Content uploaded by Alyssa Parian
Author content
All content in this area was uploaded by Alyssa Parian on Jan 07, 2016
Content may be subject to copyright.
Title Page
Title: Dietary Supplement Therapies for Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative
Colitis
Running Title: Alternative therapy in IBD
Alyssa Parian, MD (Corresponding author)
Assistant Professor
Johns Hopkins School of Medicine
Department of Gastroenterology
4940 Eastern Avenue, A-Building 502
Baltimore, MD 21224
P: 410-550-5122
F: 410-550-7861
Berkeley N. Limketkai, MD
Clinical Assistant Professor
Stanford University School of Medicine
Division of Gastroenterology and Hepatology
Dietary Supplement Therapies for Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative
Colitis
Abstract
Inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease are chronic relapsing
and remitting chronic diseases for which there is no cure. The treatment of IBD frequently requires
immunosuppressive and biologic therapies which carry an increased risk of infections and possible
malignancy. There is a continued search for safer and more natural therapies in the treatment of IBD. This
review aims to summarize the most current literature on the use of dietary supplements for the treatment
of IBD. Specifically, the efficacy and adverse effects of vitamin D, fish oil, probiotics, prebiotics,
curcumin, Boswellia serrata, aloe vera and cannabis sativa are reviewed.
Introduction
The inflammatory bowel diseases (IBD) of Crohn’s disease (CD) and ulcerative colitis (UC) are relapsing
and remitting chronic diseases of the gastrointestinal tract. The pathogenesis of IBD has not been well
elucidated, but studies so far support a multifactorial process involving genetics, environment exposures,
and the gut microbiome. There are 163 known IBD risk genes that partly explain the development of IBD
in the population.(1) Environmental factors, such as diet, medications, and hygiene, appear to
demonstrate a role in IBD pathogenesis.(2-4) Further support for the presence of environmental triggers
in IBD come from migrant studies that have demonstrated an increased incidence of IBD among those
who migrate from regions of lower IBD incidence to regions of higher incidence.(5) Alterations in the gut
microbiome, through antibiotic use (3) or acute gastroenteritis (6, 7) have been shown to increase the risk
of developing IBD.
Most IBD patients will eventually require immunosuppressant therapy to control their disease. However,
currently available medications have limitations, and despite the availability of powerful therapies, half of
CD patients may still require surgery within 10 years after diagnosis.(8) Even the anti-tumor necrosis
factor (anti-TNF) therapies – among the most potent immunosuppressants used for IBD – only has
modest response rates.(9) The additional concern with traditional immunosuppressants is the potential for
serious adverse events, such as infections (tuberculosis, reactivation of hepatitis B and fungal infections),
malignancies (lymphomas and skin cancers) and skin reactions. There is a continued search for safer and
more natural therapies to treat IBD. This review discusses the current literature on the use of selected
dietary supplement therapies for the treatment of IBD, specifically, vitamin D, fish oils, probiotics,
prebiotics, curcumin, Boswellia serrata, Aloe vera, and Cannabis sativa. The role of diet, other alternative
therapies and nutritional deficiencies in IBD are also important but were outside of the scope of this
review.
Vitamin D
Vitamin D is a fat-soluble hormone that includes ergocalciferol (D2) and cholecalciferol (D3). Sources of
vitamin D in humans include diet, vitamin supplements, and endogenous synthesis through sunlight
(ultraviolet B) exposure. Foods rich in vitamin D include fatty fish, cod liver oil, beef liver, egg yolks, and
vitamin D-fortified milk.
Vitamin D has traditionally been associated with bone health, but more recently discovered to possess
immunomodulatory properties. Some immunologic effects of vitamin D include impairment of
lymphocyte proliferation, expansion of regulatory T cells, and modulation of inflammatory cytokine
release.(10-15) Consequently, a deficiency in vitamin D has been associated with several autoimmune
disease, such as multiple sclerosis,(16) rheumatoid arthritis,(17) and systemic lupus erythematosus.(18)
Early murine studies have also shown a relationship between vitamin D and IBD (both CD and UC) [CD
or UC, it’s important to differentiate, or at least say there was none]. Vitamin D receptor (VDR) knockout
led to more severe colitis than VDR wild-type in an IBD mouse model.(19) In another experiment,
vitamin D-sufficient mice did not develop IBD symptoms, while vitamin D-deficient mice experienced
diarrhea, wasting disease, and death.(20) In humans, epidemiologic studies have shown a higher
incidence of IBD in northern latitudes, where sunlight exposure and natural vitamin D synthesis are
lower.(21, 22) Low sunlight exposure has also been associated with an increased risk for hospitalizations
and bowel surgeries related to IBD,(23) and normalization of vitamin D-deficient levels in CD may lead
to lower rates of hospitalization and surgery.(24) An analysis of the prospective Nurses’ Health Study
additionally revealed that 25-hydroxyvitamin D protected against CD, but not UC.(25) Smaller studies in
CD patients have shown a trend toward decreased relapse rates and lower disease activity scores.(26, 27)
Although there are suggestions in animal studies, epidemiologic data, and small cohort studies that
vitamin D may improve IBD (11, 15, 24-38), the evidence is still circumstantial. Larger and more robust
randomized controlled trials are needed to determine whether vitamin D can indeed influence disease
activity and to what degree. Moreover, although < 20 ng/mL vitamin D is considered “deficient” in adults,
and levels between 20 and 30 ng/mL are considered “insufficient”, the optimal dose for
immunomodulation is unclear. In any case, vitamin D deficiency occurs frequently in IBD patients due to
increased sun avoidance while on thiopurines, small bowel inflammation causing relative malabsorption,
ileal resection affecting bile salt resorption, and increased stool excretion.(39-43) Vitamin D levels should
be checked and repleted as needed in IBD patients.
Fish Oils
The fatty acids most implicated in the inflammatory pathway include the omega-3 and omega-6
polyunsaturated fatty acids.(44) Omega-3 fatty acids are believed to possess immunomodulatory
properties, while omega-6 fatty acids possess pro-inflammatory properties. Since fish oil is a rich source
of omega-3 fatty acids, there have been multiple research studies assessing the role of fish oil in the
induction and maintenance of remission in IBD.
Crohn’s Disease. Diets high in omega-3 fatty acids may be associated with a lower risk of developing
Crohn’s.(45) For CD, although there are no randomized trials that evaluated the use of fish oil for
induction of remission, several exist that evaluate fish oil for maintenance of remission. Two large multi-
national randomized controlled trials found no difference in relapse rates between participants
administered omega-3 fatty acid capsules or placebo.(46) However, a subsequent meta-analysis that
included these two trials showed some benefit of omega-3 fatty acids over placebo(47). Potential
limitation raised by the authors of the meta-analysis is the heterogeneity among the included studies.
Therefore, the utility of fish oil for the induction of remission is still unclear. Fish oil therapy may be
more efficacious for Crohn’s colitis rather than ileitis. (48) Additionally, fish oil may act synergistically
with mesalamine therapy. (49) The benefit of fish oil may however be greatest among IBD patients with
essential fatty acid deficiency.(50)
Ulcerative Colitis. An early study evaluating the treatment of both UC and CD with fish oil concluded the
clinical benefit was confined to UC patients.(51) For active UC, two small cross-over studies (17 and 24
patients, respectively) and a randomized trial (18 patients) found greater improvement in clinical and
histologic scores among participants administered fish oil when compared with placebo.(52-54) A
subsequent trial of 121 UC patients showed a more rapid reduction in prednisone dose among those who
received fish oil-enriched supplement (also including fructooligosaccharides, gum arabic, vitamin C,
vitamin E, and selenium), compared with a carbohydrate-based placebo formula, but otherwise found no
difference in clinical, endoscopic, or histologic scores.(55) A small cross-over trial of 10 UC patients
found that, compared with sulfasalazine (2 grams per day), fish oil was associated with greater
inflammation by serology (C-reactive protein, erythrocyte sedimentation rate, platelets), lower
sigmoidoscopic activity, and otherwise no difference in histologic scores.(56) These findings suggest that
sulfasalazine may be superior to fish oil for mild-to-moderate UC. For the maintenance of remission in
UC, three randomized trials that compared fish oil with placebo in 138 patients did not show a difference
in relapse rates.(57-59)
Probiotics
Probiotics are live microorganisms that confer a health benefit on the host. (60) (61) Probiotics are
believed to work through several different mechanisms: by decreasing pro-inflammatory cytokine
secretion, increasing anti-inflammatory cytokine secretion, inducing regulatory T cells, (62) decreasing
intestinal permeability (63) and increasing production of short chain fatty acids. (63) Probiotics aim to
alter the microbiome towards a more favorable, anti-inflammatory species of bacteria. (64, 65)
VSL#3
VSL #3 (Sigma-Tau Pharmaceuticals, Gaithersburg, MD) is one of the most studied probiotics for the
treatment of IBD. It contains three genera of bacteria: Lactobacilli (L casei, L plantarum, L acidophilus,
L delbrueckii), Bifidobacteria (B longum, B breve, B infantis), and Streptococcus (S salivarius).
