Dietary Factors in the Modulation of Inflammatory Bowel Disease Activity

Abstract

Context

As patients look to complementary therapies for management of their diseases, it is important that the physician know the effectiveness and/or lack of effectiveness of a variety of dietary approaches/interventions. Although the pathogenesis of the inflammatory bowel diseases (ulcerative colitis and Crohn's disease) is not fully understood, many suspect that diet and various dietary factors may play a modulating role in the disease process.

Evidence Acquisition

The purpose of this article is to present some of what is known about various dietary/nutritional factors in inflammatory bowel disease, with inclusion of evidence from various studies regarding their putative effect. MedLINE was searched (1965-present) using combinations of the following search terms: diet, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Additionally, references of the articles obtained were searched to identify further potential sources of information.

Evidence Synthesis

While much information is available regarding various dietary interventions/supplements in regard to inflammatory bowel disease, the lack of controlled trials limits broad applicability. Probiotics are one of the few interventions with promising results and controlled trials.

Conclusion

While there are many potential and promising dietary factors that may play a role in the modulation of inflammatory bowel disease, it is prudent to await further controlled studies before broad application/physician recommendation in the noted patient population.

Introduction

Across every specialty, alternative approaches to conventional diseases are beginning to take hold. This is certainly no different for patients suffering from ulcerative colitis and Crohn's disease. These 2 conditions, collectively referred to as the inflammatory bowel diseases, have an estimated prevalence of 149 per 100,000 whites, with increasing, but similar rates in blacks, and lower rates in Hispanics and Asians.[1]

Despite much effort and research, the etiology of this disease process continues to remain elusive. Many suspect an immune-mediated process, and standard therapy includes 5-aminosalicylate derivatives, corticosteroids, and various immune-modulating drugs (eg, 6-mercaptopurine, azathioprine, etc). Newer, more selective biologic agents such as monoclonal antibodies are beginning to emerge as effective from successful clinical trials.

In spite of these therapies, many turn to alternative medicine to seek relief from their symptoms. This may be secondary to a variety of reasons, including undesirable/unwanted medication side effects or lack or efficacy. Surveys have shown that those with a poorer quality of life turn to alternative medicine in greater numbers.[2] However, a poorly regulated industry that profits from the shortcomings of modern medicine awaits those patients who seek alternative therapies. There are purported miracle cures for almost any disease, often without evidence to support their purported effectiveness. However, some forms of alternative therapies have shown efficacy in clinical studies.

Diet is an especially attractive forum to modulate the inflammatory process. Dietary factors have been shown to modulate the pathogenesis of a variety of conditions, including celiac disease, colon cancer, and diverticulosis, and some believe it may play a role in the pathogenesis of inflammatory bowel disease. The purpose of this article is to provide a review of some of what is known about proposed dietary and nutritional factors and the evidence supporting its effect on inflammatory bowel disease from various research studies.

Microparticles

There is an abundance of factors that lead some to believe that diet plays an important role in the etiology of inflammatory bowel disease (IBD). Experts have observed an increased incidence of IBD in urban areas, and some believe that this may be due in part to the fact that urban diets have higher concentrations of so-called microparticles (such as titanium dioxide and aluminosilicates). These substances are believed to be inert but play no role in nutrition. It is believed that these microparticles may combine with other substances in the intestine (such as bacterial components) and form antigenic particles.[3] Microparticles have also been associated with other disease processes such as asthma.[4] The thinking is that these antigens may activate an immune-mediated inflammatory response.[3] It has been shown that a microparticle-free diet decreased Crohn's disease activity.[4]

The discovery of specific antigens, or in this case, microparticles, is a logical progression from the discovery of the gene encoding for the NOD2 protein as being associated with the pathogenesis of Crohn's disease. NOD2 is believed to play a role in the recognition of bacterial particles and subsequent activation of the inflammation cascade by the activation of NF-kappa B.[5] It is possible that other related proteins may be involved in the recognition of other antigenic substrates, and in this case, microparticles.

