Nutrition as primary therapy in ibd

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With the advent of total parenteral nutrition (TPN) came a surge of enthusiasm for placing patients with IBD on bowel rest and intravenous nutrition as primary treatment. This was particularly popular in the 1970s. Then in 1983 Muller recognized that while many patients could be put into remission of their Crohn's disease with exclusive use of TPN (aka bowel rest), the relapse rates were very high when oral intake was resumed [49]. TPN is certainly not without serious side effects and is very expensive. One of the classical studies was published in the late 1980s in a randomized, multi-center trial by Greenberg and colleagues [50]. They demonstrated that patients with refractory Crohn's disease (resistant even to steroid treatment) were not benefited by bowel rest and that there was no difference between the treatment with bowel rest, exclusive use of defined formula (tube feeding) and oral diet plus parenteral support. There was no benefit of either exclusive parenteral or enteral nutrition in patients with ulcer-ative colitis.

Enteral nutrition in Crohn's disease received the attention of clinicians initially as a result of the availability of elemental formulas (those containing amino acids rather than intact protein). Voink and colleagues observed, somewhat fortuitously, that patients being prepared for surgical resection of refractory Crohn's disease had remission of their disease when an exclusive elemental diet was given [51]. They raised the question of whether elemental formulas might be a potential primary therapy for Crohn's disease. O'Morain and colleagues [52] were proponents of the concept that the exclusive use of these pre-digested liquid diets avoided the antigenic effect of intact proteins on the inflamed intestine with Crohn's disease involvement. The use of an elemental diet has continued in pediatric patients in Great

Britain [53], although it has not been popular in North America [54]. Verma and coworkers utilized an elemental formula taken orally as a supplement to solid food intake in an attempt to maintain remission of Crohn's disease in a group of patients who had had an exacerbation within the past year and who were in documented remission [55]. Of the 17 of 21 subjects who tolerated the formula, 10 remained in remission for 12 months, compared to 4 of 18 in a control group who did not use the elemental supplement (statistically significant on an intention-to-treat basis). A later study by the same authors, however, has not supported a benefit of elemental diets, in that polymeric formulas (those containing intact protein) were equally effective in inducing clinical remission of Crohn's disease in patients who were steroid dependent [56]. Twenty-seven percent failed to tolerate the formulas (equally divided between elemental and polymeric). Of those who were successfully withdrawn from steroids (14/27), all remained in remission at 1 year and six at 2 years. Elemental formulas have been particularly challenging because of high cost and very poor compliance with treatment, as demonstrated by high drop-out rates in a variety of studies. This is at least in part due to the poor flavor of the elemental products.

Three meta-analyses found that tube enteral nutrition was not as effective as corticosteroids in inducing remission of Crohn's disease in adults [57, 58, 59]. Additionally, two Cochrane database systematic reviews [60, 61] presented a similar conclusion from available studies. However, the randomized controlled trials included in the meta-analyses were not strictly comparable, as they included very different enteral formulations and in some cases, heterogeneous disease involving small bowel only, colon only and ileo-colonic Crohn's disease. The issue of elemental vs. polymeric formulas is addressed in the meta-analyses [57, 58] and finds an odds ratio of 0.87 in favor of polymeric regimens. This speaks against the importance of avoidance of antigen exposure as being a factor in the efficacy of elemental feedings. Furthermore, the remission rates of 60% for enteral nutrition were much better than with placebo in these studies and equivalent to some treatment modalities used in lieu of prednisolone, while avoiding the complications of corticosteroids [20, 62]. Nevertheless, these meta-analyses undoubtedly damped the attitudes about a potential role for enteral nutrition in Crohn's disease, particularly in North America.