Ulcerative colitis – Two studies of VSL#3 on active UC found VSL#3 induced remission in greater than
50% of patients with no control group for comparison. (66, 67) Tursi et al. compared VSL#3 plus
balsalazide to both balsalazide alone or mesalazine alone in active UC patients and showed the VSL#3
combination with balsalazide was faster in obtaining remission and improved endoscopic and histologic
inflammation compared to the other two therapies. (68) Three placebo-controlled trials reported that
VSL#3 3600 billion CFU/daily (or weight adjusted for children) was superior in improving symptomatic
scores, inducing remission, maintaining remission and decreasing rectal bleeding in UC patients. (69-71)
A meta-analysis in 2012 concluded that 3600 billion bacteria daily of VSL#3 induced remission in UC
70% more frequently than placebo. (72) The newest meta-analysis from 2014 found a 2.4 fold increase in
remission rate with the use of VSL#3 3600 billion colony forming units daily compared to placebo
without any serious side effects. (73)
Pouchitis. The best data for the use of VSL#3 is in pouchitis prevention in UC patients with recurrent
pouchitis. Compared to placebo, VSL#3 was more likely to keep pouchitis patients in remission after
initial induction with antibiotics (p < 0.001). (74, 75) One study showed contradictory results without
higher rates of remission with VSL#3 use, although there was a high drop-out rate with a small
population.(76) Pronio et al. compared VSL#3 to placebo for 12 months in asymptomatic patients who
have undergone ileal pouch anal anastomosis (IPAA). VSL#3 treated patients had better pouchitis disease
activity index scores and an expanded number of mucosal regulatory T cells. (77) A systematic review
from 2012 concluded that VSL#3 significantly prevents relapses in IPAA patients (72) and the current
guidelines recommend VSL#3 for the prevention of recurrent pouchitis. (78)
Mild active pouchitis in 23 patients was treated with VSL#3 with 69% of patients achieving remission.
(79) Gionchetti et al. also studied whether VSL#3 could prevent the first occurrence of pouchitis in a
placebo controlled trial one week after ileostomy closure. Only 10% of patients treated with VSL#3
developed pouchitis at one year compared to 40% in the placebo group. Additionally, the symptomatic
scores were better in the VSL#3 group with a lower stool frequency and shift towards a less inflammation
pouch microbiotia.(80)
Crohn’s Disease. The studies of VSL#3 in Crohn’s patients are less promising. The largest prospective,
randomized trial in post-operative Crohn’s patients found no difference between patients treated with
VSL#3 versus placebo. However, in patients given VSL#3 within 90 days of the surgery, there was a
trend towards significance suggesting that timing may play an important role. (81) Four separate
systematic reviews did not find a significant improvement in CD patients treated with VSL#3. (82-85)
Lactobacillus
Crohn’s Disease. Lactobacillus rhamnosus GG (LGG) has been studied in Crohn’s disease without an
appreciable benefit on post-operative disease recurrence, (86) induction or maintenance of remission in
adult Crohn’s patients, (87) or the maintenance of remission in pediatric patients when added to standard
therapy.(88) In UC patients, LGG appears to have a more beneficial effect by prolonging remission.(89)
Another study showed acute pouchitis patients treated with LGG had a positive change in the pouch
microbiome, but experienced no clinical improvement. (90) However, if LGG was given immediately
after IPAA surgery, it was been shown to delay the first episode of pouchitis. (91)
Lactobacillus johnsonii, LA1, was studied in two trials for the prevention of post-operative recurrence in
Crohn’s patients. Both were randomized, placebo-controlled studies with > 50 patients each and neither
found a decrease in post-operative recurrence with the use of LA1. (92, 93) There are no published trials
of this particular strain of probiotic in UC patients.
Saccharomyces boulardii
Saccharomyces boulardii is a nonpathogenic strain of yeast that appears to have probiotic qualities with
some data to support its use in the prevention of Clostridium difficile relapses. (94, 95)
Ulcerative Colitis. In UC patients, one trial found 17 (71%) of 24 patients with mild to moderate activity
given S. boulardii plus mesalamine attained clinical and endoscopic remission suggesting S. boulardii
may be effective in treating active UC; however, there was no comparison control group.(96) A small case
series of 6 patients with left sided UC treated with S. boulardii plus rifaximin all had improvement in
symptoms. (97) Larger, placebo-controlled studies are warranted for the use of S. boulardii in UC.
Crohn’s Disease. In CD patients, S. boulardii was shown to decrease the number of daily bowel
movements (98) and maintain remission. (99) S. boulardii has also been found to improve intestinal
permeability in Crohn’s patients. (63) However, a large randomized, placebo-controlled trial found S.
boulardii was not effective in maintaining remission in CD patients after induction with steroids or
salicylates. (100) The addition of S. boulardii to standard Crohn’s therapy has not been evaluated yet and
further studies are needed to determine its role in CD treatment.
Escherichia coli Nissle 1917
Ulcerative Colitis. Escherichia coli Nissle 1917 (EcN) was found to be equivalent to low dose
mesalamine in maintaining remission of UC. (101, 102) One study showed EcN enemas to be equally as
effective as mesalamine in treating distal UC.(103) A dose-finding multicenter trial of EcN enemas was
performed on 90 patients with ulcerative proctitis or proctosigmoiditis. Due to the large drop-out rate, the
intention to treat analyses were not significant; however, per protocol analysis showed a dose dependent
efficacy and histologic improvement. At least half of the premature discontinuations were due to lack of
efficacy and the rest were due to adverse events including flatulence and “other gastrointestinal
disorders.”(104) The most recent study of 100 patients did not find EcN to have a benefit as an add on
therapy in the treatment of active UC. (105) There does appear to be a certain subset of patients that EcN
may provide benefit to, although further studies are needed to determine which patient characteristics are
associated with response rates.
Overall IBD Reviews. Systematic review and meta-analyses have been difficult to perform on the efficacy
of probiotic therapy in the treatment of IBD due to such large variation in probiotic strains, dosages used,
concomitant therapy allowed, and measured outcomes. One meta-analysis suggested that probiotics are
superior to placebo in maintaining remission in ulcerative colitis. (106)
Prebiotics
Prebiotics are non-digestible carbohydrates that selectively promote the growth of commensal
microorgamisms within the gut and improve the well-being of the host.(107) Prebiotics pass through the
upper GI tract undigested and act as a food source for commensal bacterial in the distal small bowel and
colon. Through fermentation of prebiotics, short chain fatty acids such as butyrate are produced which are
known to have anti-inflammatory effects on the colon. Prebiotics are best known for their effects on
healthy stool regulation by increasing fecal water content in patients with constipation and bulking the
stool in patients with diarrhea.
