REVIEW URRENT C OPINION
Nutritional therapy in inflammatory bowel disease Chen Sarbagili-Shabat a, Rotem Sigall-Boneh a, and Arie Levine a,b
Purpose of review An increasing body of evidence has linked diet to inflammatory bowel diseases (IBD), both Crohn’s disease and ulcerative colitis. Most of our current knowledge pertains to the link between diet and Crohn’s disease. Exclusive enteral nutrition and partial enteral nutrition are the best known dietary intervention for the induction of remission and maintenance of remission in Crohn’s disease both in children and in adults, but the mechanism whereby these interventions may cause or maintain remission and mucosal healing has remained elusive. Recent findings Recent studies have shed light on the possible mechanisms of response to dietary intervention. Epidemiological and rodent model studies over the last year have supplied us with several dietary candidates for an effect of diet on inflammation and disease pathogenesis. Others have shed insight into the effect of diet on dysbiosis and the microbiota. An elimination diet based on some of these candidates has shown clinical efficacy, and bridged the knowledge obtained from rodent models to a human intervention. Summary These studies may allow better understanding of the pathogenesis of IBD and provide new tools to treat these difficult diseases. Elimination diets based on the identification of deleterious dietary components may pave the way for an improved control of the disease in the future. Video abstract http://links.lww.com/COG/A10. Keywords Crohn’s disease, diet, enteral nutrition, inflammatory bowel disease, microbiome
INTRODUCTION Dietary therapy is an established, but underutilized and poorly understood therapy that can induce and maintain remission in Crohn’s disease [1–3]. Dietary therapy offers the possibility of reducing the burden of immunosuppressive medications, promoting growth in children, and providing insight into the possible environmental factors that may impact the disease. Inflammatory bowel diseases (IBD) arise at the interface between the resident intestinal bacteria and the innate immune system. These diseases are characterized by a decrease in microbial diversity, dysbiosis and epithelial damage [4,5]. Under normal circumstances, the mucous layer, intestinal epithelial cells and the tight junctions serve as an efficient barrier to potentially harmful bacteria, whereas the innate immune system serves as a backup mechanism to exclude enteric bacteria from penetrating or interacting with the mucosal immune cells [3–12]. Multiple studies raise the
possibility that a variety of dietary factors may be associated with IBD. These include epidemiologic studies [13,14] demonstrating a protective or harmful effect for dietary components, and rodent models that demonstrate the ability of dietary factors to induce dysbiosis, increase colonization or adherence of pathobionts associated with Crohn’s disease, or to impair the barrier function [3,13–16]. The current review will summarize the studies published over the last year that provide new insight into the role of diet on the pathogenesis and treatment for all IBD patients. As a result of the large a
Pediatric Inflammatory Bowel Disease Research Center, Holon and Wolfson Medical Center, Tel Aviv University, Tel Aviv, Israel
b
Correspondence to Arie Levine, MD, Pediatric Gastroenterology and Nutrition Unit, Pediatric Inflammatory Bowel Disease Research Center, Wolfson Medical Center, 62 Halohamim Street, Holon 58100, Israel. E-mail: [email protected] Curr Opin Gastroenterol 2015, 31:303–308 DOI:10.1097/MOG.0000000000000178
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Inflammatory bowel disease
KEY POINTS Exclusive enteral nutrition can cause high rates of mucosal healing in children with Crohn’s disease. Exclusive enteral nutrition in responders does not increase the diversity of the microbiota or short-chain fatty acids as previously hypothesized. Dietary ingredients such as a high-fat diet and gluten appear to aggravate inflammation in the rodent models of Crohn’s disease. Partial enteral nutrition with a specific exclusion diet appears to be effective for the induction of remission in children and adults with nonsevere Crohn’s disease. Ulcerative colitis appears to be accompanied by defective production of short-chain fatty acids.
body of literature available on vitamin D, we have excluded this component from the review.
