- Email: [email protected]
What is known about the mechanisms of dietary influences in Crohn's disease?
Nutrition 31 (2015) 1195–1203
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Review
What is known about the mechanisms of dietary influences in Crohn’s disease? Derek Chan M.B.B.S. a, Devinder Kumar Ph.D., F.R.C.S. a, *, Mike Mendall M.A., M.D., F.R.C.P. b a b
Department of Colorectal Surgery St George’s Hospital, London, UK Croydon University Hospital, London, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 February 2015 Accepted 16 April 2015
Much has been written about the role of diet and risk for Crohn’s disease (CD). However, the evidence is contradictory. Recent evidence has pointed to fiber playing an important role along with the possibility that dietary fat and overnutrition also have a role. Diet has a clearer place in disease modification, with some diets used in the treatment of CD. The lack of clarity stems from a poor understanding of the mechanisms underlying the relationship between diet and CD. Gut permeability is likely to play a key role in the risk for CD. Mechanisms whereby diet can affect gut permeability, including the effects of the gut microbiota, are reviewed. Modification of disease behavior is likely to be influenced by additional mechanisms, including recognition of complex food antigens. As with many other chronic diseases, a surrogate marker of CD risk would greatly aid evaluation of the dietary factors involved. Formal measures of gut permeability are too cumbersome for large-scale use, but fecal calprotectin may be a convenient measure of this. There are only preliminary data on the effect of diet and microbiota composition on fecal calprotectin and these require further investigation. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Inflammatory bowel disease Crohn’s disease Diet Fiber Gut permeability Microbiota
Introduction More than 250,000 individuals in the United Kingdom are affected by inflammatory bowel disease (IBD) and approximately 10,000 new cases are diagnosed every year. IBD comprises predominately two conditions: ulcerative colitis (UC) and Crohn’s disease (CD). CD is a chronic inflammatory disease of the gastrointestinal (GI) tract that can affect anywhere from the mouth to the anus. Individuals with this condition often experience periods of symptomatic relapse and remission. Although the etiology of IBD is not completely understood, both UC and CD are thought to occur through a combination of genetic, environmental, and immunologic factors. The current thinking is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in a genetically susceptible host, although the precise nature of this remains to be elucidated [1,2].
* Corresponding author. Tel.: þ44 208 725 1302; fax: þ44 208 725 1302. E-mail address: [email protected] (D. Kumar). http://dx.doi.org/10.1016/j.nut.2015.04.018 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.
These diseases were traditionally limited to the Western industrialized world, with a high incidence and prevelance in western Europe and North America [3]. Over the past decade, however, they are becoming more common in countries that have adopted a Western lifestyle [4] (Fig. 1). Additionally increasing numbers of first- and second-generation migrants to these Western countries are being diagnosed [5,6]. The reason for this is uncertain, however, diet is believed to play a key role in the pathogenesis. Increasing evidence supports the role of diet in the pathogenesis of CD, particularly with regard to dietary fiber intake, support for which has come from powerful prospective studies. Also, emerging studies suggest a role of overnutrition or obesity in the pathognesis of certain forms of CD. Genetic studies have identified more than 160 risk loci associated with IBD, most of which are asscoiated with both UC and CD [7]. Many of these are involved in gut epithelial barrier function and immune responses to foreign microbes and antigens. We will review the evidence to date that diet and, in particular the particular components of diet, play a role in CD pathogenesis and disease modification. Then we will explore the
1196
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Fig. 1. Worldwide Crohn’s disease incidence rates and/or prevalence for countries reporting data (A) before 1960, (B) from 1960 to 1979, and (C) after 1980. Incidence and prevalence values were ranked into quintiles representing low (dark and light blue) to intermediate (green) to high (yellow and red) occurrence of disease. Reprinted reference 3; Copyright 2012 by Elsevier. Reprinted with permission. (The color version of this figure is available online at www.nutritionjrnl.com.)
