INTEGRATIVE  THERAPIES FOR

INFLAMMATORY BOWEL DISEASE

LEO GALLAND, M.D., F.A.C.P., F.A.C.N.

FOUNDATION FOR INTEGRATED MEDICINE

PATHOPHYSIOLOGY

Crohn’s disease (CD) and ulcerative colitis (UC) are thought to result from inappropriate activation of the mucosal immune system, facilitated by regulatory defects in the mucosal immune response and failure of the mucosal barrier that separates immune response cells from the contents of the intestinal lumen. The normal flora of the gut lumen act as triggers for the inflammatory response and appear to play a central role in pathogenesis.[1] In both diseases, an increased number of surface-adherent and intracellular bacteria have been observed in mucosal biopsies.[2] [3] The immune responses provoked by these bacteria are different in the two disorders, however.[4] The immune response underlying the pathology of CD, as in other granulomatous diseases, is driven by lymphocytes with a type 1 helper-T-cell (TH1) phenotype and their cytokines: interleukin-2 (IL-2) and gamma-interferon (g-IFN). These TH-1 products promote a self-sustaining cycle of activation with macrophages that includes interleukin 12 (IL-12), which further increases TH-1 activity, and interleukins 1 and 6 (IL-1, IL-6) and tumor necrosis factor-alpha (TNF-a), which create a broader inflammatory response. Although macrophage-derived IL-6 and TNF-a are also important for the pathophysiology of UC, the lymphocytes that organize the inflammatory response in UC demonstrate an atypical type 2 helper-T-cell (TH2) phenotype, with interleukin-5 (IL-5) as a distinctive cytokine mediator[5]. The anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), is decreased in both diseases.[6]

            Malnutrition is a major reversible complication of inflammatory bowel disease (IBD). The mechanisms of malnutrition include: anorexia resulting from the systemic effects of IL-1, a catabolic state induced by TNF-a, malabsorption due to disease or surgical resection, nutrient losses through the inflamed and ulcerated gut, small bowel bacterial overgrowth resulting from strictures or fistulas, and the side effects of drug therapy.[7] Inflammation increases oxidative stress in the bowel mucosa and decreases levels of anti-oxidants.[8] Zinc and copper or the zinc- and copper-dependent enzyme, superoxide dismutase (Cu-Zn SOD), is reduced in mucosal biopsies from patients with IBD.[9] Oxidative stress caused by inflammation decreases the mucosal concentration of vitamin C.[10] Plasma levels of vitamins A and E are lower and plasma levels of the oxidative stress marker, 8-hydroxy-deoxy-guanosine (8-OHdG), are higher in IBD patients than in controls.[11] Compared to controls, children and adults with IBD have lower blood levels of zinc and selenium, mineral co-factors of antioxidant enzymes[12] [13] [14], and adults with UC may show lower levels of beta-carotene, magnesium, selenium and zinc[15]. Micronutrient deficits may favor self-perpetuation of IBD by causing defects in the mechanisms of tissue repair[16]. Micronutrient deficiencies may also contribute to some complications of IBD, such as growth retardation, osteopenia, urolithiasis and thromboembolic phenomena[17].

In CD, abnormal mucosal barrier function may play a primary role in pathogenesis. Small intestinal permeability is increased among healthy first-degree relatives of patients with CD[18] and is increased in non-inflamed enteric tissue obtained from patients[19]. Aspirin, a drug that increases intestinal permeability of healthy controls, causes an exaggerated increase in intestinal permeability of first-degree relatives of patients with CD[20]. The rate of relapse among patients who have entered remission is directly proportional to the degree of small intestinal hyperpermeability measured with chemical probes[21].  Hyperpermeability is associated with polymorphism of genes associated with regulation of epithelial barrier function[22]; it increases exposure of the intestinal immune system to luminal antigens. Intestinal epithelial lymphocytes of patients with CD are abnormally sensitive to antigens derived from Enterobacteria and Candida albicans, both normally present in the small intestine.[23] The other genetic polymorphism conferring susceptibility to CD involves genes that regulate the innate immune response to microbial antigens [ref 19]. 

The role of malnutrition, increased intestinal permeability and hypersensitivity to indigenous gut flora is significant for integrative therapies, because of the influence of diet and dietary supplements on nutritional status, intestinal permeability and the composition of the intestinal microflora.

INTEGRATIVE THERAPIES

ENTERAL FEEDING. Defined formula diets, either elemental or polymeric, are successful in improving nutritional status of patients with IBD and preventing complications of surgery [ref 6]. In CD, but not in UC, enteral feeding of defined formula diets as primary therapy has been shown to induce remission of active disease in 30 to 80 percent of patients [ref 6]. Although enteral feeding is most commonly used in pediatric patients, because of growth-enhancing and steroid-sparing effects[24], it is equally effective in adults[25] and appears to have a direct anti-inflammatory effect on the bowel mucosa[26]. Theories to explain the anti-inflammatory effect of enteral feeding in CD include: alteration in intestinal microbial flora[27], diminution of intestinal synthesis of inflammatory mediators, nonspecific nutritional repletion or provision of important micronutrients to heal the diseased intestine [ref 21]. Decreased dietary antigen uptake, an early concept, is not a likely mechanism; polymeric diets, composed of whole protein, are as effective as elemental diets, in which nitrogen is supplied as free amino acids[28] [29]. Furthermore, the addition of regular food may not diminish the effectiveness of defined formula feedings[30], although a recent pediatric study found that partial enteral nutrition with ad libitum food consumption was far less effective than total enteral nutrition without additional food.[31]

            Part of the benefit derived from enteral feeding may reflect dietary fat content [ref 6]. Those liquid diets that are most effective in inducing remission of active CD are either very low in fat or supply one-third of their dietary fat in the form of medium-chain triglycerides (MCT) from coconut oil [32] [33]. Addition of long-chain triglycerides derived from vegetable oils attenuates benefit[34], whereas diets enriched with MCT oil are as effective as very low fat diets[35]. MCT oil may have a direct anti-inflammatory effect, modulating expression of adhesion molecules and cytokines [ref 6]. The potential role of omega-3 fats in treatment of IBD is discussed below, under Supplements.

            The main advantage to enteral feeding as primary therapy for CD is avoidance of medication side effects, especially in children[36]. Although no clear clinical predictors of response have been established, clinicians believe that patients treated early in the course of CD are more likely to respond than those with longstanding disease [ref 21], and small studies indicate that remission may be more likely in patients with ileal involvement than colonic involvement only[37] and with perforating/fistulating disease than with more superficial disease[38]. The main disadvantage to enteral feedings is poor compliance due to lack of palatability and the high rate of relapse (over 60 percent) following their discontinuation. The use of exclusion diets (discussed below) may significantly extend the benefit of enteral feeding regimens.

            The specific carbohydrate diet (www.scd.org) is a food-based approach to enteral nutrition for patients with IBD for which there are many anecdotal reports of long-term remission without medication[39]. Its alleged mechanism of action is improvement of nutritional status and alteration in ileocecal flora by the proper choice of nutritious carbohydrate sources [40]. It is far more effective for patients with CD than UC (Elaine Gottschall, personal communication). In practice, the diet consists of meat, poultry, fish, eggs, most vegetables and fruits, nut flours, aged cheese, homemade yogurt and honey. Forbidden foods include all cereal grains and their derivatives (including sweeteners other than honey), legumes, potatoes, lactose-containing dairy products and sucrose. Early studies found that high sucrose intake predisposed to CD[41] [42] [43] [44] and that control of disease was enhanced by its avoidance[45]

            The author has used the specific carbohydrate diet as primary treatment for patients with CD for almost fifteen years, observing an overall response rate of 55 percent, unrelated to duration of illness but being most effective in those with ileitis[46].  Improvement occurred in symptoms and laboratory parameters, such as serum albumen and erythrocyte sedimentation rate, and permitted decreased use of glucocorticoids.

           

            Diets that induce remission of CD do not usually induce remission of UC, although they improve patients’ nutritional status and prevent complications related to surgery [ref 6]. Recent dietary approaches to treatment of UC have examined the therapeutic potential of short chain fatty acids (SCFA), butyric acid in particular [ref 6]. Not only do SCFA nourish the colonic epithelium, they lower intraluminal pH, favoring growth of Lactobacilli and Bifidobacteria (considered to be beneficial organisms, or probiotics) and inhibiting the growth of Clostridia, Bacteroides, and Escherichia coli, potential pathogens. In addition to serving as the preferred energy substrate for colonic epithelial cells, butyrate has a true anti-inflammatory effect, preventing activation of the pro-inflammatory nuclear transcription factor, NF-kappa-B[47]. When added to 5-ASA enemas, butyrate (80 mM per liter) induces remission in ulcerative proctitis that is resistant to combined 5-ASA/ hydrocortisone enemas[48]. Because butyrate is normally produced by bacterial fermentation of indigestible carbohydrate in the colon, studies have examined the effect of fiber supplementation on the course of UC. These studies are described below in the section on Prebiotics.

            Patients with UC are not deficient in butyrate, but appear unable to utilize it, perhaps because organic sulfides produced by their enteric flora inhibit the epithelial effects of butyrate[49] [50]. Protein consumption is a major determinant of sulfide production in the human colon[51]. For patients with UC in remission, the risk of relapse is directly influenced by higher consumption of protein, especially meat protein, and by total dietary sulfur, and sulfates[52]. A low sulfur diet has been advocated for maintenance of remission in UC. This diet, which is markedly different from the specific carbohydrate diet, eliminates beef, pork, eggs, cheese, whole milk, ice cream, mayonnaise, soymilk, mineral water, nuts, cruciferous vegetables, and sulfited alcoholic beverages. Controlled studies have not been performed, but a small preliminary study demonstrated the feasibility and safety of a low sulfur diet for patients with UC over a five-year period.[53]

            The differences in dietary response patterns between patients with CD and patients with UC make clarity of diagnosis essential for proper nutritional therapy.

