Title: Treating Inflammatory Bowel Disease With Diet: A Taste Test
Abstract: See "Crohn's disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial," by Levine A, Wine E, Assa A, et al, on page 440. See "Crohn's disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial," by Levine A, Wine E, Assa A, et al, on page 440. Treating inflammatory bowel disease (IBD) activity by changing a patient's diet has long been one of the most desirable therapeutic strategies for IBD. Diet is a major concern for patients with IBD and "what should I eat?" is one of their most frequently asked questions.1Lewis J.D. Abreu M.T. Diet as a trigger or therapy for inflammatory bowel diseases.Gastroenterology. 2017; 152: 398-414.e396Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Many patients also seek dietary guidance with the belief that diet is safer than medical therapies (eg, biologics). Unfortunately, the scarcity of high-quality evidence supporting a specific dietary intervention has resulted in patients following exclusion diets lacking any evidence of efficacy and safety.2Hwang C. Ross V. Mahadevan U. Popular exclusionary diets for inflammatory bowel disease: the search for a dietary culprit.Inflamm Bowel Dis. 2014; 20: 732-741Crossref PubMed Scopus (45) Google Scholar Diet seems to be a risk factor for new-onset IBD.1Lewis J.D. Abreu M.T. Diet as a trigger or therapy for inflammatory bowel diseases.Gastroenterology. 2017; 152: 398-414.e396Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Epidemiologic studies have suggested that a diet high in fruits and vegetables and low in animal fats and sugar may decrease the risk for IBD. It is hypothesized that the decrease of microbiota-accessible carbohydrates (eg, fiber) can impact the host and the gut microbiota, promoting dysbiosis and a proinflammatory state.3Daïen C.I. Pinget G.V. Tan J.K. Macia L. Detrimental impact of microbiota-accessible carbohydrate-deprived diet on gut and immune homeostasis: an overview.Front Immunol. 2017; 8Crossref PubMed Scopus (107) Google Scholar Emulsifiers have also been linked to the increasing incidence of IBD, and their intake has been shown to induce colitis in a mouse model.4Chassaing B. Koren O. Goodrich J.K. et al.Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.Nature. 2015; 519: 92-96Crossref PubMed Scopus (1311) Google Scholar Paradoxically, exclusive enteral nutrition (EEN), the nutritional intervention with the strongest evidence for the induction of clinical and endoscopic remission in pediatric patients with Crohn's disease,5Narula N. Dhillon A. Zhang D. et al.Enteral nutritional therapy for induction of remission in Crohn's disease.Cochrane Database Syst Rev. 2018; 4: Cd000542PubMed Google Scholar contains emulsifiers, has a low amount of fiber, and induces dysbiosis.6Lewis J.D. Chen E.Z. Baldassano R.N. et al.Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn's disease.Cell Host Microbe. 2017; 22: 247Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar This is an illustration of the inherent complexity in dietary research. Although dietary patterns are usually studied in large epidemiologic studies, the effects of a single nutrient are better understood in preclinical models. The translation of these different types of study into dietary guidance has been difficult, as exemplified by the contradicting results surrounding the omega-3 fatty acids. Preclinical data suggested an anti-inflammatory effect of omega-3 fatty acids7Whiting C.V. Bland P.W. Tarlton J.F. Dietary n-3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis.Inflamm Bowel Dis. 2005; 11: 340-349Crossref PubMed Scopus (86) Google Scholar and small clinical trials also suggested a clinical benefit8Belluzzi 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; 334: 1557-1560Crossref PubMed Scopus (701) Google Scholar; however, large epidemiologic studies failed to confirm a protective effect of omega-3 fatty acid intake in Crohn's disease9Ananthakrishnan A.N. Khalili H. Konijeti G.G. et al.Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.Gut. 2014; 63: 776-784Crossref PubMed Scopus (352) Google Scholar and large randomized controlled trials have showed no benefit of omega-3 fatty acid supplementation.10Feagan B.G. Sandborn W.J. Mittmann U. et al.Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials.JAMA. 2008; 299: 1690-1697Crossref PubMed Scopus (244) Google Scholar Dietary intervention trials also face several issues in their design, such as the lack of objective ways to assess dietary compliance and the difficulty of implementing a true control group.11Lewis J.D. Albenberg L. Lee D. et al.The importance and challenges of dietary intervention trials for inflammatory bowel disease.Inflamm Bowel Dis. 2017; 23: 181-191Crossref PubMed Scopus (31) Google Scholar The Crohn's disease exclusion diet (CDED) is an exclusion diet supplemented with partial enteral nutrition (PEN) developed in Israel and has been suggested to be beneficial in children and adults with IBD.12Sigall Boneh R. Sarbagili Shabat C. Yanai H. et al.Dietary therapy with the Crohn's disease exclusion diet is a successful strategy for induction of remission in children and adults failing biological therapy.J Crohns Colitis. 2017; 11: 1205-1212Crossref PubMed Scopus (133) Google Scholar In this issue of Gastroenterology, Levine et al13Levine A. Wine E. Assa A. et al.Crohn's disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial.Gastroenterology. 2019; 157: 440-450Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar reported the results of a randomized, controlled trial of 78 pediatric patients with mild to moderate Crohn's disease comparing CDED with exclusive EEN. The intervention consisted of an initial 6-week period with CDED and 50% PEN, followed by another 6-week period with CDED and 25% PEN. The control group received exclusive EEN in the first 6 weeks followed by 25% PEN and free diet in the second 6-week period. Although both interventions were deemed to be efficacious, the CDED-PEN intervention was better tolerated than EEN, and CDED-PEN was associated with higher rates of remission at week 12. A decrease in serum C-reactive protein and fecal calprotectin were paralleled by an improvement of the fecal microbial profile in the patients that responded to both therapies, notably with a decrease of Proteobacteria. Moreover, a decrease in intestinal permeability was observed in the patients who received the CDED diet. This timely study further illustrates the growing interest in treating IBD using dietary manipulation. Svolos et al14Svolos V. Hansen R. Nichols B. et al.Treatment of active Crohn's disease with an ordinary food-based diet that replicates exclusive enteral nutrition.Gastroenterology. 