Nutrition in Inflammatory Bowel Disease: Implications For Its Role in the Management of Crohn Disease and Ulcerative Colitis1
Gerald W. Dryden
Douglas L. Seidner
1Abbreviations: AA, arachidonic acid; ALA, α-linoleic acid; CD, Crohn disease; CI, confidence interval; DC, dendritic cell; DHA, docosahexaenoic acid; ECN, Escherichia coli Nissle 1917; EPA, eicosapentaenoic acid; FA, fatty acid; FD, free diet; GBF, germinated barley foodstuff; half-ED, half-elemental diet; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; LA, linoleic acid; LTB4, leukotriene B4; OR, odds ratio; PEM, protein-energy malnutrition; PGE2, prostaglandin E2; PO, Plantago ovata; RDBPC, randomized, double-blind, placebo-controlled; SCFA, short-chain fatty acid; TEN, total enteral nutrition; TPN, total parenteral nutrition; UC, ulcerative colitis; WD, Western diet.
Maintenance of human health requires the continuous ingestion of nutrients coupled with their appropriate digestion and assimilation, both of which require an appropriately functioning digestive tract. Many human diseases interfere with normal digestion. However, disruptions are particularly prominent in inflammatory conditions of the intestinal tract such as Crohn disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD). Nutrition plays three roles in IBD: instigator, victim, and healer. This chapter explores ways in which nutritional support benefits patients with IBD; but to understand the crucial role nutrition plays in IBD, the interplay of nutrition with host and environmental factors associated with the development of IBD are examined first.
ROLE OF NUTRITION IN THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE
CD and UC share a common physiologic basis: loss of tolerance to intestinal bacteria. Germ-free animals susceptible to IBD remain inflammation free until exposed to bacteria. However, humans must coexist with their gut flora for many reasons: food digestion, vitamin K production, and pathogen protection, to name a few. Loss of tolerance to one’s own flora arises from a triad of factors. First, a genetic mutation encodes susceptibility. More than 70 loci have been identified for CD (1). Second, a trigger is required to initiate inflammation. A breakdown in tolerance against the ever-present intestinal flora ensues. One well-characterized gene involved in CD susceptibility, nucleotide-binding oligomerization domain containing (NOD)-2, encodes for a bacterial defense peptide prominently expressed in ileal mucosa, the site most highly affected in CD (2, 3). However, genetic mutations alone cannot explain the rapid rise in world IBD cases over the past five or six decades (4, 5). Various hypothetical mechanisms listed in Table 78.1 provide potential explanations for the phenomenon of the rapid worldwide expansion of IBD cases (6, 7).
Diet as a Susceptibility Factor
Dietary habits typified as the Western diet (WD) offer one plausible mechanism for transforming IBD into an equal opportunity disease. These food choices, combined with preexisting genetic susceptibilities, could induce rapid proliferation of IBD. For instance, Japan has seen a significant rise in cases of IBD over the past three decades (4). This rise followed large-scale, rapid dietary changes undertaken by the Japanese population. Total calories consumed in the form of fat and animal proteins rose dramatically, displacing rice consumption. Changes in dietary intake have been linked to rising incidence rates for both CD and UC (8, 9).
Univariate analysis in one study implicated rising CD rates with total fat intake, animal fat and protein intake, and a change in the ratio of ω-6 to ω-3 fatty acid (FA) intake, whereas multivariate analysis pointed to increased animal protein intake as the strongest influence associated with new IBD cases (9). Several other studies identified
individual food choices as risk factors; in particular, refined sugars, fatty foods, and fast food all enhance development of both UC and CD (8, 10), whereas vegetables protect against UC but increase CD risk (8).
individual food choices as risk factors; in particular, refined sugars, fatty foods, and fast food all enhance development of both UC and CD (8, 10), whereas vegetables protect against UC but increase CD risk (8).