EXCLUSION DIETS.  Exclusion diets eliminate specific symptom-producing foods and have been used to maintain remission of IBD. Although self-reported food intolerance is common among patients with IBD[54], most of the data from controlled studies has been gathered from patients with CD. In the East Anglia Multicentre Controlled Trial, 84% of patients with active CD entered clinical remission after two weeks of a liquid elemental diet [55], which produced a significant decrease in erythrocyte sedimentation rate and C-reactive protein and an increase in serum albumen. Patients were then randomized to receive treatment with prednisolone or treatment with a specific food exclusion diet. To determine which foods each patient needed to avoid, a structured series of dietary challenges was conducted. Patients would introduce foods of their choice, one at a time. Any food that appeared to provoke symptoms was excluded from further consumption; foods that did not provoke symptoms were included into a maintenance diet. At six months, 70 percent of patients treated with diet were still in remission, compared with 34 percent of patients being treated with prednisolone. After two years, 38 percent of patients treated with specific food exclusion were still in remission, compared to 21 percent of steroid-treated patients. In previous uncontrolled studies, some of the same authors had used a diet consisting of one or two meats (usually lamb or chicken), one starch (usually rice or potatoes), one fruit and one vegetable instead of the elemental diet, in order to induce remission. Structured food challenges were then used to construct a maintenance diet free of symptom-provoking foods. Compliance with the specific food elimination diet was associated with a rate of relapse under 10 percent per year[56]. Individual foods found most likely to provoke symptoms in this study were wheat, cow’s milk and its derivatives, cruciferous vegetables, corn, yeast, tomatoes, citrus fruit and eggs.

            A large proportion of CD patients develop antibodies to baker’s and brewer’s yeast, Saccharomyces cerevisiae (ASCA) [57]. Lymphocytes of ASCA-positive patients proliferate after stimulation with mannan, an antigen common to most types of yeast. For these patients, lymphocyte proliferation is associated with increased production of the key inflammatory mediator, TNF-a.[58] A small placebo-controlled study found that patients with stable, chronic CD experienced a significant reduction in the CD activity index during 30 days of dietary yeast elimination and a return to baseline disease activity when capsules of S. cerevisiae were added to their diets [59].
            An observational study of patients with UC suggested that dietary practices based upon food avoidance did not appear to modify the risk of relapse[60], but a small experimental study from South Africa found that diarrhea, rectal bleeding and the appearance of the colon on sigmoidoscopy improved significantly more for patients receiving a diet that systematically eliminated symptom-provoking foods than for those assigned to only monitor their diets[61]. Patients in the diet group were given a defined menu of fish, meat, grains, vegetables and fruit from which to choose and were instructed to eat only one food at breakfast and lunch and two at dinner, rotating foods so that no specific food was eaten more than once during the first week and no food group was consumed more than once in 48 hours. Fried foods, dairy products, sugar, all condiments other than salt and all beverages other than boiled water were eliminated during the first week. At the end of week one, the menu was slowly expanded to include as many foods as tolerated. Four out of eleven patients in the diet group and no patients in the control group achieved clinical and endoscopic remission by the end of six weeks. Eight months later, three of the four patients remained in remission, despite having returned to their usual diets. The potential value of this study is reduced by the small number of patients and the maintenance of remission despite return to an unrestricted diet. Earlier reports from dietary trials led to an estimate that 15 to 20 percent of patients with UC have specific food intolerance that effects severity of illness, with cow's milk protein being the leading offender[62]
. This is consistent with the author’s clinical experience.

SUPPLEMENTS.  Nutritional supplements may be used to correct or prevent the deficiencies that are common among patients with inflammatory bowel disease or to achieve an anti-inflammatory effect.

FOLIC ACID. 5-ASA derivatives, sulfasalazine in particular, impair folic acid transport.[63] Reduced folic acid in patients with IBD is associated with hyperhomocysteinemia[64], a risk factor for deep vein thrombosis[65], an extra-intestinal complication of inflammatory bowel disease. Co-administration of folic acid with 5-ASA derivatives prevents folic acid depletion and has been shown to reduce the incidence of colon cancer in patients with ulcerative colitis[66] [67]. One study found that a high dose of folic acid (15 mg/day) reversed sulfasalazine-induced pancytopenia in two patients[68].

VITAMIN B12. Because vitamin B12 absorption may be impaired by ileal inflammation and by small bowel bacterial overgrowth, deficiency of vitamin B12 has long been described as a potential complication of CD[69].  Although frank vitamin B12 deficiency is unusual, lower vitamin B12 levels are associated with increased serum homocysteine in patients with CD[70]. Ischemic strokes in a woman with CD were associated with vitamin B12-reversible hyperhomocysteinemia.[71] A single dose of 1000 micrograms of cobalamin by injection corrects the megaloblastic anemia associated with CD[72]. 

VITAMIN B6. Median vitamin B6 levels are significantly lower in patients with IBD than controls; low levels are associated with active inflammation and hyperhomocysteinemia[73]. Although some homocysteine is removed by folate-B12-dependent remethylation, the bulk of homocysteine is converted to cystathionine in a reaction catalyzed by vitamin B6. Ischemic stroke and high-grade carotid obstruction in a young woman with CD were attributed to hyperhomocysteinemia, vitamin B6 deficiency and a heterozygous methylene-tetrahydrofolate reductase gene mutation. The authors believed that vitamin B6 deficiency was the principal cause of hyperhomocysteinemia in this patient[74].  

VITAMINS E AND C.  Blood levels of vitamins E and C are often reduced in patients with IBD[75] Administration of alpha-tocopherol 800 IU per day and vitamin C 1000 milligrams per day to patients with stable, active CD decreased markers of oxidative stress but had no effect on the CD activity index[76].

VITAMIN A.  Although levels of carotenoids[77] and retinol[78] are diminished in patients with active CD, low levels appear to be related not malabsorption but to inflammation[79] [80] and a reduction in circulating retinol binding protein [81]. Supplementation with vitamin A at doses of 100,000 to 150,000 IU per day had no effect on symptoms or disease activity[82] [83].

VITAMIN D. Reduced blood levels of 25-OH cholecalciferol, the major vitamin D metabolite, are common in patients with CD, and are related to malnutrition and lack of sun exposure[84] [85]. Administration of vitamin D, 1000 IU per day for one year, prevented bone loss in patients with active disease[86]. The major causes of bone loss in IBD, however, are the effects of inflammatory cytokines and glucocorticoid therapy[87], not vitamin D status. Calcitriol (1,25 dihydroxycholecalciferol), the most active metabolite of vitamin D, may actually be increased in patients with inflammatory bowel disease, because activated intestinal macrophages increase its synthesis; elevated calcitriol is associated with increased risk of osteoporosis and may serve as a marker of disease activity[88]. Hypercalcemia is a rare complication of excess calcitriol and serum calcium should be monitored in patients with IBD receiving vitamin D supplements[89].

VITAMIN K. Biochemical evidence of vitamin K deficiency has been found in patients with ileitis and in patients with colitis treated with sulfasalazine or antibiotics[90]. Serum vitamin K levels in CD are significantly decreased compared with normal controls and are associated with increased levels of undercarboxylated osteocalcin, indicating a low vitamin K status in bone. In patients with CD, undercarboxylated osteocalcin is inversely related to lumbar spine bone density[91]. Furthermore, the rate of bone resorption in CD is inversely correlated with vitamin K status, suggesting that vitamin K deficiency might be another etiological factor for osteopenia of IBD[92]. Optimal dose of vitamin K for correction of deficiency is not known. Patients with active disease may not absorb oral vitamin K, even at high dosage[93].

CALCIUM. Although calcium supplementation is recommended for maintaining bone density in patients with IBD, especially those receiving glucocorticoids, calcium supplementation (1000 milligrams per day) with 250 IU of vitamin D per day, conferred no significant benefit to bone density at one year in patients with corticosteroid-dependent inflammatory bowel disease and osteoporosis.[94] Nonetheless, calcium supplementation should be given to patients with low dietary calcium intake. In experimental animals, low dietary calcium increases severity of IBD[95].

ZINC. Low plasma zinc is common in patients with CD and may be associated with clinical manifestations such as acrodermatitis, decreased activity of zinc-dependent enzymes like thymulin and metallothionein, reduction in muscle zinc concentration and poor taste acuity [ref 6]. Zinc absorption is impaired and fecal zinc losses are inappropriately high[96].  Zinc deficient adolescents with CD grow and mature more normally when zinc deficiency is treated. Anecdotally, correction of zinc deficiency as a specific intervention has been associated with global clinical improvement, suggesting that zinc replacement may have beneficial effects on disease activity[97]. A small study of patients in remission from CD found that high dose supplementation with zinc sulfate, 110 milligrams three times a day for eight weeks, significantly decreased small intestinal permeability for a period of twelve months[98]. In patients with active disease, zinc sulfate, 200 milligrams per day (but not 60 milligrams per day) significantly increased plasma zinc and thymulin activity[99].

SELENIUM. Low selenium levels in patients with CD are associated with increased levels of TNF-a and decreased levels of the antioxidant enzyme, glutathione peroxidase (GSHPx) [100]. Although selenium supplementation raised plasma selenium to the level of a control population, it did not significantly increase activity of GSHPx[101]. Patients with small bowel resection are at risk for severe selenium deficiency; monitoring of selenium status and selenium supplementation have been recommended for this group in particular[102]. Patients on enteral feeding with liquid formula diets experience decreased selenium concentrations proportional to duration of feeding, suggesting that additional selenium supplementation is also needed by them[103].

MAGNESIUM.  Magnesium deficiency is a potential complication of IBD, a result of decreased oral intake, malabsorption and increased intestinal losses due to diarrhea. Urinary magnesium is a better predictor of magnesium status than serum magnesium in this setting[104]. Reduced urinary magnesium excretion is a significant risk factor for urolithiasis, one of the extraintestinal manifestations of IBD[105]. For patients with IBD, the urinary ratio of magnesium and citrate to calcium is a better predictor of lithogenic potential than urinary oxalate excretion[106]. Supplementation with magnesium and citrate may decrease urinary stone formation, but diarrhea is a dose-related, limiting side effect.

CHROMIUM. Glucocorticoid therapy increases urinary chromium excretion and chromium picolinate, 600 micrograms per day, can reverse steroid-induced diabetes in humans, with a decrease in mean blood glucose from 250 milligrams per dL to 150 milligrams per dL. Chromium supplementation may be of benefit for patients receiving glucocorticoids who manifest impaired glucose tolerance[107].