DIETARY COMPONENTS IN HEALTH AND DISEASE: ANIMAL MODELS Previously published studies have highlighted the possible deleterious effect of animal fat, milk fat, iron and emulsifiers in IBD rodent models [15,16,17 ,18, 19 ,20 ,21–23]. Martinez-Medina et al. [17 ] recently demonstrated that a high-fat, high-sugar diet led to dysbiosis and colonization with adherent invasive Escherichia coli (AIEC), depletion of the mucous layer and increased intestinal permeability in an IL10/ knockout mouse. The effect of a high-fat diet was also reproduced in the TNFDAre/wt mouse model of ileitis by comparing mice fed conventional chow or a high-fat diet [19 ]. Mice fed the high-fat diet developed increased intestinal permeability, generated Th17-driven dendritic cells and developed more severe ileitis. Gluten has also now been proposed to play a deleterious role in ileitis as well. Gluten can induce zonulin, which in turn increases small intestinal permeability [24]. In an elegant study by Wagner et al. [20 ] in the same mouse model, they compared the development of ileitis with standard chow, gluten-free chow or chow with added gluten. Exposure to chow containing gluten exacerbated ileitis, most likely by increasing the intestinal permeability. Two relatively new kids on the block in this growing list may connect diet and AIEC, a possible pathobiont in Crohn’s disease. These bacteria can translocate across ileal epithelium, survive in macrophages and generate TNF-alpha, leading to granulomas. Strains of AIEC have been isolated from the ileum and the colon of control and Crohn’s disease patients [8,25]. Maltodextrin was recently found to &&
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promote AIEC biofilms, and increase adhesion of AIEC strains to intestinal epithelial cells and macrophages via upregulation of type 1 pili expression [26]. Importantly, this mechanism does not require the usual ligand for attachment (CEACAM 6), suggesting that exposure to maltodextrin may allow AIEC to attach when it otherwise could not adhere to cells. Maltodextrin is a thickening and binding agent found in breakfast cereals as well as aspartame and sucralose, commonly used as artificial sweeteners. Iron and heme may be critical for the chain of events enabling AIEC penetration and survival in macrophages. Growth of AIEC required iron, and the enrichment of these strains with heme acquisition genes correlated with persistence in macrophages [27]. Red meat has also joined this list in rodent models, as it was recently found to promote inflammation in a dextran sulfate sodium (DSS) colitis model. Interestingly enough, the effect of red meat was ameliorated by resistant starch, one of the sources for butyrate production [28]. Two recent studies have shed light on the potential benefits and mechanisms of n-butyrate, a product of bacterial fermentation of fibers and starches, on the innate immune system [29,30]. n-Butyrate was found to reduce the secretion of interleukin (IL)-6, IL-12 and nitric oxide synthase via a direct effect on the inhibition of deacetylation of histones [29], and also found to induce differentiation of regulatory T cells [30]. However, it was ineffective in ameliorating colitis in a DSS model of colitis [29].
INSIGHT FROM EPIDEMIOLOGY AND DIETARY CHANGES IN HEALTHY INDIVIDUALS Epidemiologic studies have yielded conflicting data regarding the role of carbohydrate exposure as a risk factor [14]. A very large epidemiologic study, the European Prospective Investigation into Cancer and Nutrition (EPIC), prospectively followed 401 326 initially healthy men and women without Crohn’s disease or ulcerative colitis from centers in eight European countries. No association was found between carbohydrate intake and onset of ulcerative colitis during the follow-up [31]. Another epidemiologic study, based on yet another analysis of 170 776 women followed during the Nurses Health Study, evaluated the likelihood to develop IBD over 3 317 425 patient-years. They identified 269 incident cases of new-onset Crohn’s disease and 338 cases of new-onset ulcerative colitis. Those in the highest quintile for fiber intake were 40% less likely to develop Crohn’s disease; fiber from fruit appeared to have the greatest impact on risk reduction [32]. Volume 31 Number 4 July 2015
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Nutritional therapy in inflammatory bowel disease Sarbagili-Shabat et al.
Investigators from Harvard University and Duke University evaluated the change in microbiota upon exposure to an animal-based diet (meat, eggs and dairy) or a plant-based diet (fruits, vegetables, nuts and legumes) in healthy volunteers. The animalbased diet increased the concentration of fecal bile acids such as deoxycholic acid, increased the abundance bile-tolerant microorganisms such as Bilophila and Bacteroides, and decreased the levels of Firmicutes [33 ]. Bilophila wadsworthia is a bileacid-tolerant bacterium that has been linked to colonic inflammation, and was previously found to bloom and aggravate experimental colitis after exposure to milk fat [21] in an IL10/ knockout mouse model, whereas Firmicutes appear to be sensitive to the changes in fecal bile acids. Another study demonstrated that dietary iron may modify the gut microbiome and increase inflammation in 6-month-old Kenyan infants. Jaeggi et al. [34 ] performed two double-blind, randomized controlled trials, in which infants consumed low or high ironfortified maize porridge daily for 4 months. Iron fortification led to a significant increase in enterobacteria and a significant decrease in bifidobacteria. In addition to early-onset dysbiosis, iron fortification increased fecal calprotectin levels, an indicator of intestinal inflammation. &&
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that individuals with ulcerative colitis have decreased ability to ferment nonstarch polysaccharides and starch [36 ]. Exclusive enteral nutrition (EEN) is a well established method for inducing remission in children with recent-onset Crohn’s disease [37–39]. Partial enteral nutrition (PEN) with free diet seems to be ineffective for the induction of remission [40]. A small retrospective German study found that the majority of children successfully completing a course of EEN will relapse during the first year and that 66% will respond to a second course of EEN with remission [41]. The mechanism whereby EEN induces remission has been controversial and two recent studies have shed light on the possible mechanisms. Previously postulated mechanisms of response have included an improvement on the effect of EEN on the microbiome, including an improvement in the diversity of the microbiome, improvement in protective species or increased butyrate production [42 ]. Scottish investigators evaluated 15 children before and after successful remission with EEN along with 21 controls. Contrary to the expectations, use of EEN was associated with a further decrease in diversity, decrease in specific ‘protective species’ and a decrease in butyrate in fecal samples. A different line of thought