The pediatric literature does include a meta-analysis that indicates that exclusive enteral feedings are as effective as steroids in children with Crohn's disease [63]. In a small, multi-center trial comparing remission rates and weight gain in pediatric patients with active Crohn's disease, Ludvigsson et al. reported equivalent clinical response rates with elemental and polymeric feedings, but greater weight gain with the polymeric formula [64]. They attributed this to the greater intake of formula with the polymeric formula, hypothesizing that since part of their patients drank the formula, the flavor of the feeding was more acceptable to that group. However, even after adjustments for caloric intake, the difference in weight gain persisted. Knight and colleagues recently published a retrospective study of 44 pediatric patients who were newly diagnosed with Crohn's disease and elected to use enteral nutrition in lieu of steroids and other medications [65]. In these patients median time to remission was 6 weeks, 25 of 40 relapsed with a mean duration of remission of 54.4 weeks and time to first steroid use of 68 weeks for the 23 who eventually required steroids. The avoidance of steroids in children is particularly important with respect to growth and bone health. It has been pointed out by Afzal et al. that colonic Crohn's disease in children is less likely to respond to enteral nutrition when the ileum is not involved [66]. It is of note, however, that the remission rate in those with colonic disease alone was 50%, comparable to stated adult remission rates with enteral diets, but less than their remission rates of 82% for ileo-colonic disease and 92% in the ileal Crohn's group. Several European centers have found improvement of quality of life reported by children who used enteral feedings exclusively for treatment of active Crohn's disease although mucosal healing did not correlate with quality of life [67]. This raised the concern that sole use of the patient's sense of well-being may mislead clinicians into thinking that a patient has had remission of disease.

The reason for complete exclusion of enteral diets from recent reviews outlining treatments in IBD was the topic of speculation among several gastroenterologist/nutritionists in a discussion at a recent workshop [68]. Proposals to answer this query include the relative knowledge of nutrition between adult and pediatric practitioners, with the latter being much better informed than the former and the previous lack of a scientific explanation for demonstrated effectiveness of nutrition therapy. Discussants also felt that as pediatric patients with IBD age, they might educate adult clinicians that enteral diets can actually effectively control their disease.

Recent attention, primarily in Europe, has again turned to the use of enteral diets and supplements in Crohn's disease with special attention now to the effect of such diets on their immune benefits. A major variable with respect to enteral formulas is the lipid composition, and this was not taken into account in the meta-analyses. Indeed, there is a growing body of literature that suggests that lipids alter inflammation and that this may be of importance in the pathogenesis and treatment of IBD. Metabolites of arachidonic acid have been shown to trigger inflammation [69]. Furthermore, prostaglandins (derived from fish oil-enriched diets) were protective to the mucosa, while saturated and polyunsaturated fatty acid-enriched diets were injurious in an experimental rat model of colitis [70]. A subsequent study of hamsters given a shark fin-enriched diet found that the marine lipids partially protected against histological changes of colitis and prevented the associated permeability changes in an acetic acid model of ulcerative colitis [71]. These results in experimental animals suggest that lipids might have a causative and a curative role, depending on the specific types of triglycerides consumed.

Gonzalez-Huix and coworkers had shown in a randomized, doubleblind study that a polymeric enteral formula containing 41% of lipids as monounsaturated fatty acids (28% saturated, 18% polyunsat-urated, 13% medium-chain triglycerides) was as effective as steroids in induced remission of active Crohn's disease [72]. As a result of these studies, the same investigators [73] comparing two polymeric enteral formulas of identical macronutrient caloric distribution, but with different lipid components (79% oleate and 6.5% linoleate vs. 28% oleate and 45% linoleate) multicenter double-blind, randomized European trial in Crohn's disease. Compared to a prednisolone-treated group with a 79% remission rate, the group with the high linoleate formula had 63% remission, and the group with high oleate intake had only 27% remission. Other confounding factors could not be identified, indicating that the type of lipid was of major importance. The authors concluded that the monounsaturated fatty acid formula was less beneficial than the formula with predominant w-6 (n-6) polyun-saturated fatty acid, although this was an unanticipated outcome. It was believed that w-6 fatty acids are precursors of the synthesis of eicosanoids that have pro-inflammatory activity (prostaglandin E2, thromboxane A2 and leukotriene B4), and these may possibly be detrimental in IBD [74].