Oligofructose. Prebiotics specifically select for specific bacterial strains known to be beneficial to the
health of the GI tract such as Lactobacillus and Bifidobacterium and select against other strains known to
be harmful and proinflammatory such as Bacteriodes, Klebsiella and Streptococcus viridans. The
prebiotics inulin and oligofructoses have been shown to increase the levels of Lactobacilli and
Bifidobacteria in the colon. (60)
Inulin. This prebiotic has been shown to decrease reactive oxygen species and improve the severity of
inflammation in a rodent model of colitis. (108) In human subjects, 12 g of inulin daily was shown to
decrease fecal inflammatory markers in patients with active UC. (109) Treatment of pouchitis with 24 g
of oral inulin led to improvement in endoscopic and histologic inflammation, decreased B. fragilis
concentration and increased levels of butyrate compared to placebo. (110) Crohn’s patients also benefited
from treatment with inulin. Inulin, 10 g twice a day, led to an increased fecal concentration of butyrate
compared to placebo in CD patients. (111)
Fructooligosaccharides. These decrease intestinal inflammation and selectively alter the colonic bacteria
towards anti-inflammatory species. (112-114) A small open-label study of 10 CD patients with active
ileocolitis had improvement on the Harvey-Bradshaw index and an increased concentration of
Bifidobacteria. (115) However, a large placebo-controlled trial found no difference in clinical response
but did note a large drop-out rate in those treated with FOS due to abdominal bloating and gas. (116)
Germinated barley foodstuff (GBF) is another prebiotic with promising anti-inflammatory properties
demonstrated in rodent models. (117, 118) GBF appears to decease inflammation by reducing serum
TNF-alpha, IL-6 and IL-8 levels. (119) Several small pilot studies show promise in the treatment of active
UC with improvement in clinical activity scores, endoscopic scores and fecal butyrate levels. (120) (121)
(122) A placebo-controlled study of 59 UC patients in remission found that GBF + standard therapy
prolonged remission compared to placebo + standard therapy. (123) A second placebo controlled study of
active UC disease demonstrated GFB caused a decrease in CRP and abdominal cramping.(124)
IBD Overall. Controlled studies on prebiotics in IBD are limited presently and side effects such as
bloating, abdominal discomfort and flatulence are common with high doses of prebiotic therapy.
Prebiotics may be efficacious when used in combination with standard therapy especially in ulcerative
colitis patients. High doses of fiber are contraindicated in CD patients with active stricturing disease and
this therapy should be tailored to each individual patient. IBD patients should be referred to registered
dietitian nutritionists for nutritional counseling.
Curcumin
Turmeric, a commonly used Asian spice, contains curcumin which has been used for centuries as a topical
natural therapy for intestinal and skin disorders. Curcumin has since proven to possess anti-inflammatory
properties by inhibiting NF-κB thereby decreasing production of proinflammatory cytokines. (125-127)
Curcumin also has immunosuppressant properties through the inhibition of TNF-α and IL-2 production.
(126, 128) Curcumin acts topically without significant systemic absorption giving it an excellent safety
profile. Rodent studies have shown promising results with both prevention and successful treatment of
induced colitis. (129-133)
One of the first studies of 10 IBD patients (5 CD, 5 ulcerative proctitis) found all UC proctitis patients
symptomatically improved with reduction in medications in four. Of the five CD patients, four had a
decrease in the CDAI score as well as the sedimentation rate. (134) These exciting results led to a large,
randomized, double-blinded, placebo-controlled trial of mild UC patients in clinical remission.
Ulcerative Colitis. Curcumin 1 gram orally two times daily or placebo was given for six months. UC
patients in the treatment arm had improvement in both symptomatic scores as well as endoscopic scores
and a decreased number of disease flares. (135) A trial of curcumin enemas versus placebo was performed
in distal UC patients since curcumin is known to act topically. Unfortunately, there was a high drop-out
rate in this study making the results difficult to interpret. Although, those patients who stayed on the
enema therapy did have symptomatic and endoscopic improvement compared to those receiving placebo.
(136)
A multicenter, randomized, placebo-controlled, double-blinded study was performed on 50 patients with
active mild to moderate UC despite maximal oral and rectal mesalamine. Oral curcumin 3 grams daily
with concomitant mesalamine compared to placebo plus mesalamine for one month found curcumin had a
increase in clinical remission (p = 0.01), clinical response (p < 0.001), and endoscopic remission (p =
0.043). The authors concluded that curcumin therapy 3 grams daily in addition to mesalamine therapy
may improve clinical and endoscopic remission in mild to moderate UC. (137)
Colorectal Cancer. Curcumin is also believed to have anti-neoplastic properties against colorectal cancer
(138-140) and has been shown to decrease polyp growth in familial polyposis syndromes. (127)
IBD Overall. Curcumin therapy for the treatment of IBD has excellent promise and is being further
studied for this indication. Due to its topical nature without systemic absorption, curcumin will likely be
best served for ulcerative colitis patients who have inflammation limited to the mucosal layer as opposed
to Crohn’s patients with transmural inflammation. With a good safety profile and patient tolerability,
curcumin is a promising therapy for IBD.
Boswellia serrata
Boswellia serrata is an Ayurvedic herb used for centuries in India as a tradition remedy for the treatment
of various ailments. Boswellia serrata acts on the arachidonic acid cascade and inhibits leukotriene
biosynthesis leading to an overall decrease in proinflammatory cytokines. (141) Animal studies have
shown Boswellia serrata may be an effective therapy for IBD.(142-144) One UC (145) and two CD (146,
147) studies found Boswellia serrata to be equivalent in efficacy to mesalamine therapy for active
disease.
Crohn’s Disease. The largest study to date on Boswellia serrata in CD patients was a multicenter,
placebo-controlled, randomized, and double-blinded study in Germany. In total, 108 CD outpatients in
clinical remission were randomized to Boswelan 2400 mg daily or placebo for 52 weeks with
maintenance of remission at 52 weeks as the primary endpoint. Due to a lack of efficacy of Boswelan, the
trial was terminated early without any differences in remission rates, time to relapse or inflammatory
markers. The authors concluded there is excellent tolerability of Boswellia serrata, but no efficacy for
maintaining remission in CD patients. (148)
IBD Overall. There is no data to support the use of Boswellia serrata as monotherapy for Crohn’s disease
and further studies are needed in ulcerative colitis at this time. Further studies investigating the efficacy of
Boswellia serrata are needed for both UC and CD with specific focus on the use of this agent as add on
therapy to standard treatment.
Aloe vera
Aloe vera, part of the lily family, has been used medicinally for over 5,000 years and is thought to have
anti-inflammatory, anti-oxidant, anti-neoplastic and anti-aging properties. (149) Aloe vera has been shown
to have topical anti-inflammatory properties and is superior to placebo in the treatment of plaque
psoriasis. (150) An in vitro study on gastrointestinal mucosa found aloe vera to have dose-dependent anti-
oxidant properties and inhibitory effects on prostaglandin E2 and IL-8. (151)
Ulcerative Colitis. A randomized, double-blinded, placebo-controlled trial was performed with 44 patients
to evaluate the safety and efficacy of 4 weeks of 100 ml aloe vera oral gel in the treatment of mild to
moderate active UC. Clinical remission (SCCAI ≤ 2) and clinical improvement (SCCAI decrease of ≥3)
at 4 weeks trended towards the superiority of aloe vera but did not meet significance with large
confidence intervals suggesting the study may have been underpowered. Clinical response was found in
47% of aloe vera patients and 14% of placebo (OR 5.3; CI 1.0 – 27, p = 0.048). There was improvement
in histological score in patients given aloe vera compared to placebo (p = 0.031). However,
sigmoidoscopic and histologic remission were not achieved. Serum inflammatory markers did not
improve with aloe vera therapy. However, it was well tolerated without any significant adverse events.
(152)
IBD Overall. Aloe vera appears to be a possible therapy for mild to moderate colitis and may benefit from
being studied as adjuvant therapy. There is no data on the use of aloe vera for Crohn’s disease currently.
No adverse events have been reported in humans, but a rodent model found Aloe vera supplementation
for 2 years caused an increased rate of adenomas and neoplasms in the large intestines, mucosal
hyperplasia of the large bowel and hyperplasia of the mesenteric lymphoid system.(153)
Toxicities Associated With Herbal Medicines
Herbal medicines, dietary supplements and vitamin are not regulated or approved by the Food and Drug
Administration (FDA) like prescription medical therapy is. Therefore, the appropriate dose, interactions
with other medications and long term adverse effects may not be known. The Dietary Supplement Health
and Education Act (DSHEA) regulate all natural products and do not require additional toxicity studies in
products on the market prior to 1994. The manufacturing of these products is also not tightly controlled
and may contain varying dosages of the active ingredient and unknown contaminants.(153) Due to the
potential benefits these therapies may have, more rigorous testing and regulations are needed to determine
their safety and efficacy.
