti-inflammatory, anti-diarrheal

Vitamin C

https://www.choicesmarkets.com/health-article/the-role-of-antioxidants-ininflammatory-bowel-disease/

Anti-inflammatory, anti-oxidant, and tissue repair properties

White atractylodes

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-disease-

Aids digestion

AC C

EP

Soothing broth

ACCEPTED MANUSCRIPT

crohns-ulcerative-colitis.html http://www.regenerativenutrition.com/natural-supplements-cure-crohnsdisease.asp http://www.regenerativenutrition.com/shop-product.asp?prod=77

http://www.emaxhealth.com/1020/natural-ways-might-stop-diarrhea-crohnsdisease

SC

Zinc

Immune boosting, allowing eradication of gut candida

RI PT

Zell Oxygen live yeast extract

M AN U

Traditional Chinese Medicine Coptis root http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html http://drhoffman.com/article/inflammatory-bowel-disease-update-2/

Ginseng root

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Herbal roots: Astragalus Codonopsis Atractylodis Angelica/Dang gui, White paeony, Aucklandia, Corydalis, Ume plums, Catechu resin, Coptis, Pulsatilla Mucunae Caulis, Sargentodoxae Caulis, and Paederiae Caulis Red peony root

http://vitalitymagazine.com/article/chinese-herbs-for-crohns-colitis/

Tien Chi Root

Anti-inflammatory

“Nourishes” the spleen and stomach, aids digestion and improves diarrhea Aids digestion

Various, including anti-inflammatory, antibacterial, anti-diarrheal, improvement in tissue repair and peristalsis

AC C

EP

TE D

Ginseng

Anti-diarrheal

http://www.zhangclinicnyc.com/IBS/boweldisease.htm

Anti-inflammatory

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Analgesic, through improving “blood congestion”

http://oneearthherbs.squarespace.com/diseases/inflammatory-bowel-diseasecrohns-ulcerative-colitis.html

Ulcer healing and haemostatic effects

ACCEPTED MANUSCRIPT

http://www.tcmassistant.com/symptoms/inflammatory-bowel-disease.html

Coffee Enemas

http://www.livingwhole.org/the-coffee-enema/

Jini’s Healing Implant Enema Milk Kefir-grain enemas Yoghurt Enemas

http://www.listentoyourgut.com/symptoms/14/crohn-s-disease.html

Acupuncture

http://www.mayoclinic.org/diseases-conditions/inflammatory-boweldisease/basics/alternative-medicine/con-20034908

http://www.drdavidwilliams.com/ulcerative-colitis-natural-treatments/

SC

Gut detoxification

M AN U

http://users.sa.chariot.net.au/~dna/IBD/ http://www.naturalremedies.org/enemas/

Provides energy for colonic lining cells. Reduces diarrhea, inflammation, and bleeding

RI PT

Zhen Ren Yang Zang Tang, Wei Feng Tang, Tao Hua Tang Rectal therapies Butyric acid enemas

Anti-inflammatory Anti-inflammatory Probiotic Analgesic, reduces disease activity

TE D

http://www.healthline.com/health/crohns-disease/alternative-treatments http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#06

Abdominal and other Massage

Yoga

AC C

Other therapies Oxygen therapy

EP

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

http://drsircus.com/medicine/crohns-disease-real-causes-natural-treatments/

Anti-inflammatory

http://drsircus.com/medicine/crohns-disease-real-causes-natural-treatments/

Analgesic and stress reduction

http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#02 http://www.blissful-wisdom.com/treating-crohns-disease-constipation-anddiverticulitis.html

Relaxation of the abdominal muscles to improve function of the intestinal tract

ACCEPTED MANUSCRIPT

http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#08

Relieves stress and aids in reducing gut symptoms and flares

Homeopathy

http://www.sixpartswater.org/knowledge-centre/crohnsdisease/complementary-therapies

Various

RI PT

Meditation

http://hpathy.com/cause-symptoms-treatment/a-homeopathic-approach-toinflammatory-bowel-disease-crohns-and-colitis/’