IRON.  Anemia occurs in about 30 percent of patients with IBD[108]. Its causes include iron deficiency due to blood loss, cytokine-induced suppression of erythropoiesis and side effects of medication. Some authors have speculated that iron deficiency actually increases the IFN-g response in TH-1 driven inflammation and may contribute to aggravation of CD [ref 109]. Most clinicians, however, avoid oral iron supplements, believing they can increase oxidative stress in the gut, because very high dose iron supplementation consistently aggravates experimental colitis in rodents[109]. The doses used in rodent studies, however, are orders of magnitude greater than the doses given to patients. The relative risks and benefits of oral iron supplementation for patients with IBD are uncertain.

FISH OILS. Biochemical studies indicate that 25 percent of patients with IBD show evidence of essential fatty acid deficiency[110]. In experimental animals, fish oil feeding ameliorates the intestinal mucosal injury produced by methotrexate[111]. In tissue culture, omega-3 fatty acids stimulate wound healing of intestinal epithelial cells[112]. For patients with UC, a fish oil preparation supplying 3200 milligrams of eicosapentaneoic acid (EPA) and 2400 mg of docosahexaenoic acid (DHA) per day decreased symptoms and lowered the levels of leukotriene B4 (LTB4) in rectal dialysates, with improvement demonstrated after 12 weeks of therapy[113]. A similar preparation improved histological score and symptoms of patients with proctocolitis[114]. At a dose of 4200 milligrams of omega-3 fatty acids per day, fish oils were shown to reduce dose requirements for anti-inflammatory drug therapy of UC[115]. At a dose of 5,100 milligrams of omega-3 fatty acids per day, fish oils combined with 5-ASA derivatives prevented early relapse of UC better than 5-ASA derivatives plus placebo, but fish oils alone did not maintain remission[116].

            In all studies of UC, the fish oil preparations consisted of triacylglycerols. A delayed-release preparation of free fatty acids derived from fish oil, supplying 1,800 milligrams per day of EPA and 800 milligrams per day of DHA, was much more effective than placebo in preventing relapse of CD in patients not taking 5-ASA derivatives[117]. Based upon clinical symptoms and laboratory indices of inflammation, 59 percent of those receiving fish oil remained in remission at one year, compared to 26 percent of those receiving placebo. The main side effect of fish oil was reversible diarrhea, which occurred in 10 percent.

GLUTAMINE. Glutamine appears to have a special role in restoring normal small bowel permeability and immune function. Patients with intestinal mucosal injury secondary to chemotherapy or radiation benefit from glutamine supplementation with less villous atrophy, increased mucosal healing and decreased passage of endotoxin through the gut wall[118]. Although integrative practitioners often advocate glutamine therapy for treatment of IBD, controlled studies have shown no benefit from glutamine supplementation at doses as high as 20 grams per day in patients with CD[119] [120]. Glutamine excess aggravates experimental colitis in rodents[121]. 

N-ACETYLGLUCOSAMINE (NAG): NAG is a substrate for synthesis of glycosaminoglycans, glycoproteins that protect the bowel mucosa from toxic damage. Synthesis of NAG by N-acetylation of glucosamine is impaired in patients with IBD[122]. In explants of bowel tissue from patients, incorporation of added NAG was depressed in patients with inactive UC, increasing to control levels in those with active colitis, probably indicating response of gut tissue to inflammation[123]. In a pilot study, NAG (3 to 6 grams per day for more than two years) given orally  to children with refractory IBD produced symptomatic improvement in the majority of patients and an improvement in histopathology [124]. In children with distal colitis or proctitis, the same dose of NAG was administered by enema with similar effects [ref 123].

PROBIOTICS.  Probiotics are beneficial microorganisms. Their therapeutic use in IBD is attracting considerable attention, because of the recognition that alteration of intestinal microflora may modulate intestinal immune responses[125]. Because of the large number of probiotic preparations available, this section will only discuss those preparations that are commercially available in the United States and that have been studied in clinical trials of patients with IBD. More data exist for their benefits in UC than in CD.

VSL-3 is a proprietary mixture of Lactobacillus acidophilus, L. bulgaricus, L. casei, L plantarum, Bifidobacteriium brevis, B. infantis, B. longum and Streptococcus salivarius ssp thermophilus, supplied in sachets containing 900 billion organisms each. When added to therapy with the 5-ASA derivative balsalazide, VSL-3 (one sachet twice a day) induced faster remission of active UC than balsalazide or mesalazine alone[126]. In an uncontrolled trial, two sachets of VSL-3 twice a day for six weeks as monotherapy yielded clinical and endoscopic remission of mild to moderate UC in 54 percent of patients treated[127]. VSL-3 also prevents relapse of pouchitis (post-colectomy inflammation of the ileal pouch)[128], with two sachets once a day producing remission rates far better than placebo over a one-year period.[129] A survey done at the Cleveland Clinic, however, found poor compliance with this therapy in patients not participating in clinical trials[130].

LACTOBACILLUS GG. Lactobacillus rhamnosus var GG at a dose of 10 to 20 billion organisms per day, was found to prevent onset of pouchitis in patients with ileal pouch-anal anastomosis during the first three years after surgery in a placebo-controlled trial[131] Lactobacillus GG has been ineffective in inducing or maintaining remission of patients with CD[132] or in preventing relapse of CD after surgical resection[133].

SACCHAROMYCES BOULARDII. This plant-derived yeast has shown benefit in the treatment or prevention of traveler’s diarrhea[134], C. difficile diarrhea[135] and antibiotic-induced diarrhea[136]. Experimental data suggest that the yeast owes its antibacterial effects to stimulation of secretory IgA secretion[137] and macrophage activation[138]. Despite its stimulation of mucosal immune responses and its antigenic similarity to baker’s yeast, S.  boulardii has shown benefit in both UC and CD. The addition of S. boulardii (250 milligrams three times a day) to maintenance mesalamine therapy of patients with chronic, active UC was associated with induction of remission within four weeks in 17 out of 25 patients[139]. This trial was uncontrolled. In a placebo-controlled trial, the same dose was given to patients with stable, active CD and mild to moderate diarrhea. S. boulardii reduced the frequency of diarrhea and the clinical activity index when given over a ten-week period, with benefits apparent within two weeks[140]. When added to mesalamine therapy of patients with CD in remission, S. boulardii (1000 milligrams per day) reduced the frequency of relapse from 37.5% to 6.25% during six months, when compared to mesalamine alone[141] Although S. boulardii is considered non-pathogenic, case reports of S. boulardii fungemia have been described in critically ill or immunocompromised patients exposed to S. boulardii. At least eighteen reports of this complication have been published, including one in which airborne spread of S. boulardii occurred in an intensive care unit[142].

PREBIOTICS.   Prebiotics are non-digestible food ingredients that stimulate the growth or modify the metabolic activity of intestinal bacterial species that have the potential to improve the health of their human host. Criteria associated with the notion that a food ingredient should be classified as a prebiotic are that it remains undigested and unabsorbed as it passes through the upper part of the gastrointestinal tract and is a selective substrate for the growth of specific strains of beneficial bacteria (usually Lactobacilli or Bifidobacteria), rather than for all colonic bacteria. Prebiotic food ingredients include bran, psyllium husk, resistant (high amylose) starch, inulin (a polymer of fructofuranose), lactulose, and various natural or synthetic oligosaccharides, which consist of short chain complexes of sucrose, galactose, fructose, glucose, maltose or xylose. The best-known effect of prebiotics is to increase fecal water content, relieving constipation. Bacterial fermentation of prebiotics yields short-chain fatty acids like butyrate. Fructooligosaccharides (FOS) have been shown to alter fecal biomarkers (pH and the concentration of bacterial enzymes like nitroreductase and beta-glucuronidase) in a direction that may convey protection against the development of colon cancer[143]. Several studies have suggested benefits of various prebiotics for the treatment of UC:

            Oat bran, 60 grams per day (supplying 20 grams of dietary fiber), increased fecal butyrate by 36 per cent in patients with UC and diminished abdominal pain[144]. A dietary supplement containing fish oil and two types of indigestible carbohydrate, FOS and xanthum gum, allowed reduction of glucocorticoid dosage when compared to a placebo, in patients with steroid-dependent UC[145]. A Japanese germinated barley foodstuff (GBF) containing hemicellulose-rich fiber, at a dose of 20 to 30 grams per day, increased stool butyrate concentration[146], decreased the clinical activity index of patients with active UC[147] and prolonged remission in patients with inactive UC[148]. Wheat grass juice, 100 milliliters twice daily for one month, tested in a small placebo-controlled trial of patients with distal UC[149], produced a significant reduction in rectal bleeding, abdominal pain and disease activity as measured by sigmoidoscopy. A mixture of B. longum and inulin-derived FOS administered for one month as monotherapy to patients with UC produced improvement in sigmoidoscopic appearance, histology and several biochemical indices of tissue inflammation when compared to a placebo control[150].

BOVINE COLOSTRUM.  Colostrum is the first milk produced after birth and is particularly rich in immunoglobulins, antimicrobial peptides (eg, lactoferrin and lactoperoxidase), and other bioactive molecules, including growth factors. Recent studies suggest that the peptide growth factors in colostrum might provide novel treatment options for a variety of gastrointestinal conditions[151]. Colostrum enemas, 100 milliliters of a 10 percent solution, administered twice a day by patients with distal UC, proved superior to a control enema in promoting healing; all patients were also taking a fixed dose of mesalazine[152]. Studies of oral colostrum in IBD have not been reported, but 125 milliliters three times a day fed to healthy human volunteers was shown to prevent the increase in intestinal permeability produced by indomethacin[153], suggesting that peptide growth factors survive passage through the stomach and upper small bowel.

DEHYDROEPIANDROSTERONE (DHEA).  DHEA is the steroid hormone produced in greatest quantity by the human adrenal cortex, circulating primarily in the sulfated form, DHEA-S. DHEA inhibits activation of nuclear factor kappa B (NF-kappaB), which is activated in inflammatory lesions. Patients with IBD have lower levels of DHEA-S in serum and intestinal tissue than controls[154], partially associated with prior treatment with glucocorticoids[155]. In men with IBD, low DHEA-S is associated with increased risk of osteoporosis[156].  In a pilot study, six of seven patients with refractory CD and eight of thirteen patients with refractory UC responded to DHEA (200 milligrams per day for 56 days) with decrease in the clinical activity index[157]  A case report demonstrated benefit of the same dose of DHEA in a woman with severe refractory pouchitis, with relapse occurring 8 weeks after discontinuation of DHEA[158].