Cannabis sativa
Cannabis sativa, better known as marijuana, has been shown to have certain medicinal properties
including pain modulation, anti-nausea effects and possibly even anti-inflammatory properties. However,
the psychotropic effects have limited its use and legal availability. Two cannabinoid receptors in the gut
have been identified: cannabinoid receptor 1 and 2, CB1 and CB2.(154) CB1 and CB2 are found within
the enteric nervous system, (155-157) epithelial cells and immune cells.(155) Endogenous
endocannabinoids have been discovered which may modulate intestinal inflammation (158, 159) and
animal models suggest cannabis play a role in the treatment of colitis. (160-164)
Many of patients are already self-treating with cannabis since they cannot find full relief with current
medical therapy.(165) Cannabis may be helpful in treating some of the symptoms of IBD, including
visceral abdominal pain caused by colonic inflammation which is known to activate CB1 and CB2
receptors. (166) Diarrhea due to colitis has also been shown to be successfully managed with cannabis
due to its ability to inhibit intestinal secretion (158, 159, 167). Nausea and loss of appetite are two other
common symptoms IBD patient experience, both of which can be modulated with cannabis therapy. (168)
A questionnaire study found 50% of IBD patients reported any lifetime use and 15% reported current use
of cannabis. Use was most common in patients with previous abdominal surgeries and worse SIBDQ
scores. The most common reported side effects of cannabis in this study were dry mouth (67.6%),
drowsiness (68.0%), paranoia (32.0%), palpitations (30.5%), anxiety (23.5%), and memory loss (17.8%).
(165)
Another questionnaire study regarding personal use of cannabis in IBD patients discovered cannabis users
were more likely to have more severe disease and a higher risk for surgery although based on the design
of the study, causality is not able to be assessed. More severe IBD patients may simply be more likely to
use cannabis to treat their refractory disease. (169) However, there is also the risk that cannabis use can
cause worsening IBD symptoms and fibrosis or alternatively mask the severity of the symptoms allowing
the disease to progress.
One retrospective study found that 21 out of 30 CD patients had clinical improvement based upon
Harvey-Bradshaw Index after cannabis treatment and a decreased need for escalation of therapy and
surgery. (170) A prospective study of 21 medically refractory Crohn’s patients treated with cannabis twice
a day or placebo found a significant difference in clinical response defined as a decrease in CDAI score of
> 100 (p = 0.028). Complete remission (CDAI score < 150) was not significantly different between the
two groups, but subjects in the cannabis group reported improved sleep and appetite without any side
effects. (171) However, no objective markers such as endoscopic and laboratory values were reported in
these two studies.
The most important question is whether cannabis can ameliorate the inflammation associated with IBD.
Although there are no current answers to this question, there are ongoing clinical trials investigating this
topic. Currently, there is not enough evidence to recommend cannabis use for the treatment of IBD.
Further studies are needed to evaluate the appropriate formulation and route of administration that
cannabis may provide the most benefit with least adverse effects.
Conclusion:
This summary of dietary supplemental therapies for the treatment of IBD brings to light the lack of robust
data in this field. Currently, vitamin D remains a hot topic in both the treatment and prevention of IBD.
However, with the data available, repletion of vitamin D to normal levels in IBD patients (30 – 100) is the
only recommendation that can be made. Fish oil supplementation has some promising data for colitis,
although cannot yet be recommended as a therapy due to lack of clear benefits and unknown toxicities.
VSL #3 is a recommended therapy for the prevention of recurrent pouchitis, but not for CD or UC at this
time. The other probiotics need larger, placebo-controlled trials before any recommendations can be
made. Prebiotics appear to be a basic component to maintain healthy gut flora, but do not yet have a role
in the treatment of IBD. While curcumin appears to be effective in the treatment of mild to moderate UC
and acts synergistically with mesalamine therapy, long term adverse events have not been well studied
and should be used with caution. Boswellia serrata and aloe vera do not have enough data to recommend
their use for the treatment of IBD at this time. Cannabis therapy cannot be recommended due to the
potential for serious adverse events and long term neurologic complications. There is encouraging data
that the therapeutic component of cannabis may be extracted, eliminating the harmful adverse effects.
Only with larger, placebo-controlled studies can the true efficacy of these therapies be determined.
REFERENCES:
1. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe
interactions have shaped the genetic architecture of inflammatory bowel disease. Nature.
2012;491(7422):119-24.
2. Shoda R, Matsueda K, Yamato S, Umeda N. Epidemiologic analysis of Crohn disease in
Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to
the increased incidence of Crohn disease in Japan. The American journal of clinical nutrition.
1996;63(5):741-5.
3. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and
new diagnoses of Crohn's disease and ulcerative colitis. The American journal of
gastroenterology. 2011;106(12):2133-42.
4. Ko Y, Kariyawasam V, Karnib M, Butcher R, Samuel D, Alrubaie A, et al. Inflammatory
Bowel Disease Environmental Risk Factors: A Population-Based Case-Control Study of Middle
Eastern Migration to Australia. Clinical gastroenterology and hepatology : the official clinical
practice journal of the American Gastroenterological Association. 2015.
5. Ng SC. Emerging Leadership Lecture: Inflammatory Bowel Disease in Asia: Emergence
of a "Western Disease". Journal of gastroenterology and hepatology. 2014.
6. Porter CK, Tribble DR, Aliaga PA, Halvorson HA, Riddle MS. Infectious gastroenteritis
and risk of developing inflammatory bowel disease. Gastroenterology. 2008;135(3):781-6.
7. Gradel KO, Nielsen HL, Schonheyder HC, Ejlertsen T, Kristensen B, Nielsen H.
Increased short- and long-term risk of inflammatory bowel disease after salmonella or
campylobacter gastroenteritis. Gastroenterology. 2009;137(2):495-501.
8. Peyrin-Biroulet L, Loftus EV, Jr., Colombel JF, Sandborn WJ. The natural history of adult
Crohn's disease in population-based cohorts. The American journal of gastroenterology.
2010;105(2):289-97.
9. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et
al. Infliximab, azathioprine, or combination therapy for Crohn's disease. The New England
journal of medicine. 2010;362(15):1383-95.
10. Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-dihydroxyvitamin D3: a novel
immunoregulatory hormone. Science. 1984;224(4656):1438-40.
11. Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC. 1,25-
Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. Journal of
immunology. 1985;134(5):3032-5.
12. Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1alpha,25-
dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in
NOD mice. Diabetes. 2002;51(5):1367-74.
13. Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, et al. 1,25-
Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and
promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol.
2009;183(9):5458-67.
14. Cantorna MT, Mahon BD. D-hormone and the immune system. The Journal of
rheumatology Supplement. 2005;76:11-20.
15. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, et al. Vitamin D inhibits
monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1.
Journal of immunology. 2012;188(5):2127-35.
16. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D
levels and risk of multiple sclerosis. JAMA : the journal of the American Medical Association.
2006;296(23):2832-8.
17. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is
inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study.
Arthritis and rheumatism. 2004;50(1):72-7.
18. Monticielo OA, Teixeira TD, Chies JA, Brenol JC, Xavier RM. Vitamin D and
polymorphisms of VDR gene in patients with systemic lupus erythematosus. Clinical
rheumatology. 2012.
19. Froicu M, Weaver V, Wynn TA, McDowell MA, Welsh JE, Cantorna MT. A crucial role for
the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol.
2003;17(12):2386-92.
20. Cantorna MT, Munsick C, Bemiss C, Mahon BD. 1,25-Dihydroxycholecalciferol prevents
and ameliorates symptoms of experimental murine inflammatory bowel disease. The Journal of
nutrition. 2000;130(11):2648-52.
21. Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, et al. Incidence
of inflammatory bowel disease across Europe: is there a difference between north and south?
Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut.
1996;39(5):690-7.
22. Khalili H, Huang ES, Ananthakrishnan AN, Higuchi L, Richter JM, Fuchs CS, et al.
Geographical variation and incidence of inflammatory bowel disease among US women. Gut.
2012;61(12):1686-92.
23. Limketkai BN, Bayless TM, Brant SR, Hutfless SM. Lower regional and temporal
ultraviolet exposure is associated with increased rates and severity of inflammatory bowel
disease hospitalisation. Alimentary pharmacology & therapeutics. 2014.