was evaluated by the investigators from Israel [43 ]. They hypothesized that the major mechanism of effect is exclusion of dietary components hypothesized to cause dysbiosis or impair innate immune mechanisms such as the mucous layer, intestinal permeability or colonization and adherence with AIEC. They treated 47 patients with active Crohn’s disease with PEN and a diet they coined as the Crohn’s disease exclusion diet for 12 weeks. This is a structured diet with allowed and disallowed foods divided into two stages. Use of this diet led to clinical remission in 70% of patients by week 6. This was accompanied by a significant drop in C-reactive protein (CRP) and erythrocyte sedimentation rate through week 12, normalization of CRP in 70% of patients in remission and mucosal healing in a subset of responders. Importantly, 11 of 15 patients entering remission and practicing dietary restriction had mucosal healing. The results of this study done in humans suggest that specific dietary products play a role in inflammation. Use of PEN along with the Crohn’s disease exclusion diet which contains whole foods such as lean chicken breast, fish, eggs, vegetables and rice offers the possibility of a more palatable and feasible diet and more widespread use of dietary therapy for the induction of remission in the future. Although EEN has been widely accepted for the induction of remission, there has been a paucity of &
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DIETARY INTERVENTIONS IN ACTIVE INFLAMMATORY BOWEL DISEASE AND MECHANISMS OF RESPONSE Fiber has been touted as both harmful and beneficial in IBD, and restriction of fiber has been recommended in the past. A recent systemic review of clinical trials, involving 23 studies, found no effect for the supplementation of dietary fiber in 12 studies on Crohn’s disease, a possible weak effect in ulcerative colitis in 3 of 10 studies, and a possible effect in pouchitis. Importantly, there was no evidence that fiber intake should be restricted in patients with IBD [35]. Another study that may have some ramifications for future studies involving dietary fiber and short-chain fatty acids as a dietary strategy was performed by the investigators from Melbourne, Australia. They randomized 25 patients with ulcerative colitis in remission or 12 healthy controls to one of two diets; low resistant starch, low wheat bran exposure or high resistant starch with high wheat bran over 2 weeks, then each group crossed over to the second diet after a washout period. In contrast to conventional wisdom, increased exposure to starch and fiber in the ulcerative colitis group did not increase short-chain fatty acid production and did not lead to a change in the composition of the microbiome. The authors concluded
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data regarding complete mucosal healing using rigorous criteria and prospective data collection. The Australian investigators prospectively evaluated clinical remission and mucosal healing using the Simple Endoscopic Score (SES) in 26 children receiving EEN for 8 weeks [44 ]. They confirmed that EEN is accompanied by mucosal healing, as 84% of patients entered clinical remission and 42% had complete mucosal healing. Importantly, 58% had complete or near-complete mucosal healing. Multiple small studies have shown that PEN may be effective as a maintenance therapy to prevent clinical recurrence [45–47]. Yamamoto et al. [46] had previously shown that postoperative maintenance therapy with nightly tube feeding of an elemental formula with a low-fat diet can prevent endoscopic recurrence at 1 year. In a recent study, this same group extended their follow-up of the 40 patients in the original study to 5 years of follow-up [47]. Understandably, a decline in tube feeding was seen over time. At 5 years after resection, significantly more patients in the control group required biological therapy. A second resection was required in 5% of the PEN group and 25% of the control group (not significant). Postoperative recurrence is clearly an interesting avenue of research that has not been adequately evaluated to date. The Japanese investigators retrospectively evaluated the effect of PEN in addition to infliximab to reduce the loss of response to infliximab. Patients with normal CRP after the third induction of remission infusion were considered eligible. The authors divided their cohort of 102 patients into those who received at least 900 ml of an elemental formula in addition to infliximab (n ¼ 45) and those who received no PEN or less than 900 ml/day (n ¼ 57). Loss of response was defined as requirement for dose interval change or elevation of CRP greater than 1.5 mg/dl. At the end of follow-up, loss of response was significantly higher in the group treated solely with infliximab compared with the combination with an elemental formula [48]. These results contradict a previous prospective study that found no difference in the loss of response [49]. As this cohort was retrospective and the prospective study involved a fairly small study cohort, better studies are required before conclusions can be drawn. There are very few studies that have evaluated successful dietary interventions in ulcerative colitis. Kyaw et al. [50] suggested that a dietary intervention based on the reduction in exposure to fat, simple carbohydrates, red meat and processed food can be beneficial in ulcerative colitis. They treated 61 ulcerative colitis adult patients over 4–6 weeks during a disease flare. By week 24, there was a modest but significant improvement in the activity score, &&
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suggesting that this may improve disease activity but could not induce remission. Curcumin is a phenol compound that is the principal component of the spice turmeric [51]. Curcumin enemas were used for the induction of remission in mild-to-moderate distal colitis. Forty-five patients were randomized to either oral 5-aminosalicylic acid (5-ASA) with a curcumin enema or oral 5-ASA with a placebo enema. At week 8, clinical remission was observed in 43.4% of patients in the curcumin enema group compared with 22.7% in placebo group (not significant), and improvement on endoscopy in 52.2% of patients in active treatment group compared with 36.4% of patients in placebo group (not significant). As the authors did not show a significant difference and the study group was too small to reach significance, further studies are needed in order to evaluate the clinical significance of this type of therapy. The relative success of dietary therapy for active Crohn’s disease has led the investigators to evaluate the use of dietary therapies for other gut inflammatory conditions. Investigators from London evaluated the use of an elemental diet for chronic pouchitis [52]. Seven patients with pouchitis were treated with an exclusive elemental diet for 28 days. Use of EEN led to a significant decrease in stool frequency and the Pouch Disease Activity Index; however, there was no improvement in the endoscopic or histology scores.