BOTANICALS. In traditional Chinese medicine and Ayurveda, herbal extracts are the mainstay of treatment for IBD and appear to be effective when used by practitioners trained in those systems. Botanicals commonly taken by patients with IBD include slippery elm, fenugreek, devil’s claw, Gingko biloba, Angelica sinensis (Dong quai), and licorice. Although these all express antioxidant or anti-inflammatory activity in vitro[159] [160] [161], data from clinical trials is lacking. Two botanical therapies readily available in the United States have been studied in clinical trials, primarily of UC:

BOSWELLIA. The Ayurvedic herb, Boswellia serrata (Indian frankincense) contains boswellic acids, which inhibit leukotriene biosynthesis in neutrophilic granulocytes by noncompetitive inhibition of 5-lipoxygenase.[162]  During a small six-week trial, 350 milligrams three times a day of Boswellia gum resin was as effective as sulfasalazine 1000 milligrams three times a day in reducing symptoms or laboratory abnormalities of patients with active UC[163]. The rate of remission was 82 percent with Boswellia and 75 percent with sulfasalazine[164]. A proprietary Boswellia extract, H15, was found as effective as mesalazine in improving symptoms of active CD, in a randomized, double-blind study from Germany[165].

ALOE VERA. Aloe vera gel has a dose-dependent inhibitory effect on production of reactive oxygen metabolites, prostaglandin E2 and (at high doses) IL-8, by human colonic epithelial cells grown in tissue culture.[166]. Oral Aloe vera gel, 100 milliliters twice a day for four weeks, produced a clinical response significantly more often than placebo (response ratio 5.6) in patients with UC[167]. Remission occurred in 30 percent of patients taking aloe vera gel and 7 percent of patients receiving placebo. Aloe also reduced histological disease activity, whereas placebo did not. No significant side effects were described, although it should be noted that aloe vera gel is often used as a laxative. Acemannan, an extract of Aloe vera, concentrated to a mucopolysaccharide (MPS) concentration of thirty per cent of solid weight, has been demonstrated to reduce symptoms and indices of inflammation in controlled studies of patients with UC[168].

MIND-BODY THERAPIES. Although it is widely believed that stress aggravates IBD, a German study found no relationship between symptoms of CD or UC and stressful life events, feelings of pressure, conflict or fear of separation.[169] A prospective study did not validate the notion that stressful life events can trigger relapse[170]. Three prospective studies of different types of psychotherapy for patients with IBD failed to show any improvement in medical outcome compared with standard care.[171] [172] [173]

SELF-MANAGEMENT TRAINING. This patient-centered educational approach has a significant impact on health care utilization. In a study from the University of Manchester, when compared to a control group that received customary care, the intervention group required one-third as many doctor visits and one third as many hospitalizations. The difference in outcome was not related to specific treatments employed but rather to the empowerment of patients to be actively involved in managing their own care.[174] The method used: During a 15 to 30 minute consultation, physicians specifically ask patients about the symptoms they have experienced during past relapses and review past and current treatments that have been used to control symptoms, emphasizing the specific effectiveness of each and its acceptability to the patient. Physician and patient then design a personalized self-management strategy based upon the patient's recognition of symptoms and a mutually acceptable treatment protocol for the patient to initiate at onset of a relapse.

ACUPUNCTURE. Acupuncture and moxibustion are commonly employed by practitioners of Chinese medicine for treatment of UC. Uncontrolled studies from China claim excellent results[175] [176]. One small study of moxibustion found evidence of enhanced cellular immunity and decreased antibody production associated with improvement of diarrhea in patients with UC,[177] suggesting down-regulation of the TH-2 response network. A review of studies from both the Chinese and Western literature supports the efficacy of acupuncture in the regulation of gastrointestinal motor activity and secretion through opioid and other neural pathways.[178] Controlled clinical trials of patients with inflammatory bowel disease have not yet been reported.

ANTIBIOTICS. Antibiotics are sometimes helpful for exacerbations of IBD, especially for Crohn’s colitis and for draining fistulae[179] [180]. Metronidazole is the most commonly used agent; it is the first-line drug for treatment of pseudomembranous colitis caused by Clostridium difficile toxin, a complication of IBD that, in patients with active colitis, may occur spontaneously without prior antibiotic exposure. S. boulardii (1000 milligrams per day) enhances therapeutic efficacy of metronidazole in the treatment of recurrent C. difficile colitis[181]. Some other natural products may interfere with the efficacy of metronidazole: Silymarin, a group of flavonoids extracted from milk thistle, at a dose of 140 milligrams per day for nine days, decreased the peak plasma concentration  and bioavailability of metronidazole and its major metabolite by 30 percent in healthy volunteers[182].  Vitamin E (400 international units per day) with vitamin C (500 milligrams per day) reduced effectiveness of metronidazole against metronidazole-sensitive Helicobacter pylori infection by 40 percent[183].

 

Always ask patients about the effect of antibiotics, including those used for unrelated illnesses, on their gastrointestinal symptoms. Improvement of symptoms during antibiotic therapy may be an indication to use that antibiotic empirically during an exacerbation of symptoms. Aggravation of symptoms during antibiotic therapy may be an indication to avoid the specific antibiotic and employ probiotics.

 

5-ASA DERIVATIVES. Mesalazine, sulfasalazine, balsalazide, and olsalazine are used for inducing remission in mild cases of ulcerative or Crohn’s colitis and for maintenance of remission. The value of continuous therapy with 5-ASA derivatives at relatively high doses for maintenance of remission in ulcerative colitis is now well established. Side effects may include folic acid deficiency (discussed above), exacerbation of diarrhea, hair loss and skin rash.

The efficacy of 5-ASA derivatives in inducing remission of IBD can be enhanced by fish oils supplying 4000 milligrams of EPA plus DHA per day and by probiotics (VSL-3 2 packets a day or S. boulardii 250 milligrams three times a day).

 

GLUCOCORTICOIDS. Steroids are used to induce remission of IBD, but have shown no benefit in maintaining remission. Not only do they suppress adrenal function, causing a decline in release of DHEA (discussed above) and impair immune function, their side effects include cataracts, growth failure, hypogonadism and osteopenia. They decrease intestinal calcium absorption, increase renal calcium excretion and induce parathyroid hormone secretion.

IMMUNOSUPRESSANTS. 6-mercaptopurine and its derivative, azothioprine, are used for maintenance of remission or for induction of remission in patients with chronic, stable disease. Although usually well tolerated at low doses, they may cause leukopenia, anemia, and hepatic dysfunction and promote opportunistic infection. Immune stimulating herbs, like Echinacea and Astragalus species, may reverse the benefits of immune suppressants in the treatment of autoimmune disorders[184] [185]. Concomitant use should be avoided. Cyclosporine is occasionally used for inducing remission in refractory UC. Its absorption is drastically reduced by St. John’s wort[186] and may be dangerously increased by peppermint oil[187]. Cyclosporine nephrotoxicity is diminished by administration of fish oil supplying 3000 to 4000 milligrams of omega-3 fatty acids per day[188][189] and by vitamin E (D-alpha tocopherol, 500 international units per day)[190]. Ipriflavone, a semisynthetic isoflavonoid used for prevention of bone loss, may produce lymphopenia[191]. Patients receiving immunosuppressants should avoid it.

TNF-ALPHA BLOCKADE.             Infliximab (Remecade) is a major advance in drug therapy for inducing remission of IBD. Adverse events reported in patients treated with anti-TNF agents include acute infusion reactions, delayed hypersensitivity-type reactions, autoimmune diseases like drug-induced lupus and demyelination, and infection[192]. Cigarette smoking interferes with response to infliximab in patients with CD[193].

SURGERY.    Surgical resection of inflamed bowel is today considered a last resort in the management of patients with IBD. Correction of malnutrition and the use of probiotics (discussed above) may enhance responses to surgery for IBD.

 

SECONDARY PREVENTION

            Despite abundant speculation about the reasons for the dramatic increase in incidence of IBD in industrialized nations over the past century, no convincing strategy for primary prevention has been devised. Secondary prevention may benefit from the following interventions:

·                       Prolonged use of 5-ASA derivatives and folic acid (typically one milligram per day) to maintain remission and prevent colon cancer. Fish oils supplying about 5000 milligrams per day of omega-3 fatty acids and S. boulardii 1000 milligrams per day may enhance efficacy of 5-ASA derivatives in maintenance of remission.

·                       Folic acid, vitamin B6 and vitamin B12 at doses that keep circulating homocysteine low, to prevent thrombotic complications.

·                       Vitamin D (1000 international units per day) and vitamin K (optimal dosage unknown) to prevent bone loss.

·                       A specific food exclusion diet, individually tailored (described above), cessation of tobacco use and reduced consumption of sucrose for maintenance of remission in patients with CD.

·                       A high fiber, low meat diet for maintenance of remission in patients with ulcerative colitis.

 

LABORATORY TESTING

            All patients with IBD should be under the care of a gastroenterologist for regular endoscopic examination and prescription of appropriate drug therapy. The main role of the integrative practitioner is to enhance conventional treatment with a nutritional prescription and the use of nutritional and botanical supplements. A number of laboratory tests are useful for fulfilling this role effectively. Commonly used tests include the complete blood count, erythrocyte sedimentation rate, C-reactive protein and serum albumen. Useful markers of nutritional status in IBD also include plasma zinc and homocysteine, serum and urine magnesium, serum iron, ferritin and transferrin, and 25-OH vitamin D. In steroid-treated patients with refractory disease, serum DHEA-S may be useful. Patients with recent onset, relapse or exacerbation of IBD--especially those with diarrhea--should undergo stool testing for parasites, pathogenic bacteria and C. difficile toxins.



[1] Podolsky DK. Inflammatory bowel disease. N Eng J Med. 2002. vol 347, pp 417-429.