24. Ananthakrishnan AN, Cagan A, Gainer VS, Cai T, Cheng SC, Savova G, et al.
Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in
Crohn's disease. Inflammatory bowel diseases. 2013;19(9):1921-7.
25. Ananthakrishnan AN, Khalili H, Higuchi LM, Bao Y, Korzenik JR, Giovannucci EL, et al.
Higher predicted vitamin D status is associated with reduced risk of Crohn's disease.
Gastroenterology. 2012;142(3):482-9.
26. Jorgensen SP, Agnholt J, Glerup H, Lyhne S, Villadsen GE, Hvas CL, et al. Clinical trial:
vitamin D3 treatment in Crohn's disease - a randomized double-blind placebo-controlled study.
Alimentary pharmacology & therapeutics. 2010;32(3):377-83.
27. Yang L, Weaver V, Smith JP, Bingaman S, Hartman TJ, Cantorna MT. Therapeutic effect
of vitamin d supplementation in a pilot study of Crohn's patients. Clinical and translational
gastroenterology. 2013;4:e33.
28. Arnedo-Pena A, Juan-Cerdan JV, Romeu-Garcia A, Garcia-Ferrer D, Holguin-Gomez R,
Iborra-Millet J, et al. Latent tuberculosis infection, tuberculin skin test and vitamin D status in
contacts of tuberculosis patients: a cross-sectional and case-control study. BMC infectious
diseases. 2011;11:349.
29. Atia A, Murthy R, Bailey BA, Manning T, Garrett LL, Youssef D, et al. Vitamin D status in
veterans with inflammatory bowel disease: relationship to health care costs and services.
Military medicine. 2011;176(6):711-4.
30. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3,
and the immune system. The American journal of clinical nutrition. 2004;80(6 Suppl):1717S-
20S.
31. Harries AD, Brown R, Heatley RV, Williams LA, Woodhead S, Rhodes J. Vitamin D
status in Crohn's disease: association with nutrition and disease activity. Gut. 1985;26(11):1197-
203.
32. Hassan V, Hassan S, Seyed-Javad P, Ahmad K, Asieh H, Maryam S, et al. Association
between Serum 25 (OH) Vitamin D Concentrations and Inflammatory Bowel Diseases (IBDs)
Activity. The Medical journal of Malaysia. 2013;68(1):34-8.
33. Lim WC, Hanauer SB, Li YC. Mechanisms of disease: vitamin D and inflammatory bowel
disease. Nature clinical practice Gastroenterology & hepatology. 2005;2(7):308-15.
34. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering
of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-3.
35. Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin D-mediated human
antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of
cathelicidin. Journal of immunology. 2007;179(4):2060-3.
36. Ulitsky A, Ananthakrishnan AN, Naik A, Skaros S, Zadvornova Y, Binion DG, et al.
Vitamin D deficiency in patients with inflammatory bowel disease: association with disease
activity and quality of life. JPEN Journal of parenteral and enteral nutrition. 2011;35(3):308-16.
37. Wu S, Sun J. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and
infection. Discovery medicine. 2011;11(59):325-35.
38. Yuk JM, Shin DM, Lee HM, Yang CS, Jin HS, Kim KK, et al. Vitamin D3 induces
autophagy in human monocytes/macrophages via cathelicidin. Cell host & microbe.
2009;6(3):231-43.
39. Holick MF. Vitamin D deficiency. The New England journal of medicine. 2007;357(3):266-
81.
40. Leichtmann GA, Bengoa JM, Bolt MJ, Sitrin MD. Intestinal absorption of cholecalciferol
and 25-hydroxycholecalciferol in patients with both Crohn's disease and intestinal resection. The
American journal of clinical nutrition. 1991;54(3):548-52.
41. Rosen CJ. Clinical practice. Vitamin D insufficiency. The New England journal of
medicine. 2011;364(3):248-54.
42. Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA, Zemel BS. Vitamin D
status in children, adolescents, and young adults with Crohn disease. The American journal of
clinical nutrition. 2002;76(5):1077-81.
43. Tajika M, Matsuura A, Nakamura T, Suzuki T, Sawaki A, Kato T, et al. Risk factors for
vitamin D deficiency in patients with Crohn's disease. Journal of gastroenterology.
2004;39(6):527-33.
44. Mills SC, Windsor AC, Knight SC. The potential interactions between polyunsaturated
fatty acids and colonic inflammatory processes. Clinical and experimental immunology.
2005;142(2):216-28.
45. Chan SS, Luben R, Olsen A, Tjonneland A, Kaaks R, Lindgren S, et al. Association
between high dietary intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid and
reduced risk of Crohn's disease. Alimentary pharmacology & therapeutics. 2014;39(8):834-42.
46. Feagan BG, Sandborn WJ, Mittmann U, Bar-Meir S, D'Haens G, Bradette M, et al.
Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC
Randomized Controlled Trials. Jama. 2008;299(14):1690-7.
47. Lev-Tzion R, Griffiths AM, Leder O, Turner D. Omega 3 fatty acids (fish oil) for
maintenance of remission in Crohn's disease. The Cochrane database of systematic reviews.
2014;2:CD006320.
48. Lorenz-Meyer H, Bauer P, Nicolay C, Schulz B, Purrmann J, Fleig WE, et al. Omega-3
fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A
randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study
Group). Scandinavian journal of gastroenterology. 1996;31(8):778-85.
49. Romano C, Cucchiara S, Barabino A, Annese V, Sferlazzas C. Usefulness of omega-3
fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric
Crohn's disease: a double-blind, randomized, placebo-controlled study. World journal of
gastroenterology : WJG. 2005;11(45):7118-21.
50. Siguel EN, Lerman RH. Prevalence of essential fatty acid deficiency in patients with
chronic gastrointestinal disorders. Metabolism: clinical and experimental. 1996;45(1):12-23.
51. Lorenz R, Weber PC, Szimnau P, Heldwein W, Strasser T, Loeschke K. Supplementation
with n-3 fatty acids from fish oil in chronic inflammatory bowel disease--a randomized, placebo-
controlled, double-blind cross-over trial. Journal of internal medicine Supplement.
1989;731:225-32.
52. Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis:
a double-blind, placebo-controlled, crossover study. The American journal of gastroenterology.
1992;87(4):432-7.
53. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, et
al. Dietary supplementation with fish oil in ulcerative colitis. Annals of internal medicine.
1992;116(8):609-14.
54. Almallah YZ, Richardson S, O'Hanrahan T, Mowat NA, Brunt PW, Sinclair TS, et al.
Distal procto-colitis, natural cytotoxicity, and essential fatty acids. The American journal of
gastroenterology. 1998;93(5):804-9.
55. Seidner DL, Lashner BA, Brzezinski A, Banks PL, Goldblum J, Fiocchi C, et al. An oral
supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in
ulcerative colitis: a randomized, controlled trial. Clinical gastroenterology and hepatology : the
official clinical practice journal of the American Gastroenterological Association. 2005;3(4):358-
69.
56. Dichi I, Frenhane P, Dichi JB, Correa CR, Angeleli AY, Bicudo MH, et al. Comparison of
omega-3 fatty acids and sulfasalazine in ulcerative colitis. Nutrition. 2000;16(2):87-90.
57. Hawthorne AB, Daneshmend TK, Hawkey CJ, Belluzzi A, Everitt SJ, Holmes GK, et al.
Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised
controlled trial. Gut. 1992;33(7):922-8.
58. Loeschke K, Ueberschaer B, Pietsch A, Gruber E, Ewe K, Wiebecke B, et al. n-3 fatty
acids only delay early relapse of ulcerative colitis in remission. Digestive diseases and sciences.
1996;41(10):2087-94.
59. Mantzaris G, Archavlis E, Zografos C, Petraki K, Spiliades C, Triantafyllou G. A
prospective, randomized, placebo-controlled study of fish oil in ulcerative colitis. Hellenic
Journal of Gastroenterology. 1996;9(2):138-41.
60. Orel R, Kamhi Trop T. Intestinal microbiota, probiotics and prebiotics in inflammatory
bowel disease. World journal of gastroenterology : WJG. 2014;20(33):11505-24.
61. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus
document. The International Scientific Association for Probiotics and Prebiotics consensus
statement on the scope and appropriate use of the term probiotic. Nature reviews
Gastroenterology & hepatology. 2014;11(8):506-14.