SC

EP

TE D

Google Search Terms: • Natural treatments for inflammatory bowel disease / Crohn’s / Ulcerative Colitis • Alternative treatments for inflammatory bowel disease / Crohn’s / Ulcerative Colitis • Natural enemas for inflammatory bowel disease / Crohn’s / Ulcerative Colitis • Alternative enemas for inflammatory bowel disease / Crohn’s / Ulcerative Colitis • Holistic treatment for inflammatory bowel disease/ Crohn’s / Ulcerative Colitis • Chinese medicine for inflammatory bowel disease

AC C

a

http://www.everydayhealth.com/hs/crohns-disease-treatmentmanagement/complementary-alternative-therapies-for-crohns/#11

M AN U

Hypnotherapy

Symptom reduction, quality of life improvement, and possible immunomodulatory effects

ACCEPTED MANUSCRIPT

Supplementary Table 2. Results of randomised controlled trials examining the efficacy of fish oil or its components

Study Design

Patients

Primary End points

Quality Score

Ref

3

2

4

3

No differences in full blood count, erythrocyte sedimentation rate, sigmoidoscopic appearance or histology between the groups

4

4

No differences in relapse rate, endoscopic or histologic appearance.

No differences in haematologic and biochemical markers, or adverse events

4

5

Improvement in sigmoidoscopic and histologic scores, and reduced NK cell cytotoxic activity.

Improvement in clinical score with treatment.

3

6

No difference in relapse rate (54% with treatment vs. 63% with placebo, p=0.44).

No differences in duration of remission or time to achieve steroid-free remission. EPA: reduced median steroid doses at 1 (5 vs 8 mg) and 2 months (nil vs 5 mg; both p=0.01) Laboratory indices of inflammatory activity unchanged

5

7

5

8

Ulcerative colitis

EPA

Omega-3 fatty acids

N=18 Active disease.

Significant improvements in histology, weight gain, and reduction in rectal LTB4 levels with treatment only. No difference in clinical activity EPA: no differences in symptoms compared to placebo. SEP: improved stool consistency. No differences in relapse rate

M AN U

SC

Mean disease activity reduced with treatment 56% vs 4% with placebo (p<0.05)

N=43 Clinically stable EPA (n=16), SEP (n=19), placebo (n=8)

TE D

Free fatty acid combination: EPA, DHA and γ-linolenic acid (GLA) Fish oil extract

N=11 Mild-moderately active

N=58 In remission Treatment (n=29), placebo (n=29) N=18 Ative distal proctocolitis Treatment (n=9), placebo (n=9) N=87 ≥2 relapses in prior 3 y Treatment (n=45, 26 in relapse), Placebo (n=42, 27 in relapse)

EP

EPA

Double-blind, placebo-controlled, cross-over 2.7 g EPA/1.8 g DHA daily, vs corn oil for 8 month Multicentre, randomized, doubleblind, placebo-controlled, cross-over 3.2 g EPA/2.2 g DHA vs. vegetable oil 4-month treatment periods with 1 month washout Randomized, double-blind, placebo controlled 1 g EPA vs 250 mg super evening primrose oil (SEP) vs olive oil daily for 6 months Randomized, double-blind, placebo controlled 1.62 g EPA/0.27 g DHA/ 9.72 g GLA vs sunflower oil daily for 12 months Randomized, double-blind, placebo controlled 3.2 g EPA/2.4 g DHA vs sunflower oil daily for 6 months Randomized, double-blind, placebo controlled 4.5 g EPA vs olive oil daily for 1 y

AC C

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

Randomized, double-blind, placebo controlled 5.1 g omega-3 fatty acids vs. maize

N=64 In remission with history of flare in previous 2 y

Secondary Endpoints

RI PT

Intervention

No differences in relapse-free survival, macroscopic and histologic appearance with

No statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels.