D. Chan et al. / Nutrition 31 (2015) 1195–1203
evidence for the interaction and mechanisms between diet, the gut microbiota, and gut permeability in the pathogenesis of CD. Diet and onset of CD: The evidence It has been proposed that the Western dietdhigh in fat and protein, but low in vegetables and fruitsdhas contributed to the increase of IBD in Europe and the United States. Additionally, it is thought that the spread of the Western diet has caused an increase in IBD in places previously thought to be uncommon (e.g., China, Korea, Puerto Rico) [8]. Case–control studies A systematic review of the literature from 1966 to 2010 looked at the association between pre-illness dietary intake and the risk for developing IBD. Nineteen studies were identified. An increased risk for developing CD with a diet high in polyunsaturated fatty acids (PUFAs), u-6 fatty acids, saturated fats, and meat was reported. Decreased risk for developing CD was associated with a high intake of dietary fiber. Specifically, this was statistically significant in individuals consuming >22.1 g/d of fiber. A high intake of fruit was also found to reduce the risk for developing CD by 73% to 80% [8]. A further recent sytematic review of the literature looked at the role of habitual diet in the onset and risk for relapse in IBD. Again, some studies had found an increased risk for CD onset with a high intake of carbohydrates and a decreased risk with a high intake of fruits and vegetables. Additionally, some studies found a high intake of grain-derived products was negatively associated with the onset of CD, pointing to a possible protective role of fiber. Despite the significant associations reported by several studies, further studies have not confirmed these associations and hence no firm conclusions can be made [9]. It is important to note that none of the studies reviewed were prospective and hence they suffer from associated problems of recall bias and reverse causation. Prospective studies Stronger prospective evidence comes from data from the Nurses’ Health Study. Long-term intake of dietary fiber, particularly from fruit, was associated with a lower risk for developing CD. The association was independent of carbohydrate, protein, and fat intake [10]. This prospective cohort study began in 1976 when 121,700 female nurses in the United States, between the ages of 30 and 55 y completed a lifestyle questionnaire. In 1989, a parallel cohort study enrolled an additional 116,686 nurses between the ages of 25 and 42 y into the Nurses’ Health Study II. This included questions about body proportions. The nurses were followed up with a repeat questionnaire every 2 y for 29 y. The strengths of this study were its prospective nature and the fact that it was assessed at a number of time points before the onset of disease. The limitations of this study, however, were that it only applied to white women, with predominantly late-onset disease. Some prospective studies also have looked at more specific dietary components. A multicenter European study of 229,702 participants was the first to look at the relationship between dietary intake of the PUFA, docosahexaenoic acid (DHA), and CD. A significant inverse relationship between the development of CD and dietary intake of DHA was found [11]. However the
1197
Nurses’ Health Study I and II did not find any association with long-term intake of total fat, saturated fats, or unsaturated fats with risk for CD [12]. Recent evidence from a large European multicenter prospective study recruiting 401 326 individuals, suggested that carbohydrate does not play any role in the risk for developing CD [13]. This is further supported by a recent French study comprising 67 581 women, which again showed no relationship between risk for developing CD and carbohydrate intake. The French study, however, did find a dose–effect relationship for total protein intake and risk for developing CD, although this relationship was not observed with animal protein intake [14]. In conclusion, regarding specific dietary components, there is little evidence to support the role of any macrodietary component other than dietary fiber and possibly protein.