62. O'Mahony C, Scully P, O'Mahony D, Murphy S, O'Brien F, Lyons A, et al. Commensal-
induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB
activation. PLoS pathogens. 2008;4(8):e1000112.
63. Garcia Vilela E, De Lourdes De Abreu Ferrari M, Oswaldo Da Gama Torres H, Guerra
Pinto A, Carolina Carneiro Aguirre A, Paiva Martins F, et al. Influence of Saccharomyces
boulardii on the intestinal permeability of patients with Crohn's disease in remission.
Scandinavian journal of gastroenterology. 2008;43(7):842-8.
64. Prisciandaro L, Geier M, Butler R, Cummins A, Howarth G. Probiotics and their
derivatives as treatments for inflammatory bowel disease. Inflammatory bowel diseases.
2009;15(12):1906-14.
65. Stephani J, Radulovic K, Niess JH. Gut microbiota, probiotics and inflammatory bowel
disease. Archivum immunologiae et therapiae experimentalis. 2011;59(3):161-77.
66. Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, et al.
VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. The
American journal of gastroenterology. 2005;100(7):1539-46.
67. Huynh HQ, deBruyn J, Guan L, Diaz H, Li M, Girgis S, et al. Probiotic preparation VSL#3
induces remission in children with mild to moderate acute ulcerative colitis: a pilot study.
Inflammatory bowel diseases. 2009;15(5):760-8.
68. Tursi A, Brandimarte G, Giorgetti GM, Forti G, Modeo ME, Gigliobianco A. Low-dose
balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or
mesalazine in the treatment of acute mild-to-moderate ulcerative colitis. Medical science
monitor : international medical journal of experimental and clinical research. 2004;10(11):PI126-
31.
69. Miele E, Pascarella F, Giannetti E, Quaglietta L, Baldassano RN, Staiano A. Effect of a
probiotic preparation (VSL#3) on induction and maintenance of remission in children with
ulcerative colitis. The American journal of gastroenterology. 2009;104(2):437-43.
70. Sood A, Midha V, Makharia GK, Ahuja V, Singal D, Goswami P, et al. The probiotic
preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative
colitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the
American Gastroenterological Association. 2009;7(11):1202-9, 9 e1.
71. Tursi A, Brandimarte G, Papa A, Giglio A, Elisei W, Giorgetti GM, et al. Treatment of
relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard
pharmaceutical treatment: a double-blind, randomized, placebo-controlled study. The American
journal of gastroenterology. 2010;105(10):2218-27.
72. Jonkers D, Penders J, Masclee A, Pierik M. Probiotics in the management of
inflammatory bowel disease: a systematic review of intervention studies in adult patients. Drugs.
2012;72(6):803-23.
73. Mardini HE, Grigorian AY. Probiotic mix VSL#3 is effective adjunctive therapy for mild to
moderately active ulcerative colitis: a meta-analysis. Inflammatory bowel diseases.
2014;20(9):1562-7.
74. Gionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, et al. Oral
bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind,
placebo-controlled trial. Gastroenterology. 2000;119(2):305-9.
75. Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, et al. Once daily high
dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis.
Gut. 2004;53(1):108-14.
76. Shen B, Brzezinski A, Fazio VW, Remzi FH, Achkar JP, Bennett AE, et al. Maintenance
therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice.
Alimentary pharmacology & therapeutics. 2005;22(8):721-8.
77. Pronio A, Montesani C, Butteroni C, Vecchione S, Mumolo G, Vestri A, et al. Probiotic
administration in patients with ileal pouch-anal anastomosis for ulcerative colitis is associated
with expansion of mucosal regulatory cells. Inflammatory bowel diseases. 2008;14(5):662-8.
78. Pardi DS, D'Haens G, Shen B, Campbell S, Gionchetti P. Clinical guidelines for the
management of pouchitis. Inflammatory bowel diseases. 2009;15(9):1424-31.
79. Gionchetti P, Rizzello F, Morselli C, Poggioli G, Tambasco R, Calabrese C, et al. High-
dose probiotics for the treatment of active pouchitis. Diseases of the colon and rectum.
2007;50(12):2075-82; discussion 82-4.
80. Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, et al. Prophylaxis of
pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology.
2003;124(5):1202-9.
81. Fedorak RN, Feagan BG, Hotte N, Leddin D, Dieleman LA, Petrunia DM, et al. The
probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after
surgery for Crohn's disease. Clinical gastroenterology and hepatology : the official clinical
practice journal of the American Gastroenterological Association. 2015;13(5):928-35 e2.
82. Doherty G, Bennett G, Patil S, Cheifetz A, Moss AC. Interventions for prevention of post-
operative recurrence of Crohn's disease. The Cochrane database of systematic reviews.
2009(4):CD006873.
83. Rahimi R, Nikfar S, Rahimi F, Elahi B, Derakhshani S, Vafaie M, et al. A meta-analysis
on the efficacy of probiotics for maintenance of remission and prevention of clinical and
endoscopic relapse in Crohn's disease. Digestive diseases and sciences. 2008;53(9):2524-31.
84. Rolfe VE, Fortun PJ, Hawkey CJ, Bath-Hextall F. Probiotics for maintenance of
remission in Crohn's disease. The Cochrane database of systematic reviews.
2006(4):CD004826.
85. Shen J, Zuo ZX, Mao AP. Effect of probiotics on inducing remission and maintaining
therapy in ulcerative colitis, Crohn's disease, and pouchitis: meta-analysis of randomized
controlled trials. Inflammatory bowel diseases. 2014;20(1):21-35.
86. Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in
preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial
with Lactobacillus GG. Gut. 2002;51(3):405-9.
87. Schultz M, Timmer A, Herfarth HH, Sartor RB, Vanderhoof JA, Rath HC. Lactobacillus
GG in inducing and maintaining remission of Crohn's disease. BMC gastroenterology. 2004;4:5.
88. Bousvaros A, Guandalini S, Baldassano RN, Botelho C, Evans J, Ferry GD, et al. A
randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard
maintenance therapy for children with Crohn's disease. Inflammatory bowel diseases.
2005;11(9):833-9.
89. Zocco MA, dal Verme LZ, Cremonini F, Piscaglia AC, Nista EC, Candelli M, et al.
Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Alimentary
pharmacology & therapeutics. 2006;23(11):1567-74.
90. Kuisma J, Mentula S, Jarvinen H, Kahri A, Saxelin M, Farkkila M. Effect of Lactobacillus
rhamnosus GG on ileal pouch inflammation and microbial flora. Alimentary pharmacology &
therapeutics. 2003;17(4):509-15.
91. Gosselink MP, Schouten WR, van Lieshout LM, Hop WC, Laman JD, Ruseler-van
Embden JG. Delay of the first onset of pouchitis by oral intake of the probiotic strain
Lactobacillus rhamnosus GG. Diseases of the colon and rectum. 2004;47(6):876-84.
92. Van Gossum A, Dewit O, Louis E, de Hertogh G, Baert F, Fontaine F, et al. Multicenter
randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early
endoscopic recurrence of Crohn's disease after lleo-caecal resection. Inflammatory bowel
diseases. 2007;13(2):135-42.
93. Marteau P, Lemann M, Seksik P, Laharie D, Colombel JF, Bouhnik Y, et al.
Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in
Crohn's disease: a randomised, double blind, placebo controlled GETAID trial. Gut.
2006;55(6):842-7.
94. McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, et al. A
randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard
antibiotics for Clostridium difficile disease. Jama. 1994;271(24):1913-8.
95. Tung JM, Dolovich LR, Lee CH. Prevention of Clostridium difficile infection with
Saccharomyces boulardii: a systematic review. Canadian journal of gastroenterology = Journal
canadien de gastroenterologie. 2009;23(12):817-21.
96. Guslandi M, Giollo P, Testoni PA. A pilot trial of Saccharomyces boulardii in ulcerative
colitis. European journal of gastroenterology & hepatology. 2003;15(6):697-8.
97. Guslandi M. Saccharomyces boulardii plus rifaximin in mesalamine-intolerant ulcerative
colitis. Journal of clinical gastroenterology. 2010;44(5):385.
