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]. 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 |