CONCLUSION There is increasing evidence that dietary factors may play a role in the pathogenesis of IBD and especially Crohn’s disease. Exposure to high fat, gluten, emulsifiers and maltodextrin may be associated with the mechanisms of disease identified in Crohn’s disease or ulcerative colitis. Emerging evidence in pilot studies in Crohn’s disease has now shown for the first time that specific exclusion diets may effectively treat and induce remission in children and young adults with Crohn’s disease; however, the level of evidence is still low. Ulcerative colitis appears to be associated with decreased ability to generate shortchain fatty acids. Data regarding the effect of diet for the induction of remission and maintenance of remission in ulcerative colitis remain scarce, and cannot be recommended at this time. Acknowledgements None. Financial support and sponsorship None. Volume 31 Number 4 July 2015
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Conflicts of interest C.S.S. – none; R.S.B. – none; and A.L. – has been awarded a grant and a speakers honorarium from Nestle.
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23. Roberts C, Keita A, Duncan S, et al. Translocation of Crohn’s disease Escherichia coli across M-cells contrasting effects of soluble plant fibres and emulsifier. Gut 2010; 59:1331–1339. 24. Lammers K, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008; 135:194–204. 25. Tawfik A, Flanagan PK, Campbell BJ. Escherichia coli–host macrophage interactions in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014; 20:8751–8763. 26. Nickerson KP, McDonald C. Crohn’s disease-associated adherent-invasive Escherichia coli adhesion is enhanced by exposure to the ubiquitous dietary polysaccharide maltodextrin. PLoS One 2012; 7:e52132. 27. Dogan B, Suzuki H, Herlekar D, et al. Inflammation-associated adherentinvasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation. Inflamm Bowel Dis 2014; 20:1919–1932. 28. Le Leu RK, Young GP, Hu Y, et al. Dietary red meat aggravates dextran sulfate sodium induced colitis in mice whereas resistant starch attenuates inflammation. Dig Dis Sci 2013; 58:3475–3482. 29. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA 2014; 111:2247–2252. 30. Singh N, Gurav A, Sivaprakasam S, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 2014; 40:128–139. 31. Chan SS, Luben R, van Schaik F, et al. Carbohydrate intake in the etiology of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2014; 20:2013– 2021. 32. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of longterm intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 2013; 145:970–977. 33. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters && the human gut microbiome. Nature 2014; 505:559–563. This study in healthy volunteers demonstrated that an animal-based diet has a more significant impact than a plant-based diet on the microbiota. An animal-based diet led to dysbiosis with an increase in sulfide-reducing bacteria such as Bilophila wadsworthia and a decrease in Firmicutes. 34. Jaeggi T, Kortman GA, Moretti D, et al. Iron fortification adversely affects the && gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 2014; 0:1–12. These investigators demonstrated that iron fortification led to a significant increase in Enterobacteria and a significant decrease in Firmicutes which is similar in Crohn’s disease; as well as an increase in fecal calprotectin levels, an indicator of intestinal inflammation. 35. Wedlake L, Slack N, Andreyev HJ, Whelan K. Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis 2014; 20:576–586. 36. James SL, Christophersen CT, Bird AR, et al. Abnormal fibre usage in UC in & remission. Gut 2015; 64:562–570. This study demonstrated that patients with ulcerative colitis do not metabolize starches to short-chain fatty acids as would be anticipated. 37. Levine A, Turner D, Pfeffer Gik T, et al. Comparison of outcomes parameters for induction of remission in new onset pediatric Crohn’s disease: evaluation of the porto IBD group ‘growth relapse and outcomes with therapy’ (GROWTH CD) study. Inflamm Bowel Dis 2014; 20:278–285. 38. Buchanan E, Gaunt WW, Cardigan T, et al. The use of exclusive enteral nutrition for induction of remission in children with Crohn’s disease demonstrates that disease phenotype does not influence clinical remission. Aliment Pharmacol Ther 2009; 30:501–507. 39. Rubio A, Pigneur B, Garnier-Lengline H, et al. The efficacy of exclusive nutritional therapy in paediatric Crohn’s disease comparing fractionated oral vs. continuous enteral feeding. Aliment Pharmacol Ther 2011; 33:1332–1339. 40. Johnson T, Macdonald S, Hill S, et al. Treatment of active Crohn’s disease in children using partial enteral nutrition with liquid formula a randomised controlled trial. Gut 2006; 55:356–361. 41. Frivolt K, Schwerd T, Werkstetter KJ, et al. Repeated exclusive enteral nutrition in the treatment of paediatric Crohn’s disease: predictors of efficacy and outcome. Aliment Pharmacol Ther 2014; 39:1398–1407. 42. Gerasimidis K, Bertz M, Hanske L, et al. Decline in presumptively protective && gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn’s disease during enteral nutrition. Inflamm Bowel Dis 2014; 20:861–871. This study in Crohn’s disease patients demonstrated that the mechanism of induction of remission using exclusive enteral nutrition does not induce an improvement in diversity or bacterial metabolism as expected. They found that EEN actually decreased diversity, decreased butyric acid, increased fecal PH and increased fecal sulfide. 43. Sigall-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; 20:1353–1360. This is the first study to demonstrate that a diet based on exclusion of animal fat, gluten, emulsifiers and several other hypothetical ingredients that may cause dysbiosis or affect the mucous layer can induce remission in 70% of patients with active Crohn’s disease and was associated with mucosal healing.