Overnutrition and Crohn’s disease Additional supporting evidence of the role of diet in the pathogenesis of CD is based on studies that have suggested a link between a risk for CD and obesity, particularly later-age–onset disease. The first such study came from our research group. This case–control study of 524 patients found that patients presenting with CD were more likely to have an extremely high or extremely low body mass index (BMI) compared with individuals with UC and a sample of community controls [15]. Prospective data supporting this association has been reported, based on the Nurses’ Health Study. An increased risk for CD was associated with measures of increased adiposity, including BMI, waist-to-height ratio, and body shape many years before disease onset. The median age of diagnosis of CD was 54 y (range 29–82 y). Again, this association was not found with UC [16]. Further recent prospective data from the Danish National Registry explored the relationship between BMI and a range of autoimmune diseases, including CD and UC. Evidence was found of a U-shaped relationship with CD, with the risk for CD being highest in those of low BMI and very high BMI, but again not with UC. Overall, 75 008 women with a median age of 30.2 y were followed up for a median of 11.4 y. In all, 138 cases of CD were diagnosed and a 1.9 increased risk for CD in obese women was found. As with the Nurses’ Health study, the age at onset of disease was relatively older [17]. In summary, the only strong evidence for the role of diet in the pathogenesis of CD relates to fiber and possibly protein intake. Additionally, overnutrition may play a role, although whether certain components of the diet leading to overnutrition are important is uncertain.
Diet and disease modification Disease modification of CD is defined as reversal of mucosal and transmural inflammation, thereby preventing structural damage (strictures, fistulas, abscesses) and surgical resection, with the goal of preventing loss of intestinal function [18]. Disease modification presents a different issue to potential causes of disease. Various treatments are available for CD. These include glucocorticosteroids, immunosuppressive agents, and biologic agents. These are primarily directed against the inflammatory process of CD. Their role is to reduce inflammation, slow down disease progression, and maintain remission.
1198
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Additionally, dietary intervention has been used for both acute CD and for maintenance of remission, with varying degrees of success. Although some nutritional therapies have been shown to be efficacious, the specific mechanisms of action are not clear. Although a number of different diets have been tried to treat CD, only a few are routinely used in the clinical setting: enteral nutrition, low-residue diets, and exclusion diets. Enteral nutrition Two systematic reviews have been published in recent years examining the role of elemental and polymeric diets in maintaining remission in CD. The first, a Cochrane review, examined two randomized controlled trials. Both studies found elemental diet, polymeric diet, or a combination of the two were effective in maintaining remission of CD [19–21]. The second systematic review included 10 studies examining the efficacy of the elemental and polymeric diets and their dosages in preventing CD relapse and found them to be effective [20,22–28]. Similar dietary regimens in the postoperative setting also have been shown to be beneficial, although the specific component of the diet responsible for relapse has yet to be identified [29–32]. Low-residue diets Low-residue diets have sometimes been recommended during acute flares of stricturing CD. These diets provide foods that are easily digestible by reducing the intake of indigestible carbohydrates. Low-residue diets limit the individual to <10 to 15 g/d of fiber (generally insoluble fiber such as raw fruits and vegetables and whole grain). It is thought that this helps to reduce the frequency and volume of stools, and also reduce the risk for intestinal obstruction. There is, however, potential for deficiencies in folate, vitamins A and C, and potassium [33]. Despite the anecdotal improvements that have been seen, lowresidue diets in CD have been poorly studied. A prospective study in Italy randomized a group of 70 patients with CD to a low-residue or a normal diet for a mean period of 29 mo. The findings did not show any difference in outcome between the two groups based on symptoms, hospitalization, surgery, new complications, nutritional status, or postoperative recurrence [34].