Elemental Diets

Elemental diets have been used widely in the treatment of inflammatory bowel disease, especially with the management of Crohn's disease. These diets provide all essential nutrients, and contain protein in the form of free amino acids. These diets require no digestion, and theoretically are easily absorbed.[6]

There are several proposed mechanisms as to the efficacy of this therapy, including elimination of antigens present in food that may provoke an inflammatory response, alternation of the bacterial environment in the colon, and/or a reduction in dietary fat, which some believe may provoke inflammation (explained in more detail later).[6,7]

Elemental diets have been shown to be effective in inducing and maintaining remission, although patients frequently relapse once this therapy is halted. While they have been shown to be superior to placebo,[15] there is controversy as to whether the efficacy of this therapy is equivalent to steroid therapy. Several meta-analyses have shown corticosteroids to be superior to elemental diets in relation to efficacy in the management of IBD.[3,8,9]

In selected cases, however, elemental diet therapy may be a viable option for patients. This may be true in children and adolescents, who may experience stunted growth as a result of high-dose corticosteroid therapy.[10] The major drawback to this therapy is the fact that these diets are often unpalatable and may result in diarrhea as a result of their high osmolarity.[6] These are possible reasons why microparticle-free diets may represent a more viable alternative, if inflammatory bowel disease activity is indeed influenced by the amount of antigens presented to the intestinal immune system.[3]

Sucrose, Fructose, and Lactose

Sucrose, commonly found in table sugar, may adversely affect those with IBD. Studies that have been done comparing the eating habits of those with IBD and those without it have shown the affected persons to consume a higher amount of sucrose and refined carbohydrates. Interestingly, a high level of fructose (commonly found in fruits) was negatively associated with IBD. Starches and lactose showed no association with IBD.[3,11]

The Specific Carbohydrate Diet

The exact role of sucrose pathogenesis and progression of IBD has not yet been fully elucidated. Some believe that unrefined carbohydrates, starches and sucrose may play a role in dysbiosis (abnormal alteration of the colonic bacterial flora). This thinking is evident in a popular diet for IBD, Elaine Gottschall's specific carbohydrate diet.

The theory behind this diet is similar to elemental diets, in that the goal is to supply the body with fully digested building blocks. Complex sugars (eg, lactose and sucrose) and most starches (such as those found in corn, rice, and gluten containing products) are not to be consumed by patients. In IBD and other bowel conditions, Gottschall believes that the intestine is lacking in certain enzymes needed to break down complex sugars and starches. Because of excess undigested carbohydrates in the lumen of the gut as a result of these deficiencies, pathogenic bacteria are given a steady supply of substrates on which to feed. By decreasing the supply of these undigested carbohydrates, it is believed that the food supply to these pathogenic, but uncharacterized bacteria, will be decreased, causing death of these bacteria. Foods with so-called beneficial bacteria, such as Lactobacillus acidophilus (found in yogurt and certain over-the-counter supplements), are encouraged to repopulate the bowel flora. (These beneficial bacteria, also known as probiotics, are discussed later in this article.) As such, dysbiosis, or altered bacterial flora, is central to the theory behind this diet.

Although there have not been any controlled studies evaluating the effectiveness of this diet in patients with IBD, there is no shortage of testimonials proclaiming long-term improvement and remission (http://www.breakingtheviciouscycle.info/testimonies/testimonies.htm). A recent case report of 2 patients demonstrated symptomatic improvement following this diet was recently published.[48] Further study of this diet in the form of a controlled trial is warranted to elucidate the specific role, if any, in IBD.[12]

Probiotics

Dysbiosis, or altered intestinal bacterial flora, is thought by many to play an important role in the pathogenesis of IBD. NOD2 is involved in the recognition of specific bacterial peptides and subsequent activation of an immune response. Studies with different mouse models of IBD have shown that certain bacterial strains are protective while others are not. For example, in IL-2 deficient mice, colitis was induced with an Escherichia coli mpk strain, but not with Bacteroides vulgatus. If both of these were administered together, colitis was not observed. This indicates that B vulgatus may serve a protective role, at least in this model.[13]

In an IL-10 deficient mouse model, Lactobacillus reuteri was shown to positively affect inflammation, and in some cases, even prevent the development of colitis.[13] Increased levels of IL-10 down-regulate the production of interferon gamma, known to play a key role in granuloma formation. (Granulomas are identifying pathologic features of Crohn's disease.[14]) On the other hand, Enterococcus faecalis has been shown to precipitate colitis in this same mouse model.[15]

Schistosoma mansoni eggs down-regulate Th1-mediated inflammation in a trinitrobenzene sulphonic acid model of colitis. Increased IL-4, increased IL-10 mRNA and decreased interferon gamma levels were noted.[13]

In ulcerative colitis, a preliminary trial showed Saccharomyces boulardii to be effective in treatment.[16]

Dietary Fat

The amount of fat in enteral diets has been shown to affect remission rate. It is also believed that the type of fat may play a role. When a meta-analysis was performed looking at the rate of remission as compared to the amount of fat in enteral feedings, it was shown that fat content and remission rate were inversely related. But it was predominantly long-chain triglycerides that appeared to have this adverse effect. When medium-chain triglycerides were added, there was no noted adverse effect on remission rate.