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48. Hirai F, Ishihara H, Yada S, et al. Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn’s disease in adults. Dig Dis Sci 2013; 58:1329–1334. 49. Yamamoto T, Nakahigashi M, Umegae S, Matsumoto K. Prospective clinical trial: enteral nutrition during maintenance infliximab in Crohn’s disease. J Gastroenterol 2010; 45:24–29. 50. Kyaw MH, Moshkovska T, Mayberry J. A prospective, randomized, controlled, exploratory study of comprehensive dietary advice in ulcerative colitis: impact on disease activity and quality of life. Eur J Gastroenterol Hepatol 2014; 26:910–917. 51. Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis – a randomized, placebo-controlled, pilot study. J Crohns Colitis 2014; 8:208– 214. 52. McLaughlin SD, Culkin A, Cole J, et al. Exclusive elemental diet impacts on the gastrointestinal microbiota and improves symptoms in patients with chronic pouchitis. J Crohns Colitis 2013; 7:460–466.
Volume 31 Number 4 July 2015
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Nutritional therapy in inflammatory bowel disease Chen Sarbagili-Shabat a, Rotem Sigall-Boneh a, and Arie Levine a,b
Purpose of review An increasing body of evidence has linked diet to inflammatory bowel diseases (IBD), both Crohn’s disease and ulcerative colitis. Most of our current knowledge pertains to the link between diet and Crohn’s disease. Exclusive enteral nutrition and partial enteral nutrition are the best known dietary intervention for the induction of remission and maintenance of remission in Crohn’s disease both in children and in adults, but the mechanism whereby these interventions may cause or maintain remission and mucosal healing has remained elusive. Recent findings Recent studies have shed light on the possible mechanisms of response to dietary intervention. Epidemiological and rodent model studies over the last year have supplied us with several dietary candidates for an effect of diet on inflammation and disease pathogenesis. Others have shed insight into the effect of diet on dysbiosis and the microbiota. An elimination diet based on some of these candidates has shown clinical efficacy, and bridged the knowledge obtained from rodent models to a human intervention. Summary These studies may allow better understanding of the pathogenesis of IBD and provide new tools to treat these difficult diseases. Elimination diets based on the identification of deleterious dietary components may pave the way for an improved control of the disease in the future. Video abstract http://links.lww.com/COG/A10. Keywords Crohn’s disease, diet, enteral nutrition, inflammatory bowel disease, microbiome
INTRODUCTION Dietary therapy is an established, but underutilized and poorly understood therapy that can induce and maintain remission in Crohn’s disease [1–3]. Dietary therapy offers the possibility of reducing the burden of immunosuppressive medications, promoting growth in children, and providing insight into the possible environmental factors that may impact the disease. Inflammatory bowel diseases (IBD) arise at the interface between the resident intestinal bacteria and the innate immune system. These diseases are characterized by a decrease in microbial diversity, dysbiosis and epithelial damage [4,5]. Under normal circumstances, the mucous layer, intestinal epithelial cells and the tight junctions serve as an efficient barrier to potentially harmful bacteria, whereas the innate immune system serves as a backup mechanism to exclude enteric bacteria from penetrating or interacting with the mucosal immune cells [3–12]. Multiple studies raise the
possibility that a variety of dietary factors may be associated with IBD. These include epidemiologic studies [13,14] demonstrating a protective or harmful effect for dietary components, and rodent models that demonstrate the ability of dietary factors to induce dysbiosis, increase colonization or adherence of pathobionts associated with Crohn’s disease, or to impair the barrier function [3,13–16]. The current review will summarize the studies published over the last year that provide new insight into the role of diet on the pathogenesis and treatment for all IBD patients. As a result of the large a
Pediatric Inflammatory Bowel Disease Research Center, Holon and Wolfson Medical Center, Tel Aviv University, Tel Aviv, Israel
b
Correspondence to Arie Levine, MD, Pediatric Gastroenterology and Nutrition Unit, Pediatric Inflammatory Bowel Disease Research Center, Wolfson Medical Center, 62 Halohamim Street, Holon 58100, Israel. E-mail: [email protected] Curr Opin Gastroenterol 2015, 31:303–308 DOI:10.1097/MOG.0000000000000178
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Inflammatory bowel disease
KEY POINTS Exclusive enteral nutrition can cause high rates of mucosal healing in children with Crohn’s disease. Exclusive enteral nutrition in responders does not increase the diversity of the microbiota or short-chain fatty acids as previously hypothesized. Dietary ingredients such as a high-fat diet and gluten appear to aggravate inflammation in the rodent models of Crohn’s disease. Partial enteral nutrition with a specific exclusion diet appears to be effective for the induction of remission in children and adults with nonsevere Crohn’s disease. Ulcerative colitis appears to be accompanied by defective production of short-chain fatty acids.
body of literature available on vitamin D, we have excluded this component from the review.