ACCEPTED MANUSCRIPT

oil for 2 y

treatment

Crohn’s Disease

Omega-3 free fatty acids

Randomized, double-blind, placebocontrolled multicentre trial. 4 g omega-3 fatty acids daily for 52 weeks (EPIC 1) or 58 weeks (EPIC 2). EPIC 2: patients were on 20 mg/d prednisolone or 6mg per day budesonide at commencement of study drug, tapering to cessation over 8 weeks

EPIC 1: N=363 CDAI<150, with disease flare 3-12 months prior Treatment (n=183), placebo (n=180)

Relapse 48% (Treatment) vs 49% (Placebo) (HR, 0.90; 95% CI, 0.671.21; p=0.48).

TE D

EP

Randomized, double-blind, placebocontrolled, multicentre Omega-3 fatty acid compound 6 g vs corn oil daily for 12 months

EPIC 2: N=375 CDAI<150, following 8 weeks of steroid tapering for active disease. Treatment (n=187), placebo (n=188) N=133 CDAI >200 initially, who achieved steroidinduced remission within 3 months, on no other therapies. Omega-3 fatty acid (n=70), placebo (n=65)

AC C

Omega-3 Fatty acid compound

Remission at 1 y: 23 (59%) fish oil vs 10 (26%) placebo Odds of relapse with placebo vs treatment: OR 4.2 (95% CI 1.610.7) Relapse 32% (Treatment) vs. 36% (Placebo) (HR, 0.82; 95% CI, 0.571.19; p=0.30).

Reduction 1 y in ESR (-20% change, p<0.001), serum α2globulins and serum α1-acid glycoprotein with fish oil but not placebo No differences in change in mean CDAI and SF-36. Serum triglyceride concentration decreased in treatment group (21.5 mg/dL vs increase of 6.5 mg/dL, p<0.001) No differences in adverse events No differences in change in mean CDAI and SF-36. Serum triglyceride concentration decreased in treatment group (27.1 mg/dL vs -5.1 mg/dL, p=0.02) No differences in adverse events

RI PT

N=78 CDAI<150, not on other therapies. Fish oil (n=39), Placebo (n=39)

SC

Randomized, double-blind, placebo controlled 2.7 g omega-3 fatty acids daily for 1 y

M AN U

Fish Oil

No significant difference in relapse-free survival

5

9

5

10

5

5

11

ACCEPTED MANUSCRIPT

Supplementary Table 3. Other herbal preparations subjected to randomised controlled trials in patients with inflammatory bowel disease

Study Design

Patients (n)

Primary End points

Secondary Endpoints

Randomized, doubleblind, placebo controlled in a 2:1 ratio. 100 mg BD for 4 weeks

44 Mild-moderate UC Aloe vera (n=30), placebo (n=14)

Clinical remission: 37% Aloe vera vs 7% placebo (p=0.09) No differences in sigmoidoscopic or histologic remission

Randomized, doubleblind A. panniculata 1200 mg/day versus Mesalazine 4500 mg/day for 8 weeks

108 Mild-moderate UC

Randomized, doubleblind, placebo controlled. 1200 mg/d vs 1800 mg/d vs placebo for 8 weeks

224 Mild-moderate UC

Clinical status at week 8: Remission @ week 8: 21% A. panniculata vs 16% of mesalazine. Partial remission: 36% vs 36% At least 25% response: 76% vs 82% (p<0.001 compared to baseline; no between-group difference) Clinical response at week 8: 40% for placebo; 60% for 1800mg (p = 0.01); 45% for 1200 mg/d (p=0.6)

Open, non-randomized, single-centre Boswellia vs. sulfasalazine 3 g daily 300 mg TDS for 6 weeks Open label, nonrandomized study. Boswellia vs. Sulfasalazine 1g TDS 350 mg TDS for 6 weeks Double-blind,

“Chronic Colitis” Boswellia (n=20) sulfasalazine (n=10)

Clinical remission: 90% for Boswellia vs 60% sulfasalazine (p=ns) Endoscopic improvement: 75% vs 40% (p=ns)