TABLE 78.1 THEORIES FOR THE RAPID SPREAD OF INFLAMMATORY BOWEL DISEASE | |||
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As an alternative explanation to an individual’s food choices, the cold-chain hypothesis uniquely links systemwide changes in food consumption to the expansion of IBD cases to the rise of commercial refrigeration (11). Post-World War II economic prosperity made the refrigerator widely available. Refrigeration quickly transformed food consumption from a pattern of daily use of perishables to a dependence on long-term refrigerated storage. Support for this theory rests on identification of organisms that thrive at (near)-freezing temperatures. Some psychotropes (Yersinia and Legionella) are associated with IBD-like infections of the gut (12). These data demonstrate that food choices likely play a role in IBD susceptibility, but elimination of individual food items will not likely alter disease course. However, nutrition still can play a significant therapeutic role in IBD.
Roles of Nutrition
IBD therapy optimally induces rapid disease remission, maintains that remission, and improves quality of life (13). Nutritional therapy can fulfill these goals as a primary IBD intervention. Primary nutrition therapy for IBD traditionally has referred to either total parenteral nutrition (TPN) or total enteral nutrition (TEN). However, the concept of nutritional therapy has broadened to include other tools for an IBD treatment plan, including interventions to alter intestinal epithelial function, enhance enteric flora, or reduce intestinal epithelial inflammation. These options provide clinicians multiple choices for providing therapeutically sound nutritional prescriptions to patients with IBD.
Nutritional Status of Patients with Inflammatory Bowel Disease
Protein-energy malnutrition (PEM)—an imbalance between the body’s demand for nutrients, the energy requirements for normal growth and homeostasis, and the available supply of nutrients (14)—is the most common form of malnutrition in patients with IBD, particularly CD (15). Up to 75% of hospitalized CD patients exhibit PEM evidenced by excessive weight loss and hypoalbuminemia (16), whereas up to 50% of outpatient CD patients weigh less than normal, even in remission (17).
TABLE 78.2 MICRONUTRIENTS COMMONLY AFFECTED BY INFLAMMATORY BOWEL DISEASE | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Multiple IBD-related factors contribute to PEM, including mucosal disease-related nutrient malabsorption/ loss, systemic cytokine-driven increases in metabolic requirements, and restricted oral intake for controlling diarrhea and abdominal pain related to small bowel strictures. Patients with IBD also exhibit many vitamin and mineral deficiencies (Table 78.2) (16). Although iron deficiency is more commonly found in UC (up to 81%) than in CD, this form of anemia is common in both disease states, affecting at least two thirds of patients. Anemia from folate or vitamin B12 deficiencies is more likely in CD (16). Medications used to treat IBD also play a significant role in exacerbating nutrient deficiencies through a variety of mechanisms (Table 78.3). In addition to macronutrient therapy, targeted micronutrient supplementation is often necessary to replete specific deficiencies acquired in the course of IBD (see Table 78.2) (18, 19).
TABLE 78.3 MEDICATION-ASSOCIATED NUTRIENT EFFECTS IN INFLAMMATORY BOWEL DISEASE | |||||||||||||||
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NUTRITION-BASED THERAPY FOR INFLAMMATORY BOWEL DISEASE
Total Parenteral Nutrition
Complete dietary replacement with TPN has the longest history of nutrition therapy for IBD, and likely works by eliminating antigenic stimuli from intact food molecules, altering intestinal bacteria, and removing large, nondigestible food components, which generate obstructive symptoms at intestinal strictures. Introduced as primary or adjunctive therapy for severe cases of IBD in the 1960s (20, 21), early studies were plagued by inconsistent disease activity measurements, clinical end points, and limitations on concomitant steroids (22, 23). Regardless, TPN appeared to induce CD remission effectively (65% to 100%) but rarely maintained it (0% to 33%) (24, 25). In addition, long-term TPN can be complicated by line sepsis, access problems, cholestasis, and high cost. TPN results for UC are less impressive, with lower remission rates (27% to 58%) and abysmal maintenance rates (0% to 15%) (24, 26, 27).
The days heralding TPN as a long-term primary treatment for IBD have passed (23), because poor efficacy, high cost, and frequent side effects prompt evidencebased guidelines currently to not recommend TPN as a primary treatment for IBD (28). There may be a role for supplemental parenteral nutrition or TPN as a short-term adjunctive approach to replete micronutrients and provide macronutrients for anabolism when the patient is hospitalized for an acute IBD flare and otherwise consuming minimal or no enteral nutrients orally or cannot tolerate liquid nutrient formulations, but such a practice is not currently evidence based. These circumstances pertain to the management of patients with short gut, prolonged ileus or obstruction, or postoperative fistulas from anastomotic leaks. In these cases, TPN may help to prevent severe malnutrition, particularly in already malnourished patients who may require elective surgery, including further bowel resection resulting from refractory IBD.