[2]  Darfeuille-Michaud A, Neut C, Barnich N et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease, Gastroenterology 1998, vol 115, pp 1405-1413.

[3] Swidinski A, Vladhoff A, Pernthaler A, et al. Mucosal flares in inflammatory bowel disease. Gastroenterology 2002, vol 122, pp 44-54.

[4] MacDonald TT, DiSabatino A, Gordon, JN, Immunopathogenesis of Crohn's Disease, Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 90040, 2005 S118-S125

[5] Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease: Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5.  J Immunol 1996, vol 157, pp 1261-1270.

[6] Dionne S, D’Agata ID, Hiscott J et al. Colonic explant production of IL-1 and its receptor antagonist in imbalanced in inflammatory bowel disease. Clin Exper Immunol 1998, vol 112, pp 381-387.

[7] Gassull MA, Nutrition and Inflammatory Bowel Disease: Its Relation to Pathophysiology, Outcome and Therapy. Dig Dis 2003;21:220–227

[8] Simmonds NJ, Rampton SD. Inflammatory bowel disease—a radical view. Gut 1993, vol 34, pp 865-868.

[9] Lih-Brody L, Powell SR, Collier KP, et al. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Digestive Diseases and Sciences, 1996, vol 41, pp 2078-2086.

[10] Buffinton GD, Doe WF. Altered ascorbic acid status in the mucosa from inflammatory bowel disease patients. Free Radic Res 1995 Feb;22(2):131-43

[11] D'Odorico A, Bortolan S, Cardin R, D'Inca' R, Martines D, Ferronato A, Sturniolo GC. Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease.
Scand J Gastroenterol 2001 Dec;36(12):1289-94

[12] Ojuawo A, Keith L. The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease. Cent Afr J Med. 2002 Sep-Oct;48(9-10):116-9.

[13]  Hendricks KM, Walker WA. Zinc deficiency in inflammatory bowel disease. Nutrition reviews, 1988, vol 46, pp 401-408.

 

[14] Hinks LJ, Inwards KD, Lloyd B, Clayton B. Reducaed concentrations of selenium in mild Crohn’s disease. J Clin Pathol 1988, vol 41, pp 198-201.

[15] Geerling BJ, Badart-Smook A, Stockbrugger RW, Brummer RJ, Comprehensive nutritional status in recently diagnosed patients with inflammatory bowel disease compared with population controls. Eur J Clin Nutr. 2000 Jun;54(6):514-21.

[16] Gassull MA,  Review article: the role of nutrition in the treatment of inflammatory bowel disease.
Aliment Pharmacol Ther. 2004 Oct;20 Suppl 4:79-83.

[17] Gassull MA, Nutrition and Inflammatory Bowel Disease: Its Relation to Pathophysiology, Outcome and Therapy. Dig Dis 2003;21:220–227 (same as reference 6)

[18] Hollander D, Vadherim CM, Brettholz, et al. Increased intestinal permeability in patient’s with Crohn’s disease and their relatives, a possible etiologic factor. Annals of Internal medicine 1986, vol 105, pp 883-885.

[19] Peeters M, Ghoos Y, Maes B et al. Increased permeability of macroscopically normal; small bowel in Crohn’s disease. Digestive Diseases and Sciences, 1994, vol  39, pp 2170-2176.

[20] Hilsden RJ, Meddings J, Sutherland LR. Aspirin provokes an exaggerated increase in the lactulose-mannitol permeability index in first-degree relatives of Crohn’s patients. Gastroenterology 1995, vol 108, p A834.

[21] Wyatt J, Vogelsgang H, Hubl W etal. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet 1993, vol 341, pp 1437-1439.

[22] Thomas T. MacDonald, FRCPath, Antonio DiSabatino, MD and John N. Gordon, BM, ChB, Immunopathogenesis of Crohn's Disease, Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 90040, 2005 S118-S125

[23] Pirzer U, Schonhaar A, Fleischer B, et al. Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn’s disease. Lancet 1991, vol 338, pp 1238-1239.

[24]. Griffiths AM, Enteral Nutrition in the Management of Crohn's Disease, JPEN J Parenter Enteral Nutr, 2005; 29: S108 - S117.

[25] Dray X, Marteau P., The use of enteral nutrition in the management of Crohn's disease in adults.
JPEN J Parenter Enteral Nutr. 2005 Jul-Aug;29(4 Suppl):S166-9

[26] Sanderson IR, Croft NM., The anti-inflammatory effects of enteral nutrition. JPEN J Parenter Enteral Nutr. 2005;29(4 Suppl):S134-8

[27] Lionetti P, Callegari ML, Ferrari S, Cavicchi MC, Pozzi E, de Martino M, Morelli L., Enteral nutrition and microflora in pediatric Crohn's disease. JPEN J Parenter Enteral Nutr. 2005 Jul-Aug;29(4 Suppl):S173-5

[28] Verma S, Brown S, Kirkwood B, Giaffer MH. Polymeric versus elemental diet as primary treatment in active Crohn's disease: a randomized, double-blind trial.
Am J Gastroenterol. 2000 Mar;95(3):735-9.

[29] Zachos M, Tondeur M, Griffiths AM.  Enteral nutritional therapy for inducing remission of Crohn's disease.
Cochrane Database Syst Rev. 2001;(3):CD000542.

[30] Greenberg GR, Fleming CR, Jeejeebhoy KN, et al. Controlled trial of bowel rest and nutritional support in the management of Crohn's disease.Gut. 1988;29:1309 –1315.

[31] Johnson T, Macdonald S, Hill SM, Thomas A, Murphy MS., Treatment of active Crohn's disease in children using partial enteral nutrition with liquid formula: a randomised controlled trial. Gut. 2005 Sep 14; [Epub ahead of print]

[32] Gonzalez-Huix F, de Leon R, Fernandez-Bañares F, Esteve M, Cabré E, Acero D, Abad-

Lacruz A, Figa M, Guilera M, Planas R, Gassull MA: Polymeric enteral diets as primary

treatment of active Crohn’s disease: A prospective steroid-controlled trial. Gut 1993;34:778–782.

[33] 91 Middleton SJ, Rucker JT, Kirby GA, Riordan AM, Hunter JO: Long-chain triglycerides reduce

the efficacy of enteral feeds in patients with active Crohn’s disease. Clin Nutr 1995;

14:229–236.

 

[34] Bamba T, Shimoyama T, Sasaki M, Tsujikawa T, Fukuda Y, Koganei K, Hibi T, Iwao Y, Munakata A, Fukuda S, Matsumoto T, Oshitani N, Hiwatashi N, Oriuchi T, Kitahora T, Utsunomiya T, Saitoh Y, Suzuki Y, Nakajima M. Dietary fat attenuates the benefits of an elemental diet in active Crohn's disease: a randomized, controlled trial.
Eur J Gastroenterol Hepatol. 2003 Feb;15(2):151-7.

[35] Sakurai T, Matsui T, Yal T et al: Short-term

efficacy of enteral nutrition in the treatment

of active Crohn’s disease: A randomized-controlled

trial comparing nutrient formulas. J

Parenter Enteral Nutr 2002,26:98–103.

[36] Knight C, El-Matary W, Spray C, Sandhu BK. Long-term outcome of nutritional therapy in paediatric Crohn's disease. Clin Nutr. 2005 Oct;24(5):775-9.

 

[37] Afzal NA, Davies S, Paintin M, Arnaud-Battandier F, Walker-Smith JA, Murch S, Heuschkel R, Fell J., Colonic Crohn's disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved. Dig Dis Sci. 2005 Aug;50(8):1471-5.

[38] Ikeuchi H, Yamamura T, Nakano H, Kosaka T, Shimoyama T, Fukuda Y., Efficacy of nutritional therapy for perforating and non-perforating Crohn's disease.
Hepatogastroenterology. 2004 Jul-Aug;51(58):1050-2.

[39] Nieves r, jackson RT, Specific carbohydrate diet in treatment of inflammatory bowel disease. Tennessee med 2004; 97: 407.

[40] Gottschall E, Breaking the Vicious Cycle,  Kirkton Press, Kirkton, Ontario, 1994

[41] Matsui T, Mitsuo I, Fujishima M, et al. Increased sugar consumption in Japanese patients with Crohn’s disease. Gastroenterologica Japonica 1990, vol 25, p 271

[42] Martini GA, Brandes JW. Increased consumption of refined carbohydrates in patients with Crohn’s disease. Klin Wochens 1976, vol 54, pp 367-371.

[43] Thurnton JR, Emmett PM, Heaton KW. Diet and Crohn’s disease: characteristics of the pre-illness diet. Br Med J 1979, vol 2, pp 762-764.

[44] Mayberry JF, Rhodfes J, Newcombe RC. Increased sugar consumption in Crohn’s disease. 1980, Digestion, vol 20,pp 323-326.

[45] Heaton KW, Thornton JR, Emmett PM. Treatment of Crohn’s disease with an unrefined-carbohydrate, fiber-rich diet. Br Med J 1979, vol 2, pp 764-766

[46] Galland L. Nutritional therapy for Crohn’s disease: disease modifying and medication sparing. Alternative Therapies 1999, vol 5, pp 94-95.

[47] Inan MS, Rasoulpour RJ, Yin L, Hubbard

AK, Rosenberg DW, Giardina C: The luminal

short-chain fatty acid butyrate modulates

NF-ÎB activity in a human colonic epithelial

cell line. Gastroenterology 2000;118:724–

734.

[48] Vernia P, Annese V, Bresci G, d'Albasio G, D'Inca R, Giaccari S, Ingrosso M, Mansi C, Riegler G, Valpiani D, Caprilli R; Gruppo Italiano per lo Studio del Colon and del Retto, Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial.
Eur J Clin Invest. 2003 Mar;33(3):244-8.

[49] Roediger WE, Duncan A, Kapaniris O, Millard S. Reducing sulfur compounds of the colon impair colonocyte nutrition: implications for ulcerative colitis. Gastroenterology 1993 Mar;104(3):802-9

[50] Roediger WE, Moore J, Babidge W., Colonic sulfide in pathogenesis and treatment of ulcerative colitis.
Dig Dis Sci. 1997 Aug;42(8):1571-9.