98. Plein K, Hotz J. Therapeutic effects of Saccharomyces boulardii on mild residual
symptoms in a stable phase of Crohn's disease with special respect to chronic diarrhea--a pilot
study. Zeitschrift fur Gastroenterologie. 1993;31(2):129-34.
99. Guslandi M, Mezzi G, Sorghi M, Testoni PA. Saccharomyces boulardii in maintenance
treatment of Crohn's disease. Digestive diseases and sciences. 2000;45(7):1462-4.
100. Bourreille A, Cadiot G, Le Dreau G, Laharie D, Beaugerie L, Dupas JL, et al.
Saccharomyces boulardii does not prevent relapse of Crohn's disease. Clinical gastroenterology
and hepatology : the official clinical practice journal of the American Gastroenterological
Association. 2013;11(8):982-7.
101. Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M. Double-blind comparison of an
oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis.
Alimentary pharmacology & therapeutics. 1997;11(5):853-8.
102. Kruis W, Fric P, Pokrotnieks J, Lukas M, Fixa B, Kascak M, et al. Maintaining remission
of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with
standard mesalazine. Gut. 2004;53(11):1617-23.
103. Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic
Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial.
Lancet. 1999;354(9179):635-9.
104. Matthes H, Krummenerl T, Giensch M, Wolff C, Schulze J. Clinical trial: probiotic
treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917
(EcN). BMC complementary and alternative medicine. 2010;10:13.
105. Petersen AM, Mirsepasi H, Halkjaer SI, Mortensen EM, Nordgaard-Lassen I, Krogfelt
KA. Ciprofloxacin and probiotic Escherichia coli Nissle add-on treatment in active ulcerative
colitis: a double-blind randomized placebo controlled clinical trial. Journal of Crohn's & colitis.
2014;8(11):1498-505.
106. Sang LX, Chang B, Zhang WL, Wu XM, Li XH, Jiang M. Remission induction and
maintenance effect of probiotics on ulcerative colitis: a meta-analysis. World journal of
gastroenterology : WJG. 2010;16(15):1908-15.
107. Roberfroid M. Prebiotics: the concept revisited. The Journal of nutrition. 2007;137(3
Suppl 2):830S-7S.
108. Abdelouhab K, Rafa H, Toumi R, Bouaziz S, Medjeber O, Touil-Boukoffa C. Mucosal
intestinal alteration in experimental colitis correlates with nitric oxide production by peritoneal
macrophages: effect of probiotics and prebiotics. Immunopharmacology and immunotoxicology.
2012;34(4):590-7.
109. Casellas F, Borruel N, Torrejon A, Varela E, Antolin M, Guarner F, et al. Oral
oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and
associated with lowered faecal calprotectin. Alimentary pharmacology & therapeutics.
2007;25(9):1061-7.
110. Welters CF, Heineman E, Thunnissen FB, van den Bogaard AE, Soeters PB, Baeten
CG. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with
an ileal pouch-anal anastomosis. Diseases of the colon and rectum. 2002;45(5):621-7.
111. De Preter V, Joossens M, Ballet V, Shkedy Z, Rutgeerts P, Vermeire S, et al. Metabolic
profiling of the impact of oligofructose-enriched inulin in Crohn's disease patients: a double-
blinded randomized controlled trial. Clinical and translational gastroenterology. 2013;4:e30.
112. Johnson-Henry KC, Pinnell LJ, Waskow AM, Irrazabal T, Martin A, Hausner M, et al.
Short-chain fructo-oligosaccharide and inulin modulate inflammatory responses and microbial
communities in Caco2-bbe cells and in a mouse model of intestinal injury. The Journal of
nutrition. 2014;144(11):1725-33.
113. Winkler J, Butler R, Symonds E. Fructo-oligosaccharide reduces inflammation in a
dextran sodium sulphate mouse model of colitis. Digestive diseases and sciences.
2007;52(1):52-8.
114. Koleva PT, Valcheva RS, Sun X, Ganzle MG, Dieleman LA. Inulin and fructo-
oligosaccharides have divergent effects on colitis and commensal microbiota in HLA-B27
transgenic rats. The British journal of nutrition. 2012;108(9):1633-43.
115. Lindsay JO, Whelan K, Stagg AJ, Gobin P, Al-Hassi HO, Rayment N, et al. Clinical,
microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn's
disease. Gut. 2006;55(3):348-55.
116. Benjamin JL, Hedin CR, Koutsoumpas A, Ng SC, McCarthy NE, Hart AL, et al.
Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn's
disease. Gut. 2011;60(7):923-9.
117. Araki Y, Fujiyama Y, Andoh A, Koyama S, Kanauchi O, Bamba T. The dietary
combination of germinated barley foodstuff plus Clostridium butyricum suppresses the dextran
sulfate sodium-induced experimental colitis in rats. Scandinavian journal of gastroenterology.
2000;35(10):1060-7.
118. Araki Y, Andoh A, Koyama S, Fujiyama Y, Kanauchi O, Bamba T. Effects of germinated
barley foodstuff on microflora and short chain fatty acid production in dextran sulfate sodium-
induced colitis in rats. Bioscience, biotechnology, and biochemistry. 2000;64(9):1794-800.
119. Faghfoori Z, Navai L, Shakerhosseini R, Somi MH, Nikniaz Z, Norouzi MF. Effects of an
oral supplementation of germinated barley foodstuff on serum tumour necrosis factor-alpha,
interleukin-6 and -8 in patients with ulcerative colitis. Annals of clinical biochemistry. 2011;48(Pt
3):233-7.
120. Mitsuyama K, Saiki T, Kanauchi O, Iwanaga T, Tomiyasu N, Nishiyama T, et al.
Treatment of ulcerative colitis with germinated barley foodstuff feeding: a pilot study. Alimentary
pharmacology & therapeutics. 1998;12(12):1225-30.
121. Kanauchi O, Suga T, Tochihara M, Hibi T, Naganuma M, Homma T, et al. Treatment of
ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open
control trial. Journal of gastroenterology. 2002;37 Suppl 14:67-72.
122. Kanauchi O, Mitsuyama K, Homma T, Takahama K, Fujiyama Y, Andoh A, et al.
Treatment of ulcerative colitis patients by long-term administration of germinated barley
foodstuff: multi-center open trial. International journal of molecular medicine. 2003;12(5):701-4.
123. Hanai H, Kanauchi O, Mitsuyama K, Andoh A, Takeuchi K, Takayuki I, et al. Germinated
barley foodstuff prolongs remission in patients with ulcerative colitis. International journal of
molecular medicine. 2004;13(5):643-7.
124. Faghfoori Z, Shakerhosseini R, Navai L, Somi MH, Nikniaz Z, Abadi A. Effects of an Oral
Supplementation of Germinated Barley Foodstuff on Serum CRP Level and Clinical Signs in
Patients with Ulcerative Colitis. Health Promot Perspect. 2014;4(1):116-21.
125. Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Henry E, et al.
Chemopreventive and therapeutic effects of curcumin. Cancer letters. 2005;223(2):181-90.
126. Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, et al. Curcumin
blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by
inhibiting inhibitory factor I-kappa B kinase activity. Journal of immunology. 1999;163(6):3474-
83.
127. Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, et al.
Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of
familial adenomatous polyposis. Cancer epidemiology, biomarkers & prevention : a publication
of the American Association for Cancer Research, cosponsored by the American Society of
Preventive Oncology. 2002;11(6):535-40.
128. Midura-Kiela MT, Radhakrishnan VM, Larmonier CB, Laubitz D, Ghishan FK, Kiela PR.
Curcumin inhibits interferon-gamma signaling in colonic epithelial cells. American journal of
physiology Gastrointestinal and liver physiology. 2012;302(1):G85-96.
129. Deguchi Y, Andoh A, Inatomi O, Yagi Y, Bamba S, Araki Y, et al. Curcumin prevents the
development of dextran sulfate Sodium (DSS)-induced experimental colitis. Digestive diseases
and sciences. 2007;52(11):2993-8.
130. Jian YT, Mai GF, Wang JD, Zhang YL, Luo RC, Fang YX. Preventive and therapeutic
effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid.
World journal of gastroenterology : WJG. 2005;11(12):1747-52.
131. Sugimoto K, Hanai H, Tozawa K, Aoshi T, Uchijima M, Nagata T, et al. Curcumin
prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in mice. Gastroenterology.