The determination as to whether a triglyceride is classified as a long or short chain is based on the number of carbons the fatty acids contains. Greater than 12 carbons in a fatty acid signifies a long-chain triglyceride, and between 6 and 12 carbon atoms classifies it as a medium chain. Medium-chain triglycerides are digested and absorbed more completely than their long-chain counterparts, and are water soluble. Medium-chain triglycerides are found in coconut oil, whereas safflower and soybean oil are good sources of long-chain triglycerides.[17]

Other small studies have shown that low-fat diets and diets with medium-chain triglycerides are superior to higher fat diets in the induction and maintenance of remission.[18,19]

Case control studies have shown that ulcerative colitis may be associated with an increased intake of monosaturated and polyunsaturated fats. It has been also shown that omega-6 fatty acids are positively correlated with IBD, whereas omega-3 fatty acids are negatively correlated.[3,20] Omega-6 fatty acids are the precursor to synthesis of arachidonic acid, which is degraded into powerful mediators of inflammation by phospholipase A2.[14] However, omega-3 fatty acids compete with omega-6 fatty acids in the synthesis pathway of arachidonic acid, thereby decreasing its synthesis, and subsequently the synthesis of inflammatory mediators.

Sources of omega-3 fatty acids include fish, fish oil, algae, walnuts, leafy green vegetables, flax, and canola oils. Sources of omega-6 fatty acids include corn, soy, primrose, sunflower and safflower oils, red meat, and borage.[21,22] Various studies have shown that administration of omega-3 fatty acids has a positive effect on IBD.[3,20,22–25]

Dietary Fiber and Short-Chain Fatty Acids

High levels of dietary fiber have been shown to decrease the relative risk for Crohn's disease.[25] In a trinitrobenzenesulfonic acid model of colitis, dietary fiber was shown to decrease the production of TNF-alpha and nitric oxide (known mediators of inflammation). It was also noted that there was a higher concentration of short-chain fatty acids, which Rodriguez-Cabezas and colleagues[28] conclude may play a role in both decreasing the production of the certain inflammatory mediators and also contribute to the repair and regeneration of the damaged colonic cells. Butyrate and other short-chain fatty acids such as acetate, propionate, and valerate are created when soluble fibers are fermented in the intestine. Some believe that the production of the short-chain fatty acids, which are decreased in colitis, is important to maintain microbial balance and prevent dysbiosis.[6]

Butyrate is believed to exert anti-inflammatory effects by decreasing the production of cytokines thought to up-regulate inflammation, such as IL-6 and IL-8.[50] Additionally, colonic cells use these short-chain fatty acids (such as butyrate) as their main source of oxidative fuels. Although butyrate administration does result in improvement, the studies done on butyrate in ulcerative colitis are conflicting as to the statistical significance of improvement.[10]

A recent randomized controlled trial comparing Plantago ovata seeds (a form of dietary fiber whose fermentation in the colon results in the production of butryrate) to oral mesalamine demonstrated equal effectiveness in the maintenance of remission in patients with ulcerative colitis.[49] Two open-labeled trials (one at 4 weeks and the other at 6 months) have demonstrated clinical improvement in patients with ulcerative colitis via the administration of germinated barley foodstuff. Germinated barley foodstuff is believed to exert its influence by increasing butyrate production, and possibly encouraging the growth of beneficial bacteria, including Bifidobacterium and Eubacterium limosum (believed to produce butyrate).[50,51]

Glutamine

Glutamine is sometimes advocated as being beneficial in the management of inflammation. Although not an essential amino acid, glutamine is believed to play a role in the maintenance of the colonic mucosal barrier, and is an energy substrate for colonic cells. It is believed that altered mucosal permeability can foster translocation of colonic flora and/or toxins, contributing and/or initiating an inflammatory response.

However, not all of the studies regarding glutamine show positive benefit in IBD. When administered in a trinitrobenzenesulfonic acid-induced colitis model, there was actually a worsening of intestinal inflammation. Other studies in different models, however, have shown an improvement. As suggested by Akobeng and colleagues,[28] there may be an optimal level of glutamine necessary for improvement; alteration from that level may have deleterious effects.