 

[51] Magee EA, Richardson CJ, Hughes R, Cummings JH,, Contribution of dietary protein to sulfide production in the large intestine: an in vitro and a controlled feeding study in humans.
Am J Clin Nutr. 2000 Dec;72(6):1488-94.

 

 

[52] Jowett SL, Seal CJ, Pearce MS, Phillips E, Gregory W, Barton JR, Welfare MR. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study.
Gut. 2004 Oct;53(10):1479-84.

 

[53] Roediger WE.Decreased sulphur aminoacid intake in ulcerative colitis.Lancet. 1998 May 23;351(9115):1555.

 

[54] Ballegaard M, Bjergstrom A, Brondum S et al. Self reported food intolerance in chronic inflammatory bowel disease. Scand J Gastroenterol 1997, vol 32, pp 569-571.

[55] Riordan AM, Hunter JO, Cowan RE et al. Treatment oif active Crohn’s disease by exclusion diet: East Anglican multicentre controlled trial. Lancet 1993, vol 342, pp 1131-1134.

[56] Alun Jones V, Workman E, Freeman AH. Crohn’s disease: maintenance of remission by diet. Lancet 1985, vol ii, pp177-180.

[57] Barnes RMR, Allan S, Taylor-Robinson CH, et al. Serum antibodies reactive with Saccharomyces cerevisiae in inflammatory bowel disease: is IgA antibody a marker for Crohn’s disease? Int Arch Allergy Appl Immunol 1990, vol 92, pp 9-15

[58] Konrad A, Rutten C, Flogerzi B, Styner M, Goke B, Seibold F., Immune sensitization to yeast antigens in ASCA-positive patients with Crohn's disease.
Inflamm Bowel Dis. 2004 Mar;10(2):97-105.

[59] The effect of dietary yeast on the activity of stable chronic Crohn's disease.
Author:Barclay GR, McKenzie H, Pennington J, Parratt D, Pennington CR.,  Volume:27   Issue:3,  Page:196-200  Year:1992
Source:Scand J Gastroenterol, 

[60] Jowett SL, Seal CJ, Phillips E, Gregory W, Barton JR, Welfare MR, Dietary beliefs of people with ulcerative colitis and their effect on relapse and nutrient intake.
Clin Nutr. 2004 Apr;23(2):161-70.

[61] Canbdy S, Borok G, Wright JP et al, The value of an elimination diet in the management of patients with ulcerative colitis. S Afr med J 1995; 85: 1176-79.

[62] Wright R, Truelove SC. A controlled trial of various diets in ulcerative colitis. Br Med J.  1965, vol 2, pp 138-141.

[63] Mason JB.. Folate, colitis, dysplasia, and cancer. Nutr Rev. 1989 Oct;47(10):314-7.

 

[64] Chowers Y, Sela BA, Holland R et al: Increased

levels of homocysteine in patients with Crohn’s

disease are related to folate levels. Am J Gastroenterol

2000;95:3498–3502.

 

[65] Den Heijer M, Koster T, Blom HJ et al: Hyperhomocysteinemia

as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759–762.

 

[66] Lashner BA, Provencher KS, Seidner DL, Knesebeck A, Brzezinski A. et al, Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology. 1989 ;97: 255-59.

[67] Diculescu M, Ciocirlan M, Ciocirlan M, Pitigoi D, Becheanu G, Croitoru A, Spanache S et al, Folic acid and sulfasalazine for colorectal carcinoma chemoprevention in patients with ulcerative colitis: the old and new evidence. Rom J Gastroenterol. 2003; 12: 283-86.

 

[68] Logan EC, Williamson LM, Ryrie DR, Sulphasalazine associated pancytopenia may be caused by acute folate deficiency. Gut. 1986; 27: 868-72.

 

[69] Beeken WL. Remediable defects in Crohn disease. Arch Int med 1975, vol 135, pp 686-690.

[70] Romagnuolo J, Fedorak RN, Dias VC: Hyperhomocysteinemia

and inflammatory bowel disease:

Prevalence and predictors in a cross-sectional

study. Am J Gastroenterol 2001;96:

2143–2149.

 

[71] Penix LP., Ischemic strokes secondary to vitamin B12 deficiency-induced hyperhomocystinemia.
Neurology. 1998 Aug;51(2):622-4.

[72] Abe S, Wakabayashi Y, Hirose S., Megaloblastic anemia associated with diffuse intestinal Crohn's disease]
Rinsho Ketsueki. 1989 Jan;30(1):51-5.

[73] Saibeni S, Cattaneo M, Vecchi M et al: Low vitamin B6 plasma levels, a risk factor for

thrombosis, in inflammatory bowel disease: Role of inflammation and correlation with

acute phase reactants. Am J Gastroenterol 2003:98:112–117.

[74] Younes-Mhenni S, Derex L, Berruyer M, Nighoghossian N, Philippeau F, Salzmann M, Trouillas P, Large-artery stroke in a young patient with Crohn's disease. Role of vitamin B6 deficiency-induced hyperhomocysteinemia. J Neurol Sci. 2004 Jun 15;221(1-2):113-5.

[75] Fernandez-Banares F, Abad-Lacruz A, Xiol X, Gine JJ, Dolz C, Cabre E, Esteve M, Gonzalez-Huix F, Gassull MA., Vitamin status in patients with inflammatory bowel disease.Am J Gastroenterol. 1989 Jul;84(7):744-8.

[76] Aghdassi E, Wendland E, Steinhard H et al. Antioxidant vitamin supplementation in

Crohn’s disease decreases oxidative stress: A randomized controlled trial. Am J Gastroenterol 2003;98:348–353.

 

[77] Rumi G Jr, Szabo I, Vincze A, Matus Z, Toth G, Mozsik G., Decrease of serum carotenoids in Crohn's disease. J Physiol Paris. 2000 Mar-Apr;94(2):159-61.

[78] Bousvaros A, Zurakowski D, Duggan C, Law T, Rifai N, Goldberg NE, Leichtner AM, Vitamins A and E serum levels in children and young adults with inflammatory bowel disease: effect of disease activity. J Pediatr Gastroenterol Nutr. 1998 Feb;26(2):129-35.

[79] Reimund JM, Arondel Y, Escalin G, Finck G, Baumann R, Duclos B., Immune activation and nutritional status in adult Crohn's disease patients. Dig Liver Dis. 2005 Jun;37(6):424-31.

[80] Sampietro GM, Cristaldi M, Cervato G, Maconi G, Danelli P, Cervellione R, Rovati M, Porro GB, Cestaro B, Taschieri AM. Oxidative stress, vitamin A and vitamin E behaviour in patients submitted to conservative surgery for complicated Crohn's disease. Dig Liver Dis. 2002 Oct;34(10):696-701.

[81] Janczewska I, Bartnik W, Butruk E, Tomecki R, Kazik E, Ostrowski J., Metabolism of vitamin A in inflammatory bowel disease. Hepatogastroenterology. 1991 Oct;38(5):391-5.

[82] Wright JP, Mee AS, Parfitt A, Marks IN, Burns DG, Sherman M, Tigler-Wybrandi N, Isaacs S, Vitamin A therapy in patients with Crohn's disease. Gastroenterology. 1985 Feb;88(2):512-4.

[83] Norrby S, Sjodahl R, Tagesson C., Ineffectiveness of vitamin A therapy in severe Crohn's disease.
Acta Chir Scand. 1985;151(5):465-8.

[84] 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 Nov;26(11):1197-203.

[85] Vogelsang H, Ferenci P, Woloszczuk W, Resch H, Herold C, Frotz S, Gangl A, Bone disease in vitamin D-deficient patients with Crohn's disease. Dig Dis Sci. 1989 Jul;34(7):1094-9.

[86] Vogelsang H, Ferenci P, Resch H, Kiss A, Gangl A, Prevention of bone mineral loss in patients with Crohn's disease by long-term oral vitamin D supplementation. Eur J Gastroenterol Hepatol. 1995 Jul;7(7):609-14.

[87] Trebble TM, Wootton SA, Stroud MA, Mullee MA, Calder PC, Fine DR, Moniz C, Arden NK. Laboratory markers predict bone loss in Crohn's disease: relationship to blood mononuclear cell function and nutritional status. Aliment Pharmacol Ther. 2004 May 15;19(10):1063-71.

[88] Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, Matuk R, Daigle K, Chen S, Zehnder D, Lin YC, Yang H, Hewison M, Adams JS. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut. 2004 Aug;53(8):1129-36.

[89] Tuohy KA, Steinman TI, Hypercalcemia due to excess 1,25-dihydroxyvitamin D in Crohn's disease.
Am J Kidney Dis. 2005 Jan;45(1):e3-6.

[90] Krasinski SD, Russell RM, Furie BC, Kruger SF, Jacques PF, Furie B, The prevalence of vitamin K deficiency in chronic gastrointestinal disorders. Am J Clin Nutr. 1985 Mar;41(3):639-43.

[91] Schoon EJ, Muller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrugger RW, Low serum and bone vitamin K status in patients with longstanding Crohn's disease: another pathogenetic factor of osteoporosis in Crohn's disease? Gut. 2001 Apr;48(4):473-7.

[92] Duggan P, O'Brien M, Kiely M, McCarthy J, Shanahan F, Cashman KD., Vitamin K status in patients with Crohn's disease and relationship to bone turnover. Am J Gastroenterol. 2004 Nov;99(11):2178-85.

[93] Fugate SE, Ramsey AM., Resistance to oral vitamin K for reversal of overanticoagulation during Crohn's disease relapse. J Thromb Thrombolysis. 2004 Jun;17(3):219-23.

[94] Bernstein CN, Seeger LL, Anton PA, Artinian L, Geffrey S, Goodman W, Belin TR, Shanahan F, A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease: a pilot study.
Aliment Pharmacol Ther. 1996 Oct;10(5):777-86.

[95] Cantorna MT, Zhu Y, Froicu M, Wittke A., Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1717S-20S.

[96] Griffin IJ, Kim SC, Hicks PD, Liang LK, Abrams SA, Zinc metabolism in adolescents with Crohn's disease. Pediatr Res. 2004 Aug;56(2):235-9.