DIETARY COMPONENTS IN HEALTH AND DISEASE: ANIMAL MODELS Previously published studies have highlighted the possible deleterious effect of animal fat, milk fat, iron and emulsifiers in IBD rodent models [15,16,17 ,18, 19 ,20 ,21–23]. Martinez-Medina et al. [17 ] recently demonstrated that a high-fat, high-sugar diet led to dysbiosis and colonization with adherent invasive Escherichia coli (AIEC), depletion of the mucous layer and increased intestinal permeability in an IL10/ knockout mouse. The effect of a high-fat diet was also reproduced in the TNFDAre/wt mouse model of ileitis by comparing mice fed conventional chow or a high-fat diet [19 ]. Mice fed the high-fat diet developed increased intestinal permeability, generated Th17-driven dendritic cells and developed more severe ileitis. Gluten has also now been proposed to play a deleterious role in ileitis as well. Gluten can induce zonulin, which in turn increases small intestinal permeability [24]. In an elegant study by Wagner et al. [20 ] in the same mouse model, they compared the development of ileitis with standard chow, gluten-free chow or chow with added gluten. Exposure to chow containing gluten exacerbated ileitis, most likely by increasing the intestinal permeability. Two relatively new kids on the block in this growing list may connect diet and AIEC, a possible pathobiont in Crohn’s disease. These bacteria can translocate across ileal epithelium, survive in macrophages and generate TNF-alpha, leading to granulomas. Strains of AIEC have been isolated from the ileum and the colon of control and Crohn’s disease patients [8,25]. Maltodextrin was recently found to &&
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promote AIEC biofilms, and increase adhesion of AIEC strains to intestinal epithelial cells and macrophages via upregulation of type 1 pili expression [26]. Importantly, this mechanism does not require the usual ligand for attachment (CEACAM 6), suggesting that exposure to maltodextrin may allow AIEC to attach when it otherwise could not adhere to cells. Maltodextrin is a thickening and binding agent found in breakfast cereals as well as aspartame and sucralose, commonly used as artificial sweeteners. Iron and heme may be critical for the chain of events enabling AIEC penetration and survival in macrophages. Growth of AIEC required iron, and the enrichment of these strains with heme acquisition genes correlated with persistence in macrophages [27]. Red meat has also joined this list in rodent models, as it was recently found to promote inflammation in a dextran sulfate sodium (DSS) colitis model. Interestingly enough, the effect of red meat was ameliorated by resistant starch, one of the sources for butyrate production [28]. Two recent studies have shed light on the potential benefits and mechanisms of n-butyrate, a product of bacterial fermentation of fibers and starches, on the innate immune system [29,30]. n-Butyrate was found to reduce the secretion of interleukin (IL)-6, IL-12 and nitric oxide synthase via a direct effect on the inhibition of deacetylation of histones [29], and also found to induce differentiation of regulatory T cells [30]. However, it was ineffective in ameliorating colitis in a DSS model of colitis [29].
INSIGHT FROM EPIDEMIOLOGY AND DIETARY CHANGES IN HEALTHY INDIVIDUALS Epidemiologic studies have yielded conflicting data regarding the role of carbohydrate exposure as a risk factor [14]. A very large epidemiologic study, the European Prospective Investigation into Cancer and Nutrition (EPIC), prospectively followed 401 326 initially healthy men and women without Crohn’s disease or ulcerative colitis from centers in eight European countries. No association was found between carbohydrate intake and onset of ulcerative colitis during the follow-up [31]. Another epidemiologic study, based on yet another analysis of 170 776 women followed during the Nurses Health Study, evaluated the likelihood to develop IBD over 3 317 425 patient-years. They identified 269 incident cases of new-onset Crohn’s disease and 338 cases of new-onset ulcerative colitis. Those in the highest quintile for fiber intake were 40% less likely to develop Crohn’s disease; fiber from fruit appeared to have the greatest impact on risk reduction [32]. Volume 31 Number 4 July 2015
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Investigators from Harvard University and Duke University evaluated the change in microbiota upon exposure to an animal-based diet (meat, eggs and dairy) or a plant-based diet (fruits, vegetables, nuts and legumes) in healthy volunteers. The animalbased diet increased the concentration of fecal bile acids such as deoxycholic acid, increased the abundance bile-tolerant microorganisms such as Bilophila and Bacteroides, and decreased the levels of Firmicutes [33 ]. Bilophila wadsworthia is a bileacid-tolerant bacterium that has been linked to colonic inflammation, and was previously found to bloom and aggravate experimental colitis after exposure to milk fat [21] in an IL10/ knockout mouse model, whereas Firmicutes appear to be sensitive to the changes in fecal bile acids. Another study demonstrated that dietary iron may modify the gut microbiome and increase inflammation in 6-month-old Kenyan infants. Jaeggi et al. [34 ] performed two double-blind, randomized controlled trials, in which infants consumed low or high ironfortified maize porridge daily for 4 months. Iron fortification led to a significant increase in enterobacteria and a significant decrease in bifidobacteria. In addition to early-onset dysbiosis, iron fortification increased fecal calprotectin levels, an indicator of intestinal inflammation. &&