There are possible reasons why excess glutamine may not serve a beneficial purpose. It is understood that glutamine up-regulates the immune system. Glutamine is also a precursor to nitric oxide. Nitric oxide plays a key role in inflammation and injury and hence may not be beneficial to patients with IBD.[28,29]

Iron/Vitamin E/Catechins

In several models of colitis, including an IL-10 deficient model and an iodoacetamide-induced model, iron supplementation has been shown to adversely affect inflammation. It is believed that this is due to the fact that free radicals are produced through the iron-catalyzed Fenton reaction. This poses a problem in part because the majority of ingested iron is not absorbed, and consequently the intestines receive a large amount of iron substrate.[30,31]

A significant proportion of patients develop iron-deficiency anemia secondary to blood loss, and hence, if the free radicals are clinically significant, iron supplementation may worsen inflammation. A study done by Carrier and colleagues[32] demonstrated that the supplementation of vitamin E to iron regimens reduced the adverse effect that iron had on colitis disease activity in a dextran sulfate sodium-induced colitis model.[32]

In addition to vitamin E (alpha tocopherol), catechins have been shown to have an anti-inflammatory effect in a trinitrobenzene sulfonic acid-induced model of ulcerative colitis.[33] Alpha tocopherol is an antioxidant, which may explain its effectiveness in colitis and also as a protective role when administered with iron, which is known to generate free radicals.[6]

Catechins are flavonoids. Flavonoids are noted to have a variety of functions, including anti-inflammatory, anti-allergic, antiviral, and anticarcinogenic actions. They are also believed to be antioxidants. Flavonoids are found in diverse food sources such as citrus fruits, berries, onions, parsley, legumes, green tea, and red wine.[6] Effects of catechins that may be beneficial in IBD include antioxidant and anti-endotoxin effects. Because of noted side effects such as autoimmune hemolysis, febrile reactions, and urticaria, care must be exercised when using this product and larger studies are warranted before this is accepted as a valid alternative therapy for IBD.[6]

1, 25-Dihydrocholecalciferol

1, 25-dihydrocholecalciferol, the active form of vitamin D, has been shown in an IL-10 knock-out model of ulcerative colitis to reduce symptoms. This compound has been shown to be immunosuppressant, and has been shown to positively affect the disease process in a variety of diseases believed to be mediated by autoimmune processes. While a definite mechanism has not been fully elucidated, it is believed that 1, 25-dihydrocholecalciferol stimulates the production of transforming growth factor beta-1 and IL-4. These cytokines may suppress T-cell-mediated inflammatory activity.[34,35]

Potato Alkaloids

Epidemiologic studies have indicated that the prevalence of IBD is directly correlated to consumption of fried potato products.

Altered intestinal permeability is believed by some to play a key role in the initiation and propagation of the inflammatory process. It is thought that bacterial products or even bacteria themselves may penetrate this altered epithelial barrier, activating the intestinal immune system. Potatoes have a high concentration of glycoalkaloids, specifically alpha-solanine and alpha-chaconine. These molecules “permeabilize cholesterol-containing membranes” and this is believed to alter the intestinal epithelial barrier. These glycoalkaloids are concentrated when potatoes are fried.

These molecules are present in potato as a sort of defense mechanism for the potato plant, playing a key role in defending the plant against fungi, bacteria, and parasites. However, these molecules have been shown to adversely affect the permeability of epithelial cells in the intestine, and this may aggravate IBD. These compounds have been shown to adversely affect the intestine permeability in an IL-10-deficient mice model of colitis, but not in normal mice, suggesting that those patients with IBD may be predisposed to this adverse effect.[36]

Colostrums and Milk-Derived Peptide Growth Factors

Epidermal growth factor (EGF) has been shown to have positive effects in a trinitrobenzenesulfonic acid/ethanol model of colitis.[37] Colostrum, which contains certain cytokines such as platelet-derived growth factor, EGF, insulin-like growth factor, and transforming growth factor beta may therefore be beneficial in IBD.[38]

IGF-1 has been shown to promote gastrointestinal healing.[39] However, it is also a mitogen because it promotes cell growth, and because of the lack of large randomized controlled trials, caution should be exercised.[39] Of note, however, in an oral dextran sulphate sodium-induced model of colitis, short-term administration of IGF-1 was shown to have beneficial healing effects.[40] Another study showed that EGF enemas combined with oral mesalamine had a positive effect on ulcerative colitis disease activity.[41]

Wheatgrass Juice

Wheatgrass juice has been investigated as a possible therapy for ulcerative colitis. The components of wheatgrass juice include chlorophyll; vitamins A, C, and E; and various amino acids. It has been demonstrated that wheatgrass juice is anti-mutagenic. One constituent of wheatgrass is apigenin, which is believed to possess both anti-inflammatory and antioxidant properties. Some believe that this constituent may be beneficial in ulcerative colitis.[42,44] It is a bioflavonoid that has been shown to inhibit TNF-induced transactivation.[43]