2019; 156: 1354-1367.e1356Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar recently tested the Crohn disease treatment-with-eating diet (CD-TREAT) in mice, healthy volunteers and 5 children with active Crohn's disease. This open-label trial of CD-TREAT led to a decrease in fecal calprotectin and to clinical remission in 3 of 5 children with active Crohn's disease after 8 weeks of diet.14Svolos V. Hansen R. Nichols B. et al.Treatment of active Crohn's disease with an ordinary food-based diet that replicates exclusive enteral nutrition.Gastroenterology. 2019; 156: 1354-1367.e1356Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar In the Food and Crohn's Disease Exacerbation Study (FACES) trial, conducted in patients with Crohn's disease in remission, avoidance of red and processed meat alone did not lead to a significant decrease of disease relapses, possibly suggesting that a modification of a sole component in diet is insufficient to control disease activity.15Albenberg L. Brensinger C.M. Wu Q. et al.A diet low in red and processed meat does not reduce rate of Crohn's disease flares.Gastroenterology. 2019; 157: 128-136Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar The Food influence on the Intestinal microbioTa diet,16Sabino J. Vieira-Silva S. Machiels K. et al.Therapeutic manipulation of the gut microbiota through diet to reduce intestinal inflammation: results from the FIT trial.Gastroenterology. 2017; 152: S1Abstract Full Text PDF Google Scholar the Specific Carbohydrate Diet (SCD),17Cohen S.A. Gold B.D. Oliva S. et al.Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease.J Pediatr Gastroenterol Nutr. 2014; 59: 516-521Crossref PubMed Scopus (168) Google Scholar the Anti-Inflammatory Diet,18Olendzki B.C. Silverstein T.D. Persuitte G.M. et al.An anti-inflammatory diet as treatment for inflammatory bowel disease: a case series report.Nutr J. 2014; 13: 5Crossref PubMed Scopus (160) Google Scholar and the low-fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (low FODMAP) diet19Prince A.C. Myers C.E. Joyce T. et al.Fermentable carbohydrate restriction (low FODMAP diet) in clinical practice improves functional gastrointestinal symptoms in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2016; 22: 1129-1136Crossref PubMed Scopus (136) Google Scholar are other examples of diets that have been tested in IBD, using different study designs, variable end points, and/or a small number of patients. This growing body of evidence is beginning to make it easier for clinicians to make recommendations to their patients regarding diet. Although none of the studies published to date suggest that dietary therapy should completely replace traditional therapy with medications or surgery, in appropriately selected patients, diet could be attempted as a first-line therapy with close follow-up and change of therapy if complete response is not achieved. In other patients, dietary modification can be used to potentially augment the effectiveness of medications. The questions that remain are what is the best diet to recommend for those patients in whom a dietary therapy would be appropriate and how best to assess response to this therapy. If a dietary intervention is to be used, the CDED is a reasonable choice because it allows for the consumption of common table foods. Indeed, whether the PEN is required for the CDED to be effective is unknown and anecdotally, some patients have responded without consuming the PEN.20Sigall-Boneh R. Pfeffer-Gik T. Segal I. et al.Partial enteral nutrition with a Crohn's disease exclusion diet is effective for induction of remission in children and young adults with Crohn's disease.Inflamm Bowel Dis. 2014; 20: 1353-1360Crossref PubMed Scopus (203) Google Scholar Nonetheless, it is worth noting the limitations of the available data on the CDED. The most recent clinical trial was only powered to assess the tolerance of 2 different diets and not their relative efficacy. Furthermore, although higher rates of remission were seen at week 12, the calprotectin levels remained elevated in many patients. The lack of endoscopic evaluation is an important limitation of this trial, because this is now considered as a key primary end point in IBD. In conclusion, the renewed interest in dietary research in IBD is welcomed and further adequately conducted clinical research will eventually set the stage for the role of diet in treatment of IBD as monotherapy or in combination. This will be especially interesting in developing nations where increasing IBD incidence and prevalence will result in the absolute need for less costly but efficient therapeutic alternatives to biologicals. In this context, the results of ongoing trials, such as the DINE-CD trial comparing the SCD diet with the Mediterranean diet (NCT03058679), the DIETOMICS-CD trial comparing CDED diet with EEN and PEN (NCT02843100), and the PRODUCE trial comparing SCD with modified SCD (NCT03301311) are eagerly awaited. As illustrated in Figure 1, there is huge variability and sometimes contradiction across diets that are currently being tested regarding which component should be recommended or avoided, making any translation into clinical practice difficult. For now, simple dietetic recommendations such as consuming a well-balanced diet prepared largely from fresh ingredients and thereby avoidance of emulsifiers and other additives and processed foods are appropriate for all patients. In select patients, such as those with a short segment of inflammatory, nonpenetrating, nonstricturing Crohn's disease and mild to moderate symptoms, a trial of dietary therapy alone with a diet such as CDED could be attempted for a short period of time, with close follow-up, and with agreement with the patient that failure to fully respond is an indication to escalate therapy. The latter caveats are essential to avoid missing the window of opportunity when an effective medication can block IBD progression toward complications, surgery, and disability. Notably, this is not a recommendation against diet per se as a therapy, but rather the strategy we should be taking when starting any new therapy. Crohn's Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled TrialGastroenterologyVol. 157Issue 2PreviewExclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. Full-Text PDF