red meat and other forms of animal protein appear to be beneficial [35]. Fiber Managing IBD with dietary fiber was first investigated >30 y ago. A recent review studied investigations on the efficacy and mechanisms of action of fiber in IBD. To 2012, 12 randomized control trials investigating fiber in CD were found. The studies recruited patients with varying stages of disease (active, remission, and mixed), with fiber being increased through supplementation or dietary advice. None of the studies found any significant health benefit of a high-versus low-fiber diet, with one study finding negative results for high-versus low-fiber diet [36]. In conclusion, although clear evidence exists that certain diets are effective in the treatment of CD, the precise components that are important are not well understood. This stems from a lack of understanding of the underlying pathogenic mechanisms. Diet in the pathogenesis of CD: Mechanisms There are a number of possibilities as to how diet could affect the risk for developing CD and modify disease behavior. It is likely that different aspects of diet are important in these contexts. Evidence from genetic and clinical studies point to the importance of gut barrier function and handling of gut bacteria in the pathogenesis of CD. Possible mechanisms therefore could be related to the effects of diet on gut barrier function, either directly or indirectly, such as through alterations in gut microbiota for which there is emerging evidence of the importance in CD pathogenesis. Impaired gut barrier function leads to exposure of foreign food and microbial antigens, which likely play a role in perpetuating the mucosal inflammation found in CD. After a description of the defects in gut barrier function and alterations in gut microbiota found in CD, we will consider the evidence that diet can alter gut barrier function, whether through direct mechanisms or through effects mediated by the gut microbiota. Much of the evidence comes from animal studies, but special attention will be paid to studies in humans. Gut permeability and the intestinal barrier
Exclusion diet Therapeutic dietary regimens have involved elemental diet alone for a specified period of time. This is followed by reintroducing food types one at a time and assessing clinical response. This process is complex, time-consuming, and has poor patient compliance. Exclusion diets also have been administered by restricting foods that the patient recalls as triggers of disease exacerbation. IgG4-directed exclusion diets Recently trials of more targeted exclusion diets have been designed, guided by immunoglobulin (Ig)G4 activity to a set of food types. IgG4 is a regulatory antibody that is produced in response to chronic exposure to an antigenic stimulus. Results have shown benefit for patients with CD, based on clinical disease activity and quality-of-life scores. In particular, exclusion of
The gut epithelial cell barrier is composed of a single layer of gut epithelial cells. Each cell’s role is to maintain close association with its ajoining neighbors, sealing the surface of the gut with tight junctions (Fig. 2). In the proximal and mid small intestine, the bulk of gut antigen exposure comes from dietary intake, whereas in the ileum and large intestine, further antigen load comes from the complex gut microbiota. The other major antigenic challenge facing the gut comes from ingested food antigens [37]. The integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, and epithelial cell integrity, as well as the production of mucus. Genetic polymorphisms related to the functioning of all of these elements have been associated with CD. Impairment of one or all of these functions led to intestinal inflammation in a range of animal models, through the presence of antigen or microbes, in and beyond the epithelial layer and
D. Chan et al. / Nutrition 31 (2015) 1195–1203
1199
FC and hence gut permeability in a healthy middle-aged population. The main dietary determinant of FC was dietary fiber intake, agreeing with the findings from epidemiologic studies. Significantly, fat and protein intake were not related [45]. It is therefore likely that dietary fiber may be an important determinant of gut permeability in humans, but the question remains as to by what mechanisms. The gut microbiota: What is it and what is the dysbiosis in CD?
Fig. 2. Anatomy of the mucosal barrier. The human intestinal mucosa is composed of a simple layer of columnar epithelial cells, as well as the underlying lamina propria and muscular mucosa. Goblet cells, which synthesize and release mucin, as well as other differentiated epithelial cell types, are present. The unstirred layer, which cannot be seen histologically, is located immediately above the epithelial cells. The tight junction, a component of the apical junctional complex, seals the paracellular space between epithelial cells. Intraepithelial lymphocytes are located above the basement membrane, but are subjacent to the tight junction. The lamina propria is located beneath the basement membrane and contains immune cells. Reprinted from “Intestinal mucosal barrier function in health and disease,” by Turner JR 2009, Nature Reviews Immunology, vol 9(1), p.799 to 809. Copyright 2009 by Nature Publishing Group. Adapted with permission.