2002;123(6):1912-22.
132. Zeng Z, Zhan L, Liao H, Chen L, Lv X. Curcumin improves TNBS-induced colitis in rats
by inhibiting IL-27 expression via the TLR4/NF-kappaB signaling pathway. Planta medica.
2013;79(2):102-9.
133. Venkataranganna MV, Rafiq M, Gopumadhavan S, Peer G, Babu UV, Mitra SK. NCB-02
(standardized Curcumin preparation) protects dinitrochlorobenzene- induced colitis through
down-regulation of NFkappa-B and iNOS. World journal of gastroenterology : WJG.
2007;13(7):1103-7.
134. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot
study. Digestive diseases and sciences. 2005;50(11):2191-3.
135. Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, et al. Curcumin
maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-
controlled trial. Clinical gastroenterology and hepatology : the official clinical practice journal of
the American Gastroenterological Association. 2006;4(12):1502-6.
136. Singla V, Pratap Mouli V, Garg SK, Rai T, Choudhury BN, Verma P, et al. Induction with
NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis - a randomized, placebo-
controlled, pilot study. Journal of Crohn's & colitis. 2014;8(3):208-14.
137. Lang A, Salomon N, Wu JC, Kopylov U, Lahat A, Har-Noy O, et al. Curcumin in
Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative
Colitis in a Randomized Controlled Trial. Clinical gastroenterology and hepatology : the official
clinical practice journal of the American Gastroenterological Association. 2015.
138. Chen A, Xu J, Johnson AC. Curcumin inhibits human colon cancer cell growth by
suppressing gene expression of epidermal growth factor receptor through reducing the activity
of the transcription factor Egr-1. Oncogene. 2006;25(2):278-87.
139. Devasena T, Menon Venugopal VP, Rajasekaran KN. Chemoprevention of colon cancer
by a synthetic curcumin analog involves amelioration of oxidative stress. Toxicology
mechanisms and methods. 2005;15(5):355-9.
140. Johnson JJ, Mukhtar H. Curcumin for chemoprevention of colon cancer. Cancer letters.
2007;255(2):170-81.
141. Gayathri B, Manjula N, Vinaykumar KS, Lakshmi BS, Balakrishnan A. Pure compound
from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse
macrophages through inhibition of TNFalpha, IL-1beta, NO and MAP kinases. International
immunopharmacology. 2007;7(4):473-82.
142. Hartmann RM, Fillmann HS, Martins MI, Meurer L, Marroni NP. Boswellia serrata has
beneficial anti-inflammatory and antioxidant properties in a model of experimental colitis.
Phytotherapy research : PTR. 2014;28(9):1392-8.
143. Hartmann RM, Morgan Martins MI, Tieppo J, Fillmann HS, Marroni NP. Effect of
Boswellia serrata on antioxidant status in an experimental model of colitis rats induced by acetic
acid. Digestive diseases and sciences. 2012;57(8):2038-44.
144. Kiela PR, Midura AJ, Kuscuoglu N, Jolad SD, Solyom AM, Besselsen DG, et al. Effects
of Boswellia serrata in mouse models of chemically induced colitis. American journal of
physiology Gastrointestinal and liver physiology. 2005;288(4):G798-808.
145. Gupta I, Parihar A, Malhotra P, Singh GB, Ludtke R, Safayhi H, et al. Effects of Boswellia
serrata gum resin in patients with ulcerative colitis. European journal of medical research.
1997;2(1):37-43.
146. Gupta I, Parihar A, Malhotra P, Gupta S, Ludtke R, Safayhi H, et al. Effects of gum resin
of Boswellia serrata in patients with chronic colitis. Planta medica. 2001;67(5):391-5.
147. Gerhardt H, Seifert F, Buvari P, Vogelsang H, Repges R. [Therapy of active Crohn
disease with Boswellia serrata extract H 15]. Zeitschrift fur Gastroenterologie. 2001;39(1):11-7.
148. Holtmeier W, Zeuzem S, Preiss J, Kruis W, Bohm S, Maaser C, 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. Inflammatory bowel diseases. 2011;17(2):573-
82.
149. Grindlay D, Reynolds T. The Aloe vera phenomenon: a review of the properties and
modern uses of the leaf parenchyma gel. Journal of ethnopharmacology. 1986;16(2-3):117-51.
150. Syed TA, Ahmad SA, Holt AH, Ahmad SA, Ahmad SH, Afzal M. Management of psoriasis
with Aloe vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med
Int Health. 1996;1(4):505-9.
151. Langmead L, Makins RJ, Rampton DS. Anti-inflammatory effects of aloe vera gel in
human colorectal mucosa in vitro. Alimentary pharmacology & therapeutics. 2004;19(5):521-7.
152. Langmead L, Feakins RM, Goldthorpe S, Holt H, Tsironi E, De Silva A, et al.
Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative
colitis. Alimentary pharmacology & therapeutics. 2004;19(7):739-47.
153. Dunnick JK, Nyska A. The toxicity and pathology of selected dietary herbal medicines.
Toxicologic pathology. 2013;41(2):374-86.
154. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid
receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561-4.
155. Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, et al. Differential
expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial
wound healing. Gastroenterology. 2005;129(2):437-53.
156. Brusberg M, Arvidsson S, Kang D, Larsson H, Lindstrom E, Martinez V. CB1 receptors
mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in
rodents. J Neurosci. 2009;29(5):1554-64.
157. Kulkarni-Narla A, Brown DR. Localization of CB1-cannabinoid receptor immunoreactivity
in the porcine enteric nervous system. Cell Tissue Res. 2000;302(1):73-80.
158. Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver
diseases: basic and clinical aspects. Gut. 2008;57(8):1140-55.
159. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging
concepts. Pharmacol Ther. 2010;126(1):21-38.
160. Storr MA, Keenan CM, Emmerdinger D, Zhang H, Yuce B, Sibaev A, et al. Targeting
endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1
and CB2 receptors. Journal of molecular medicine. 2008;86(8):925-36.
161. Borrelli F, Aviello G, Romano B, Orlando P, Capasso R, Maiello F, et al. Cannabidiol, a
safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a
murine model of colitis. Journal of molecular medicine. 2009;87(11):1111-21.
162. Borrelli F, Fasolino I, Romano B, Capasso R, Maiello F, Coppola D, et al. Beneficial
effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory
bowel disease. Biochemical pharmacology. 2013;85(9):1306-16.
163. Schicho R, Storr M. Topical and systemic cannabidiol improves trinitrobenzene sulfonic
acid colitis in mice. Pharmacology. 2012;89(3-4):149-55.
164. Jamontt JM, Molleman A, Pertwee RG, Parsons ME. The effects of Delta-
tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in
vitro motility disturbances in rat colitis. British journal of pharmacology. 2010;160(3):712-23.
165. Lal S, Prasad N, Ryan M, Tangri S, Silverberg MS, Gordon A, et al. Cannabis use
amongst patients with inflammatory bowel disease. European journal of gastroenterology &
hepatology. 2011;23(10):891-6.
166. Izzo AA, Capasso R, Aviello G, Borrelli F, Romano B, Piscitelli F, et al. Inhibitory effect of
cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on
inflammation-induced hypermotility in mice. British journal of pharmacology. 2012;166(4):1444-
60.
167. Izzo AA, Capasso F, Costagliola A, Bisogno T, Marsicano G, Ligresti A, et al. An
endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice.
Gastroenterology. 2003;125(3):765-74.
168. Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic potential of cannabis.
The Lancet Neurology. 2003;2(5):291-8.
169. Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. Cannabis use provides
symptom relief in patients with inflammatory bowel disease but is associated with worse disease
prognosis in patients with Crohn's disease. Inflammatory bowel diseases. 2014;20(3):472-80.
170. Naftali T, Lev LB, Yablecovitch D, Half E, Konikoff FM. Treatment of Crohn's disease with
cannabis: an observational study. Isr Med Assoc J. 2011;13(8):455-8.
171. Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff
FM. Cannabis induces a clinical response in patients with Crohn's disease: a prospective
placebo-controlled study. Clinical gastroenterology and hepatology : the official clinical practice
journal of the American Gastroenterological Association. 2013;11(10):1276-80 e1.