No differences in pain, stool properties, histopathology, hemoglobin rise

0

42 UC, Mild-Mod severity Boswellia (n=34), sulfasalazine (n=8)

Remission in 82% Boswellia vs 75% sulfasalazine (p=ns)

Similar improvements in histology, stool properties, iron, hemoglobin, protein, leukocytes

0

16

82

Maintenance of remission: 60%

No difference in mean time to relapse,

4

17

Aloe vera gel

Boswellia serrata gum resin

Boswellia

TE D

EP

AC C

Boswellia Boswellia serrata compound

M AN U

Andrographis Andrographis panniculata ethanol extract (HMPL-004)

Ref

Clinical response: Aloe vera 47% vs 14% (P=0.048) Reduction in median SCCAI score (6.5 to 6.0, p=0.01) No differences in IBD-Q, physician global assessment, laboratory values or adverse events.

5

12

28% in both groups in remission Mucosal healing: 28% A. panniculata vs 24% mesalazine (p=ns)

4

13

Clinical remission at week 8: 38% vs 34% vs 25% (p=ns) Mucosal healing: 50% for 1,800 mg/d vs 33% placebo (p=0.04) Adverse event rates similar

5

14

SC

Aloe vera

Quality Score

RI PT

Intervention

15

serrata extract

CD in clinical remission Boswelan (n = 42), placebo (n=40)

Boswellan vs 55% placebo (P=0.85)

Randomized, controlled, open-label Low-dose (1.5 mg/kg/d) TWHF vs high-dose TWHF (2.0 mg/kg/d) vs mesalazine 3 g/d for 52 weeks Randomized, controlled, open label TWHF (1.5 mg/kg/d) vs azathioprine (2.0 mg/kg/d) for 52 weeks

N=198 CD, CDAI<150 following recently induced remission High dose (n=71), Low dose (n=68), Mesalazine (n=59) N=90 CD with recent ileal or ileocolonic resection TWHF (n=45), Azathioprine (n=45)

Clinical recurrence: high-dose TwHF 7/71 vs low-dose TwHF 15/68 (p=0.047) vs mesalazine 17/59 (p=0.006), at week 52.

Randomized, controlled, single-blind Treatment (1 mg/kg/d) vs oral mesalazine (4 g daily) for 52 weeks

N=36 CD, CDAI<150 following curative resection TwHF (n=19), Mesalazine (n=17)

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randomized, placebocontrolled, multicentre trial, for 800 mg TDS for 12 months (prematurely ceased).

Randomized, doubleblind, placebo-controlled 100 mL daily for 1 month

23 Active distal UC. Wheat grass (n=11), placebo (n=12)

Randomized, double blind, placebocontrolled, multicentre trial.

N=40 CD on ≤ 40mg/d prednisolone. Wormwood (n=20),

Wheat grass juice

Wormwood Dried powdered wormwood

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Rate of endoscopic recurrence: TWHF 32/43 (74%) vs azathioprine 21/42 (50%) at 52 weeks (p=0.03). Mean IBDQ scores: better with TWHF at week 26 (p=0.04) and 52 (p=0.02) No difference in rate of adverse events at week 52, withdrawal for adverse events, CDAI, CRP or ESR Endoscopic recurrence at week 52: TwHF 4/19 (21%) vs mesalazine 9/17 (53%; p<0.001) No difference in adverse event rates, CRP or ESR.

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19

3

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Disease activity index: 10 wheat grass vs. 5 placebo improved (p=0.031)

Improvement in abdominal pain and patient’s retrospective evaluation. No difference in mucus or bloating.

5

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CDAI reduced by ≥70 in 65% of treatment vs. 0% placebo (p=0.01)

Improvement in depression scores with treatment (p=0.01). Resolution of depression in 70% vs 0%.

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Rates of adverse events: high-dose (21/71) or low-dose (19/68) vs. mesalazine (8/59), p<0.05.

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Clinical recurrence: TwHF 12/45 (27%) vs azathioprine 8/45 (18%) at 52 weeks (p=0.45).