[97] Hendricks KM, Walker WA. Zinc deficiency in inflammatory bowel disease. Nutrition Reviews 1988, vol 46, pp 401-408.

[98] Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Inca R., Zinc supplementation tightens "leaky gut" in Crohn's disease.  Inflamm Bowel Dis. 2001 May;7(2):94-8.

[99] Brignola C, Belloli C, De Simone G, Evangelisti A, Parente R, Mancini R, Iannone P, Mocheggiani E, Fabris N, Morini MC, et al., Zinc supplementation restores plasma concentrations of zinc and thymulin in patients with Crohn's disease. Aliment Pharmacol Ther. 1993 Jun;7(3):275-80.

[100] Reimund JM, Hirth C, Koehl C, Baumann R, Duclos B., Antioxidant and immune status in active Crohn's disease. A possible relationship. Clin Nutr. 2000 Feb;19(1):43-8.

[101] Geerling BJ, Badart-Smook A, van Deursen C, van Houwelingen AC, Russel MG, Stockbrugger RW, Brummer RJ. Nutritional supplementation with N-3 fatty acids and antioxidants in patients with Crohn's disease in remission: effects on antioxidant status and fatty acid profile. Inflamm Bowel Dis. 2000 May;6(2):77-84.

[102] Rannem T, Ladefoged K, Hylander E, Hegnhoj J, Jarnum S.. Selenium status in patients with Crohn's disease. Am J Clin Nutr. 1992 Nov;56(5):933-7.

[103] Kuroki F, Matsumoto T, Iida M. Selenium is depleted in Crohn's disease on enteral nutrition.
Dig Dis. 2003;21(3):266-70.

[104] Galland L, Magnesium and inflammatory bowel disease. Magnesium. 1988;7(2):78-83.

[105] Bohles H, Beifuss OJ, Brandl U, Pichl J, Akcetin Z, Demling L., Urinary factors of kidney stone formation in patients with Crohn's disease. Klin Wochenschr. 1988 Feb 1;66(3):87-91.

[106] McConnell N, Campbell S, Gillanders I, Rolton H, Danesh B., Risk factors for developing renal stones in inflammatory bowel disease. BJU Int. 2002 Jun;89(9):835-41.

[107] Ravina A, Slezak L, Mirsky N, Bryden NA, Anderson RA et al, Reversal of corticosteroid-induced diabetes mellitus with supplemental chromium. Diabet Med.1999; 16: 164-67.

 

[108] Gasche C, Lomer MC, Cavill I, Weiss G, Iron, anaemia, and inflammatory bowel diseases.
Gut. 2004 Aug;53(8):1190-7.

[109] Oldenburg B, Koningsberger JC, Van Berge Henegouwen GP, Van Asbeck BS, Marx JJ. Iron and inflammatory bowel disease. Aliment Pharmacol Ther. 2001 Apr;15(4):429-38.

[110] Siguel EN, Lerman RH. Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders. Metabolism 1996, vol 45, pp 12-23.

[111] Vanderhoof, J.A., et al., Effect of dietary menhaden oil on normal growth and development and on ameliorating mucosal injury in rats. Am J Clin Nutr, 1991. 54(2): p. 346-50.

[112] Ruthig DJ, Meckling-Gill KA. Both (n-3) and (n-6) fatty acids stimulate wound healing in the rat intestinal epiuthelial cell line, IEC-6. J Nutrition 1999, vol 129, pp 1791-1798.

[113] Stenson WF, Cort D, Rodgers J, et al. Dietary supplementation with fdish oil in ulcerative colitis. Ann Int Med 1992, vol 116, pp 609-615.

[114] Almallah YZ, Ewen SW, El-Tahir A, Mowat NA, Brunt PW, Sinclair TS, Heys SD, Eremin O. et al, Distal proctocolitis and n-3 polyunsaturated fatty acids (n-3 PUFAs): the mucosal effect in situ. J Clin Immunol. 2000; 20: 68-76.

 

[115]  Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992; 87: 432-37.

[116] Loeschke K, Ueberschaer B, Pietsch A, Gruber E, Ewe K, Wiebecke B, Heldwein W, Lorenz R et al, n-3 Fatty acids retard early relapse in ulcerative colitis in remission. Dig Dis Sci 1996; 41: 2087-94..

[117] Belluzzi A, Brignola C, Campieri M, et al. Effect of an enteric coated fish-oil preparation on relapses in Crohn’s disease. N Engl J Med 1996, vol 334, pp 1557-1560.

[118] van der Hulst, R.R., et al., Glutamine and the preservation of gut integrity. Lancet, 1993. 341(8857): p. 1363-5.

[119] Akobeng AK, Miller V, Stanton J, Elbadri AM, Thomas AG., Double-blind randomized controlled trial of glutamine-enriched polymeric diet in the treatment of active Crohn's disease. J Pediatr Gastroenterol Nutr. 2000 Jan;30(1):78-84.

[120] Den Hond E, Hiele M, Peeters M, Ghoos Y, Rutgeerts P, Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn's disease.
JPEN J Parenter Enteral Nutr. 1999 Jan-Feb;23(1):7-11

[121] Shinozaki M, Saito H, Muto T., Excess glutamine exacerbates trinitrobenzenesulfonic acid-induced colitis in rats. Dis Colon Rectum. 1997 Oct;40(10 Suppl):S59-63.

[122] Burton AF, Anderson FH, Decreased incorporation of 14C-glucosamine relative to 3H-N-acetyl glucosamine in the intestinal mucosa of patients with inflammatory bowel disease. Am J Gastroenterol. 1983; 78: 19-22.

[123] Ryder SD, Raouf AH, Parker N, Walker RJ, Rhodes JM et al, Abnormal mucosal glycoprotein synthesis in inflammatory bowel diseases is not related to cigarette smoking. Digestion. 1995; 56: 370-76.

 

[124] Salvatore S, Heuschkel R, Tomlin S, Davies SE, Edwards S, Walker-Smith JA, French I, Murch SH et al, A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease. Aliment Pharmacol Ther. 2000; 14: 1567-79.

[125] O'Sullivan GC, Kelly P, O'Halloran S, Collins C, Collins JK, Dunne C, Shanahan F, Probiotics: an emerging therapy. Curr Pharm Des. 2005;11(1):3-10

[126] 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. Med Sci Monit. 2004 Nov;10(11):PI126-31

[127] Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, De Simone C, Sartor RB. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 2005 Jul;100(7):1539-46.

[128] Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind placebo controlled trial, Gastroernterology 2000, vol 119, pp305-309.

[129]Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis.
Gut. 2004 Jan;53(1):108-14.

[130] Shen B, Brzezinski A, Fazio VW, Remzi FH, Achkar JP, Bennett AE, Sherman K, Lashner BA, Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice.
Aliment Pharmacol Ther. 2005 Oct 15;22(8):721-8.

[131] 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. Dis Colon Rectum. 2004 Jun;47(6):876-84

[132] Schultz M, Timmer A, Herfarth HH, Sartor RB, Vanderhoof JA, Rath HC, Lactobacillus GG in inducing and maintaining remission of Crohn's disease. BMC Gastroenterol. 2004 Mar 15;4(1):5.

[133] 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 Sep;51(3):405-9.

[134] McFarland V, Bernasconi P. A review of a novel biotherapeutic agent: Saccharomyces boulardii. Microb Ecology Health Dis. 1993, vol 6, pp 157-171.

[135] Surawicz, C.M., et al., Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol, 1989. 84(10): p. 1285-7.

[136] Surawicz, C.M., et al., Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology, 1989. 96(4): p. 981-8.

[137] . Buts, J.-P., et al., Stimulation of secretory IgA and secretory component of immunoglobulins in small intestine of rats treated with Saccharomyces boulardii. Digestive diseases and Scioences,1990, vol 35, pp 251-256. .

 

[138] Machado Caetano JA, Parames MT, Babo MJ, et al. Immunopharmacological effects of Saccharomyces boulardii in healthy human volunteers. Int J Immunopharmacol 1986, vol 8 pp 245-259.

[139] Guslandi M, Giollo P, Testoni PA, A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur J Gastroenterol Hepatol. 2003 Jun;15(6):697-8.

[140] 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. Z Gastroenterol. 1993 Feb;31(2):129-34.

[141] Guslandi M, Mezzi G, Sorghi M, Testoni PA., Saccharomyces boulardii in maintenance treatment of Crohn's disease.Dig Dis Sci. 2000 Jul;45(7):1462-4.

[142]Cassone M, Serra P, Mondello F, Girolamo A, Scafetti S, Pistella E, Venditti M.et al, Outbreak of Saccharomyces boulardii subtype boulardii fungaemia in patients neighboring those treated with a probiotic preparation of the organism. J Clin Microbiol 2003; 41: 5340-43.

[143] Galland L, Functional Foods: Health Effects and Clinical Applications, in Encyclopedia of Human Nutrition, 2nd edition, London, John Wiley & Sons, 2005, pp 360-66.

[144] Hallert C, Bjorck I, Nyman M, Pousette A, Granno C, Svensson H. Increasing fecal butyrate in ulcerative colitis patients by diet: controlled pilot study.
Inflamm Bowel Dis. 2003 Mar;9(2):116-21.

 

[145] Seidner DL, Lashner BA, Brzezinski A, Banks PL, Goldblum J, Fiocchi C, Katz J, Lichtenstein GR, Anton PA, Kam LY, Garleb KA, Demichele SJ.An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: a randomized, controlled trial.
Clin Gastroenterol Hepatol. 2005 Apr;3(4):358-69.

 

[146] Bamba T, Kanauchi O, Andoh A, Fujiyama Y.A new prebiotic from germinated barley for nutraceutical treatment of ulcerative colitis. J Gastroenterol Hepatol 2002 Aug;17(8):818-24


[147] Kanauchi O, Mitsuyama K, Homma T, Takahama K, Fujiyama Y, Andoh A, Araki Y, Suga T, Hibi T, Naganuma M, Asakura H, Nakano H, Shimoyama T, Hida N, Haruma K, Koga H, Sata M, Tomiyasu N, Toyonaga A, Fukuda M, Kojima A, Bamba T., Treatment of ulcerative colitis patients by long-term administration of germinated barley foodstuff: multi-center open trial.
Int J Mol Med. 2003 Nov;12(5):701-4.