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that individuals with ulcerative colitis have decreased ability to ferment nonstarch polysaccharides and starch [36 ]. Exclusive enteral nutrition (EEN) is a well established method for inducing remission in children with recent-onset Crohn’s disease [37–39]. Partial enteral nutrition (PEN) with free diet seems to be ineffective for the induction of remission [40]. A small retrospective German study found that the majority of children successfully completing a course of EEN will relapse during the first year and that 66% will respond to a second course of EEN with remission [41]. The mechanism whereby EEN induces remission has been controversial and two recent studies have shed light on the possible mechanisms. Previously postulated mechanisms of response have included an improvement on the effect of EEN on the microbiome, including an improvement in the diversity of the microbiome, improvement in protective species or increased butyrate production [42 ]. Scottish investigators evaluated 15 children before and after successful remission with EEN along with 21 controls. Contrary to the expectations, use of EEN was associated with a further decrease in diversity, decrease in specific ‘protective species’ and a decrease in butyrate in fecal samples. A different line of thought was evaluated by the investigators from Israel [43 ]. They hypothesized that the major mechanism of effect is exclusion of dietary components hypothesized to cause dysbiosis or impair innate immune mechanisms such as the mucous layer, intestinal permeability or colonization and adherence with AIEC. They treated 47 patients with active Crohn’s disease with PEN and a diet they coined as the Crohn’s disease exclusion diet for 12 weeks. This is a structured diet with allowed and disallowed foods divided into two stages. Use of this diet led to clinical remission in 70% of patients by week 6. This was accompanied by a significant drop in C-reactive protein (CRP) and erythrocyte sedimentation rate through week 12, normalization of CRP in 70% of patients in remission and mucosal healing in a subset of responders. Importantly, 11 of 15 patients entering remission and practicing dietary restriction had mucosal healing. The results of this study done in humans suggest that specific dietary products play a role in inflammation. Use of PEN along with the Crohn’s disease exclusion diet which contains whole foods such as lean chicken breast, fish, eggs, vegetables and rice offers the possibility of a more palatable and feasible diet and more widespread use of dietary therapy for the induction of remission in the future. Although EEN has been widely accepted for the induction of remission, there has been a paucity of &
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DIETARY INTERVENTIONS IN ACTIVE INFLAMMATORY BOWEL DISEASE AND MECHANISMS OF RESPONSE Fiber has been touted as both harmful and beneficial in IBD, and restriction of fiber has been recommended in the past. A recent systemic review of clinical trials, involving 23 studies, found no effect for the supplementation of dietary fiber in 12 studies on Crohn’s disease, a possible weak effect in ulcerative colitis in 3 of 10 studies, and a possible effect in pouchitis. Importantly, there was no evidence that fiber intake should be restricted in patients with IBD [35]. Another study that may have some ramifications for future studies involving dietary fiber and short-chain fatty acids as a dietary strategy was performed by the investigators from Melbourne, Australia. They randomized 25 patients with ulcerative colitis in remission or 12 healthy controls to one of two diets; low resistant starch, low wheat bran exposure or high resistant starch with high wheat bran over 2 weeks, then each group crossed over to the second diet after a washout period. In contrast to conventional wisdom, increased exposure to starch and fiber in the ulcerative colitis group did not increase short-chain fatty acid production and did not lead to a change in the composition of the microbiome. The authors concluded
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data regarding complete mucosal healing using rigorous criteria and prospective data collection. The Australian investigators prospectively evaluated clinical remission and mucosal healing using the Simple Endoscopic Score (SES) in 26 children receiving EEN for 8 weeks [44 ]. They confirmed that EEN is accompanied by mucosal healing, as 84% of patients entered clinical remission and 42% had complete mucosal healing. Importantly, 58% had complete or near-complete mucosal healing. Multiple small studies have shown that PEN may be effective as a maintenance therapy to prevent clinical recurrence [45–47]. Yamamoto et al. [46] had previously shown that postoperative maintenance therapy with nightly tube feeding of an elemental formula with a low-fat diet can prevent endoscopic recurrence at 1 year. In a recent study, this same group extended their follow-up of the 40 patients in the original study to 5 years of follow-up [47]. Understandably, a decline in tube feeding was seen over time. At 5 years after resection, significantly more patients in the control group required biological therapy. A second resection was required in 5% of the PEN group and 25% of the control group (not significant). Postoperative recurrence is clearly an interesting avenue of research that has not been adequately evaluated to date. The Japanese investigators retrospectively evaluated the effect of PEN in addition to infliximab to reduce the loss of response to infliximab. Patients with normal CRP after the third induction of remission infusion were considered eligible. The authors divided their cohort of 102 patients into those who received at least 900 ml of an elemental formula in addition to infliximab (n ¼ 45) and those who received no PEN or less than 900 ml/day (n ¼ 57). Loss of response was defined as requirement for dose interval change or elevation of CRP greater than 1.5 mg/dl. At the end of follow-up, loss of response was significantly higher in the group treated solely with infliximab compared with the combination with an elemental formula [48]. These results contradict a previous prospective study that found no difference in the loss of response [49]. As this cohort was retrospective and the prospective study involved a fairly small study cohort, better studies are required before conclusions can be drawn. There are very few studies that have evaluated successful dietary interventions in ulcerative colitis. Kyaw et al. [50] suggested that a dietary intervention based on the reduction in exposure to fat, simple carbohydrates, red meat and processed food can be beneficial in ulcerative colitis. They treated 61 ulcerative colitis adult patients over 4–6 weeks during a disease flare. By week 24, there was a modest but significant improvement in the activity score, &&