A randomized controlled trial of wheatgrass juice in the management of ulcerative colitis has demonstrated some efficacy. While sigmoidoscopic evaluation failed to demonstrate a statistically significant difference between the treatment and control group, it was demonstrated that there was a significant difference in other symptomatic indicators of disease activity, such as rectal bleeding. Although there was not a statistically significant difference in relation to sigmoidoscopic evaluation, 78% of the treatment group improved compared to 30% of the control group.[44]

Lycopene

Two studies have indicated that lycopene, an antioxidant, found in high quantities in foods that have a natural red color (eg, tomato, watermelon, pink grapefruit, etc) may play a role in attenuating the inflammatory process. Lycopene, a member of the carotenoid family, is a free radical scavenger and is only found in plant products.[45] Studies done using indoacetamide rat model of colitis showed that lycopene and 5-aminosalicylate (either in combination or as monotherapy) attenuated the inflammatory response in rat models given iron supplementation. The studies used levels of myeloperoxidase to evaluate inflammation.[46] In a 2,4,6-trinitrobenzenesulfonic acid-induced rat models of colitis, lycopene supplementation was shown to decrease tissue levels of myeloperoxidase and a decreased histological immune response.[47] Translational research is necessary before lycopene becomes more mainstream adjunctive therapy.

Aloe Vera

Aloe vera is used by some patients with IBD. Few studies have been performed evaluating the effectiveness of aloe vera in the management of IBD. A randomized, double-blind, placebo-controlled trial of aloe vera in patients with mild to moderate ulcerative colitis demonstrated improved clinical symptoms (P = .01) and histologic scores (P = .03) in patients taking aloe vera vs placebo. The exact mechanism of action of aloe vera is unclear, but may include antioxidant and immunosuppressive effects. In vitro studies on human colon mucosa have demonstrated that aloe vera gel inhibits prostaglandin E₂ and IL-8.[52,53]

Bromelain

A case report of 2 patients may indicate the potential use of bromelain as an adjunctive agent in the treatment of ulcerative colitis. The 2 patients were unable to achieve remission on standard therapy. Clinical and endoscopic evidence of improvement was documented. Bromelain is derived from the stems of pineapple, and is believed to be a proteolytic enzyme.[54] A more recent study, documenting the use of bromelain in an IL-10-deficient murine model of IBD, demonstrated that bromelain supplementation resulted in decreased clinical and histological severity of colonic inflammation. The proteolytic property of bromelain is necessary for its anti-inflammatory properties, and some hypothesize that cell surface molecules and consequently T-cell activation may be altered by bromelain.[55]

Boswellia Serrat/Indian Frankincense

The use of Boswellia serrata in inflammatory bowel disease has been studied in several studies.

A randomized, double-blind controlled study comparing Boswellia serrata extract H15 with mesalamine in patients with Crohn's disease demonstrated no statistical difference in the Crohn's Disease Activity Index, indicating that Boswellia serrata may play a helpful role in Crohn's disease.[56] Other studies have shown possible effectiveness of Boswellia serrata gum resin in patients with ulcerative colitis. Proposed mechanisms of effect of Boswellia serrata include inhibition of 5-lipoxygenase.[57,58]

Conclusion

Physicians may benefit from several sources when questioned by patients and/or colleagues about various complementary/alternative approaches to IBD. These include The Cochrane Collaboration (evidence based reviews on a multitude of topics; www.cochrane.org), Natural Medicines Comprehensive Database (evidence-based reviews of natural supplements and medicines; www.naturaldatabase.com), and The Crohn's and Colitis Foundation of America (www.ccfa.org).

It is also important to advise patients to look carefully at various manufacturers when choosing a particular supplement/intervention (ie, probiotics). There is a lack of oversight into the manufacturing and quality assurance of these supplements. Particular factors that may lead one to pick one manufacturer over another is their funding of published research relating to their product, length of time in business, affiliation with consumer agencies, and previous experience/outcomes.

As more research is being done regarding complementary/alternative approaches to a multitude of diseases, we can expect a multitude of articles and recommendations in the mainstream medical literature. As randomized trials are few and the evidence is not equivocal, we should be careful with broad recommendations and endorsements of these approaches. As we can see, there are a multitude of dietary variables that show promise as natural ways to affect the inflammatory bowel disease process. Although more evidence is needed before these become widely accepted as standard therapy, they represent an exciting and largely unexplored field in potential therapies for IBD.