Total Enteral Nutrition
In contrast to the foregoing, over time evidence has mounted for the benefits of TEN for the treatment of active IBD. TEN replaces a patient’s caloric and nutrient intake with a processed liquid nutritional supplement administered by mouth or feeding tube. TEN theoretically prevents small bowel mucosal villous atrophy from long-term bowel rest, maintains epithelial integrity, and reduces intestinal immune system activation.
The first randomized, controlled clinical trial demonstrated that TEN could achieve remission as frequently as corticosteroids (29), but several small, follow-on studies produced conflicting results. A well-executed metaanalysis clarified the situation. For induction of clinical remission, the odds ratio (OR) for steroid therapy versus TEN was 0.35 (95% confidence interval [CI], 0.23 to 0.53), indicating short-term superiority of steroid therapy, but not at 1 year (OR, 0.97; 95% CI, 0.31 to 3.00) (30). Unfortunately, poor patient compliance with long-term TEN complicates this form of therapy, at least in adult populations.
Compliance rates vary greatly among adult patients with CD from country to country. Although patients in the United States rarely accept long-term TEN, this approach is an important first-line therapy for both inducing and maintaining CD remission in Japan (31, 32). Similarly, European guidelines promote TEN for adults with active CD complicated by effects of steroids, as supplemental TEN for undernourished children with CD, or as first-line therapy for children with active CD to induce remission (33).
The percentage of calorie intake from TEN influences success. Consumption of greater than or equal to 900 kcal/ day of TEN resulted in lower hospitalization rates compared with subjects receiving fewer calories (32). This effect was most noticeable in patients with ileitis. A “half-elemental” diet (half-ED) has also been evaluated for maintaining CD remission (34). Patients in remission by TEN, prednisolone, induction infliximab, or surgery were randomized to half-ED (900 to 1200 kcal) or free diet (FD) and evaluated for relapse over a 2-year follow-up period. Patients in the half-ED group recurred less frequently (35%) than patients in the FD group (64%; CI = 0.16 to 0.98) (34).
When examined in aggregate as a primary therapy, TEN induces remission almost as effectively as corticosteroid therapy, without steroid-related side effects. TEN can be administered via tube or mouth, in elemental or semielemental form, and can be continued on a long-term basis to maintain CD remission induced by all standard methods. In pediatrics, EN improves growth velocity hampered by corticosteroid therapy (35). However, cultural preferences, palatability, feeding tube aversion, and cost hinder widespread use of TEN in the United States.
NUTRITION SUPPLEMENTS FOR INFLAMMATORY BOWEL DISEASE
Probiotics
Basis for Efficacy
Acceptance of unregulated supplements, such as prebiotics and probiotics or other bioactive substances, is high among US patients with IBD. One of the most popular nutritional supplements with patients with IBD today, the use of “beneficial” bacteria for health was first advocated by Elie Metchnikoff in the early twentieth century (36). Given the central role bacteria play in IBD, strategies to enhance anti-inflammatory bacterial populations provide an attractive alternative to pharmacologic therapy. To this point, germ-free human leukocyte antigen (HLA)-B27 transgenic rats exhibit no demonstrable colitis (37). However, animals exposed to single strains or combinations of bacteria develop cecal inflammation.
To evaluate the role of a common probiotic organism in intestinal inflammation, germ-free HLA-B27 rats were monoassociated with Bacteroides vulgates, Escherichia coli, or a mixture of bacteria from a CD patient (37). Rats monoassociated with either the bacterial mixture or B. vulgates developed cecal inflammation, whereas rats monoassociated with E. coli exhibited no significant inflammation. Later, specific pathogen free HLA-B27 transgenic rats were monoassociated with Bacteroides vulgates and one of two strains of Lactobacillus. Neither Lactobacilli species prevented colitis, but when animals received antibiotics after monoassociation, the probiotic Lactobacillus GG (LGG) prevented recurrent colitis (38).
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