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suggesting that this may improve disease activity but could not induce remission. Curcumin is a phenol compound that is the principal component of the spice turmeric [51]. Curcumin enemas were used for the induction of remission in mild-to-moderate distal colitis. Forty-five patients were randomized to either oral 5-aminosalicylic acid (5-ASA) with a curcumin enema or oral 5-ASA with a placebo enema. At week 8, clinical remission was observed in 43.4% of patients in the curcumin enema group compared with 22.7% in placebo group (not significant), and improvement on endoscopy in 52.2% of patients in active treatment group compared with 36.4% of patients in placebo group (not significant). As the authors did not show a significant difference and the study group was too small to reach significance, further studies are needed in order to evaluate the clinical significance of this type of therapy. The relative success of dietary therapy for active Crohn’s disease has led the investigators to evaluate the use of dietary therapies for other gut inflammatory conditions. Investigators from London evaluated the use of an elemental diet for chronic pouchitis [52]. Seven patients with pouchitis were treated with an exclusive elemental diet for 28 days. Use of EEN led to a significant decrease in stool frequency and the Pouch Disease Activity Index; however, there was no improvement in the endoscopic or histology scores.
CONCLUSION There is increasing evidence that dietary factors may play a role in the pathogenesis of IBD and especially Crohn’s disease. Exposure to high fat, gluten, emulsifiers and maltodextrin may be associated with the mechanisms of disease identified in Crohn’s disease or ulcerative colitis. Emerging evidence in pilot studies in Crohn’s disease has now shown for the first time that specific exclusion diets may effectively treat and induce remission in children and young adults with Crohn’s disease; however, the level of evidence is still low. Ulcerative colitis appears to be associated with decreased ability to generate shortchain fatty acids. Data regarding the effect of diet for the induction of remission and maintenance of remission in ulcerative colitis remain scarce, and cannot be recommended at this time. Acknowledgements None. Financial support and sponsorship None. Volume 31 Number 4 July 2015
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Conflicts of interest C.S.S. – none; R.S.B. – none; and A.L. – has been awarded a grant and a speakers honorarium from Nestle.
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Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis 2014; 20:576–586. 36. James SL, Christophersen CT, Bird AR, et al. Abnormal fibre usage in UC in & remission. Gut 2015; 64:562–570. This study demonstrated that patients with ulcerative colitis do not metabolize starches to short-chain fatty acids as would be anticipated. 37. Levine A, Turner D, Pfeffer Gik T, et al. Comparison of outcomes parameters for induction of remission in new onset pediatric Crohn’s disease: evaluation of the porto IBD group ‘growth relapse and outcomes with therapy’ (GROWTH CD) study. Inflamm Bowel Dis 2014; 20:278–285. 38. Buchanan E, Gaunt WW, Cardigan T, et al. The use of exclusive enteral nutrition for induction of remission in children with Crohn’s disease demonstrates that disease phenotype does not influence clinical remission. Aliment Pharmacol Ther 2009; 30:501–507. 39. 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This study in Crohn’s disease patients demonstrated that the mechanism of induction of remission using exclusive enteral nutrition does not induce an improvement in diversity or bacterial metabolism as expected. They found that EEN actually decreased diversity, decreased butyric acid, increased fecal PH and increased fecal sulfide. 43. Sigall-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; 20:1353–1360. This is the first study to demonstrate that a diet based on exclusion of animal fat, gluten, emulsifiers and several other hypothetical ingredients that may cause dysbiosis or affect the mucous layer can induce remission in 70% of patients with active Crohn’s disease and was associated with mucosal healing.
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48. Hirai F, Ishihara H, Yada S, et al. Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn’s disease in adults. Dig Dis Sci 2013; 58:1329–1334. 49. Yamamoto T, Nakahigashi M, Umegae S, Matsumoto K. Prospective clinical trial: enteral nutrition during maintenance infliximab in Crohn’s disease. J Gastroenterol 2010; 45:24–29. 50. Kyaw MH, Moshkovska T, Mayberry J. A prospective, randomized, controlled, exploratory study of comprehensive dietary advice in ulcerative colitis: impact on disease activity and quality of life. Eur J Gastroenterol Hepatol 2014; 26:910–917. 51. Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis – a randomized, placebo-controlled, pilot study. J Crohns Colitis 2014; 8:208– 214. 52. McLaughlin SD, Culkin A, Cole J, et al. Exclusive elemental diet impacts on the gastrointestinal microbiota and improves symptoms in patients with chronic pouchitis. J Crohns Colitis 2013; 7:460–466.
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