Reimund et al. subsequently studied in vitro production of cytokines and cell viability of peripheral blood mononuclear cells from healthy volunteers incubated with three different lipid emulsions containing different ratios of long chain and medium chain triglycerides [75]. The lipid formula containing the highest ratio of w-6 to w-3 fatty acids as well as the highest amount of the monounsaturated fatty acid—oleic acid—had the least inhibition of TNFa and IL-1p (i.e., had less anti-inflammatory effect) than the lipids with much lower amounts of oleic acid and lower w-6 to w-3 fatty acids ratios. The authors cautioned that inferences to the in vivo situation should be made cautiously, but these findings in the context of currently available clinical studies add important information to support the concept that anti-inflammatory enteral feeding formulae may have a role in immunomodulation in the treatment of IBD.

Bamba and colleagues prospectively treated patients with active Crohn's disease using equicaloric, equinitrogenous elemental formulas supplemented with long chain triglyceride to provide 3.06, 16.56 and 30.06 g of fat daily (52% linoleic acid; 24% oleic acid) [76]. Their results showed an inverse relationship between the dietary long chain triglyceride content and 4-week rate of remission judged by C-reactive protein, erythrocyte sedimentation rates and International Organization of Inflammatory Bowel Disease symptom scores. The remission rates ranged from 80% for the low fat diet to 25% for the high fat diet. Subsequently, Yamamoto and coworkers reported the effects of a very low fat elemental formula (< 2% of calories as fat) on mucosal cytokine production and disease activity in active Crohn's disease [77]. They found that 71% of their patients had symptomatic remission, with endoscopic and histologic improvement in ~ 77% and resolution in ~ 40%. Pro-inflammatory cytokine levels in biopsy tissue were significantly decreased, and anti-inflammatory cytokines were increased.

The w-3 fatty acids—a-linolenic acid, eicosapentanoic acid and docosahexanoic acid—are important for their immunomodulatory and anti-inflammatory effects [78]. Thus, there have been suggestions that fish oil, which is rich in w-3 fatty acids, could have a therapeutic benefit in Crohn's disease [79]. Indeed, increased consumption of w-6 fatty acids and animal protein and the decreased level of w-3 fatty acids have been implicated in the increased incidence of Crohn's disease in Japan [80]. Middleton reported that supplementation of the diet of patients who had active Crohn's disease with a liquid formula containing w-3 fatty acids and antioxidants improved serum antioxidant status, decreased the proinflammatory arachidonic acid, increased the anti-inflammatory eicos-apentanoic acid and docosahexanoic acid in plasmaphospholipid and adipose tissue [81]. Geerling and colleagues described similar effects of w-3 fatty acids and antioxidants in quiescent Crohn's disease [82]. Belluzzi et al. found that supplementation of diet with2.7g w-3 fatty acids was effective in maintaining remission of Crohn's disease compared to placebo [83]. However, the results of a randomized, controlled, multicenter trial reported by Lorenz-Meyer and colleagues failed to demonstrate such effectiveness when w-3 fatty acids (6 g of ethyl ester fish oil concentrate containing 55% eicosapentanoic acid and 30% docosa-hexanoic acid) were used in conjunction with a low carbohydrate diet in patients with Crohn's disease [84]. Of note, 23% of individuals in the supplement group and 36% of the placebo were judged to be non-compliant with the study protocol.

A double-blind, placebo-controlled, crossover study of fish oil (4.2 g daily: 2.7 g eicosapentanoic acid; 1.8 g docosahexanoic acid) given to patients with mild to moderate ulcerative colitis reported improvements histologically and by a disease activity index, but the pro-inflammatory cytokine, leukotriene B4, levels were not decreased contrary to expectations [85]. Eight of the patients could either stop or reduce antiinflammatory drugs. However, 6 of the original 17 patients in this study withdrew, and analyses were done on only the remaining 11. A recent randomized, placebo-controlled trial of a lipid supplement providing a lower daily dose of w-3 fatty acids (1.6 g gamma linolenic acid, 270 mg eicosapentanoic acid and 455 mg docosahexanoic acid) to patients with ulcerative colitis showed no benefit in maintaining remission of disease [86].

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