 

[148] Hanai H, Kanauchi O, Mitsuyama K, Andoh A, Takeuchi K, Takayuki I, Araki Y, Fujiyama Y, Toyonaga A, Sata M, Kojima A, Fukuda M, Bamba T. Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. Int J Mol Med. 2004 May;13(5):643-7.

[149] Ben-Ayre E, Goldin E, Wengrower E, et al. Wheat grass juice in the treatment of active distal alternative colitis. Scand J Gastroenterol 2002, vol 37, pp 444-449

[150] Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O'neil DA, Macfarlane GT Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial.Gut. 2005 Feb;54(2):242-9.

[151] Playford RJ, Macdonald CE, Johnson WS, Colostrum and milk-derived peptide growth factors for the treatment of gastrointestinal disorders. Am J Clin Nutr. 2000 Jul;72(1):5-14.

[152] Khan Z, Macdonald C, Wicks AC, Holt MP, Floyd D, Ghosh S, Wright NA, Playford RJ. et al, Use of the 'nutriceutical', bovine colostrum, for the treatment of distal colitis: results from an initial study. Aliment Pharmacol Ther. 2002; 16: 1917-22.

 

[153] Playford RJ, MacDonald CE, Calnan DP, Floyd DN, Podas T, Johnson W, Wicks AC, Bashir O, Marchbank T. Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability.
Clin Sci (Lond). 2001 Jun;100(6):627-33.

 

[154] de la Torre B, Hedman M, Befrits Ret al, Blood and tissue dehydroepiandrosterone sulphate levels and their relationship to chronic inflammatory bowel disease. Clin Exp Rheumatol. 1998; 16: 579-82.

[155] Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T. et al, Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease.Am J Gastroenterol. 1998; 93: 2197-202.

[156] Szathmari M, Vasarhelyi B, Treszl A, Tulassay T, Tulassay Zi et al, Association of dehydroepiandrosterone sulfate and testosterone deficiency with bone turnover in men with inflammatory bowel disease. Int J Colorectal Dis. 2002; 17: 63-6.

[157] Andus T, Klebl F, Rogler G, Bregenzer N, Scholmerich J, Straub RH et al, Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study. Aliment Pharmacol Ther. 2003; 17: 409-14.

[158] Klebl FH, Bregenzer N, Rogler G, Straub RH, Scholmerich J, Andus T, Treatment of pouchitis with dehydroepiandrosterone (DHEA) - a case report. Z Gastroenterol. 2003 Nov;41(11):1087-90.

[159] Kang OH, Kim JA, Choi YA, Park HJ, Kim DK, An YH, Choi SC, Yun KJ, Nah YH, Cai XF, Kim YH, Bae KH, Lee YM, Inhibition of interleukin-8 production in the human colonic epithelial cell line HT-29 by 18 beta-glycyrrhetinic acid. Int J Mol Med. 2005 Jun;15(6):981-5.

[160] Langmead L, Dawson C, Hawkins C, Banna N, Loo S, Rampton DS. Antioxidant effects of herbal therapies used by patients with inflammatory bowel disease: an in vitro study. Aliment Pharmacol Ther. 2002 Feb;16(2):197-205.

[161] Dong WG, Liu SP, Zhu HH, Luo HS, Yu JP et al, Abnormal function of platelets and role of angelica sinensis in patients with ulcerative colitis. World J Gastroenterol. 2004; 10: 606-09

[162] Ammon HP, Boswellic acids (components of frankincense) as the active principle in treatment of chronic inflammatory diseases. Wien Med Wochenschr. 2002;152(15-16):373-8.

[163] Gupta I, Parihar A, Malhotra P, Gupta S, Ludtke R, Safayhi H, Ammon HP. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med 2001 Jul;67(5):391-5

 

[164] Gupta I, Parihar A, Malhotra P, Singh GB, Ludtke R, Safayhi H, Ammon HP , Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res. 1997 Jan;2(1):37-43.

[165] Gerhardt H, Seifert F, Buvari P, Vogelsang H, Repges R. Therapy of active Crohn disease with Boswellia serrata extract H 15. Z Gastroenterol. 2001 Jan;39(1):11-7.

[166] Langmead L, Makins RJ, Rampton DS., Anti-inflammatory effects of aloe vera gel in human colorectal mucosa in vitro. Aliment Pharmacol Ther. 2004 Mar 1;19(5):521-7

[167] Langmead L, Feakins RM, Goldthorpe S, Holt H, Tsironi E, De Silva A, Jewell DP, Rampton DS, Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis.Aliment Pharmacol Ther. 2004 Apr 1;19(7):739-47.

[168] Robinson M..Medical therapy of inflammatory bowel disease for the 21st century. Eur J Surg Suppl 1998;(582):90-8

 

[169] von Wietersheim J, Kohler T, Feiereis H. Relapse-precipitating life events and feelings in patients with inflammatory bowel disease.
Psychother Psychosom 1992;58(2):103-12

[170] Do life events or depression exacerbate inflammatory bowel disease? A prospective study.
Author:North CS, Alpers DH, Helzer JE, Spitznagel EL, Clouse RE.,  Volume:114   Issue:5,  Page:381-6  Year:1991 Mar 1
Source:Ann Intern Med

[171] Maunder RG.  Esplen MJ. Supportive-expressive group psychotherapy for persons with

inflammatory bowel disease. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie. 46(7):622-6, 2001

[172] Jantschek G.  Zeitz M.  Pritsch M.  Wirsching M.  Klor HU.  Studt HH.

Rasenack J.  Deter HC.  Riecken EO.  Feiereis H.  Keller W. Effect of  psychotherapy on the course of Crohn's disease. Results of the German prospective multicenter psychotherapy treatment study on Crohn's disease. German Study Group on Psychosocial Intervention in Crohn's Disease. Scandinavian Journal of Gastroenterology.  33(12):1289-96, 1998

[173] Schwarz SP.  Blanchard EB. Evaluation of a psychological treatment for inflammatory bowel disease. Behaviour Research & Therapy.  29(2):167-77, 1991.

[174] Robinson A, Thompson DG, Wilin W, et al. Guided self-management and patient-directed follow-up of ulcerative colitis: a randomized trial. Lancet 2001, vol 358, pp 976-981.

[175] Yang C.  Yan H. Observation of the efficacy of acupuncture and moxibustion in 62 cases

of chronic colitis. Journal of Traditional Chinese Medicine.  19(2):111-4, 1999

 

[176] Zhang X. 23 cases of chronic nonspecific ulcerative colitis treated by

acupuncture and moxibustion. Journal of Traditional Chinese Medicine.  18(3):188-91, 1998

[177] Wu H.  Chen H.  Hua X.  Shi Z.  Zhang L.  Chen J. Clinical therapeutic effect of drug-separated moxibustion on chronic diarrhea and its immunologic mechanisms. Journal of Traditional Chinese Medicine.  17(4):253-8,

 

[178] Li Y.  Tougas G.  Chiverton SG.  Hunt RH.

The effect of acupuncture on gastrointestinal function and disorders.

American Journal of Gastroenterology.  87(10):1372-81, 199

[179] Sutherland L, Singlewton J, Sessions J et al. Double blind placebo-controlled trial of metronidazole in Crohn’s disease. Gut 1991, vol 32, pp 1071-1075.

[180] Turunen UM, Farkkila MA, Hakala K, Seppala K, Sivonen A, Ogren M, Vuoristo M, Valtonen VV, Miettinen TA.

Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study.
Gastroenterology. 1998 Nov;115(5):1072-8.

 

[181] McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL, Noorani Z,  et al, A randomized, placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271: 1913-18

 

[182] Rajnarayana K, Reddy MS, Vidyasagar J, Krishna DR. et al, Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneimittelforschung 2004; 54: 109-13.

[183] Chuang CH, Sheu BS, Huang AH, Yang HB, Wu JJ. et al, Vitamin C and E supplements to lansoprazole-amoxacillin-metronidazole triple therapy may reduce the eradication rate of metronidazole-sensitive Helicobacter pylori infection. Helicobacter 2002;  7: 310-16.

 

[184] Lee AN, Wirth VP, Activation of autoimmunity following use of immunostimulatory herbal supplements. Arch Dermatol. 2004; 140: 723-77.

[185] Chu DT, Wong WL, Mavligit GM. et al, Immunotherapy with Chinese medicinal herbs. II. Reversal of cyclophosphamide-induced immune suppression by administration of fractionated Astragalus membranaceus in vivo. J Clin Lab Immunol. 1988; 25: 125-29.

[186] Ernst E, St. John's Wort supplements endanger the success of organ transplantation. Arch Surgery 2002; 137: 316-19.

[187] Wacher VJ, Wong S, Wong HT, Peppermint oil enhances cyclosporine bioavailability in rats: comparison with D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) and keotconazole. J Pharm Sci 2002; 91: 77-90.

[188] Homan van der Heide JJ, Bilo HJ, Tegzess AM, Donker AJ et al, The effects of dietary supplementation with fish oil on renal function in cyclosporine-treated renal transplant recipients. Transplantation 1990; 49: 523-27

[189] Badalamenti S, Salerno F, Lorenzano E, Paone G, Como G, Finazzi S, Sacchetta AC, Rimola A, Graziani G, Galmarini D, et al, Renal effects of dietary supplementation with fish oil in cyclosporine-treated liver transplant recipients. Hepatology 1995; 22: 1695-71

[190] de Lorgeril M, Boissonnat P, Salen P, Monjaud I, Monnez C, Guidollet J, Ferrera R, Dureau G, Ninet J, Renaud S. et al, The beneficial effect of dietary antioxidant sup[plementation on platelet aggregation and cyclosporine treatment in heart transplant patients. Transplantation 1994; 58: 193-95.

[191] Agnusdei D, Bufalino L, Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcif Tissue Int. 1997;61 Suppl 1: S23-7.

[192] Sandborn WJ, New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease.
Rev Gastroenterol Disord. 2005 5(1):10-8.

[193] Parsi MA, Achkar JP, Richardson S, Katz J, Hammel JP, Lashner BA, Brzezinski A Predictors of response to infliximab in patients with Crohn's disease. Gastroenterology. 2002 Sep;123(3):707-13.

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