Clinical recurrence at week 52: TwHF 1/19 (5%) vs mesalazine 4/17 (24%; p<0.001)

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Wheat grass

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Tripterygium wilfordii Hook F extract (TwHF)

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Tripterygium wilfordii Hook F

CDAI, IBDQ

Successful steroid weaning over 10

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weeks in 90% vs 45% (p=ns) Reduction in CDAI and TNF-α levels in treatment group only.

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Clinical remission in 6 of 10 vs 0 of 10 Trend toward improved IBDQ and depression score

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Reduction in CDAI and TNF-α levels in treatment group only.

Clinical remission in 6 of 10 vs 0 of 10 Trend toward improved IBDQ and depression score

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Placebo (n=20) N=20 CD, CDAI>200 Wormwood (n=10), vs no additional therapy (n=10) N=20 CD, CDAI>200 Wormwood (n=10), vs no additional therapy (n=10)

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500 mg TDS for 10 weeks Randomized, open-label, multicentre trial. Wormwood 750mg TDS vs no additional medication for 6 weeks Randomized, open-label, multicentre trial. Wormwood 750mg TDS vs no additional medication for 6 weeks

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Supplementary Table 3. The link between exercise and inflammatory bowel disease (IBD)

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Table 3. The link between exercise and inflammatory bowel disease (IBD)

Principle

Key evidence

Prospective long-term study of Swedish men presenting for military conscription medical assessments: the

adolescents and young adults is predictive of

least active quintile had a Hazard Ratio of 1.32 (95% CI 1.05-1.66) relative to those in the most active

subsequent development of IBD

quintile24

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The degree of exercise undertaken by healthy

Women in the Nurses’ study: the most physically active quintile had a HR of 0.64 (0.44-0.94) compared with

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those in the least active quintile25. Levels of physical activity in patients with quiescent

Chance of self-reported relapse over a 6-month period after measuring exercise levels via a validated

disease predict risk of subsequent relapse

leisure-time activity index one-third lower in 1308 patients with CD who engaged in higher exercise levels (adjusted RR 0.72 (95% CI 0.55-0.94). Risk of disease flares in UC or indeterminant colitis (N=549) one-

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quarter lower in those with the greatest exercise levels (adjusted RR 0.78 (95% CI 0.54-1.13)26. Voluntary exercise reduces inflammation in murine models of chemically-induced colitis 27.

Biological plausibility in the defined or postulated

Mechanisms by which regular exercise has anti-inflammatory effects:

mechanisms between exercise and intestinal

•

Release from muscles of an array of soluble factors27.

inflammation

•

Possibly by altering microbiota28.

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Experimental animal evidence

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Mechanisms by which higher intensity exercise can be pro-inflammatory: •

Patients with ileal CD (N=6): one-hour’s moderate aerobic exercise (maximum 60% oxygen consumption) induced neutrophil activation, increased oxidative stress and zinc loss in the urine29.

•

Extreme exercise can result in intestinal ischemia30.

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SUPPLEMENTARY TEXT

Acupuncture and moxibustion in rat models of IBD. Moxibustion appears to alleviate histologic injury31-34, thought to be mediated by improved epithelial integrity with increased expression of tight junction proteins35-37, and anti-inflammatory activity. Higher 36

, mast cell

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levels of anti-inflammatory IL-1038 with reduced TNF, TNF receptor 1 and 232-34,

degranulation31, TLR238, IL-1233, IL1-β34, 39, and IL-634, 39 have been shown, along with alterations in intestinal

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microbiota33.

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Acupuncture alone appears to improve epithelial integrity and histology34, 37, with increased expression of anti-inflammatory cytokines IL-1040, 41 and IL-442, and reduced pro-inflammatory agents TNF-alpha34, 43, IL634, 39, IL-841, IL-1 β34, 39, 42, 44, NFkB p6541, 44, MPO45, TLR941, and markers of oxidative stress40. It may also

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alter colonic motility through a possible endogenous opioid pathway 45.

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