due to the inability of the innate immune system to deal effectively with them [38]. Increased gut permeability is increased in 30% to 65% of patients with CD. Many of the genetic loci associated with CD code for genes that regulate gut permeability. Abnormal gut permeability has been seen with early replase of CD; with a sevenfold increase in the relapse rates in patients with increased gut permeability compared with normal permeability. This increased permeability can predict relapses by up to 1 y [39,40]. Additionally, alteration in gut permeability correlates with disease activity, such that improvement in the disease activity corresponds with improvement in gut permeability [41]. Also, first-degree relatives of those with CD have significantly increased gut permeability compared with healthy controls [42]. Altered expression of tight junction proteins has also been observed in patients with CD and their relatives [43]. In healthy humans, measures of gut permeability correlate closely with the presence of inflammation. The clearest evidence for this comes from studies comparing gut permeability with fecal levels of calprotectin; a calcium-binding protein found only in cells from a myelmonocytic lineage. The two correlate closely and also with Indium-labeled white cell excretion studies [44]. It is important to note that it is therefore likely that both gut permeability and fecal calprotectin (FC) are affected by the same factors. To our knowledge, our research group conducted the only cross-sectional population-based study into the determinants of
Growing evidence implicates the human microbiota in a variety of diseases, including diabetes, atherosclerosis, asthma, and colon cancer, as well as IBD [46]. Major shifts of bacterial taxa in the gut microbiota have been observed with changes in diet. The gut microbiota from children in Africa and Europe have been found to have significant differences, perhaps reflecting the dietary disparities in fiber, fat, and protein intake. African children had a greater abundance of Bacteroidetes and a lower abundance of Firmicutes compared with the European cohort, with a significant enrichment of bacteria from the Prevotella and Xylanibacter genera, highlighting the effect of diet on gut microbial composition [46]. This geographic change in population and gut microbiota has been reproduced in subsequent studies [47]. Additionally, changes in diet have been shown to influence the gut microbiota within the same individual. Obese individuals assigned to a fat-restricted or to a carbohydrate-restricted diet experienced an increase in the ratio of firmicutes to bacteroides [48]. Evidence of the effect of diet on the gut microbiota and gut permeability has been shown in mouse models, with a selective change in gut microbiota with prebiotics, causing improvement in gut barrier function [49]. In CD, there is various reasoning implicating bacteria in its pathogenesis. The sites of highest concentrations of bacteria in the gut correspond to the areas of the most frequent disease; namely the distal small bowel and colon. Additionally, this inflammation may be improved with antibiotics [50,51]. Diversion of the fecal stream, which contains a high content of microbiota, away from inflamed bowel is associated with disease improvement and relapse on restoration or exposure to fecal material, although this could equally support the importance of diet-related antigens [52,53]. Tissue biopsies taken from colons affected by CD have a reduced functional antimicrobial activity compared with normal tissues [54]. Finally, animal models of IBD have shown that inflammation does not occur in a microbial-free environment [55]. Many studies have observed changes in the composition of the microbiota in patients with IBD, particularly in those with CD, compared with healthy individuals. There is a decrease in general bacterial biodiversity. At the group-specific level, several studies have shown lower numbers of members of the Firmicutes phylum and of the Clostridium cluster IV. Several studies have also shown increase in mucosa-associated Escherhia coli. At the species-specific level, the bacterium Faecalibacterium prausnitzii has been consistently shown to be reduced in patients with CD compared with healthy individuals. Additionally, Bifidobacteria and Lactobacillus have been found to be reduced in individuals with CD [56–59]. It is still not clear whether the dysbiosis observed in patients with CD is a cause or consequence of the disease. Several hypotheses have been put forward as to how the microbiota could be linked to CD [60] (Table 1).
1200
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Table 1 Proposed mechanisms for the direct role of the gut microbiota in CD The microbiota as a whole could act as a surrogate pathogen Specific members of the microbiota could be overt pathogens and cause gut inflammation Changes in the proportions of different bacterial groups could initiate or perpetuate the inflammation by providing pathogenic antigens CD, Crohn’s disease
Diet, gut microbiota, and gut permeability: The evidence (Fig. 3) High fat diets, obesity, and western diets As summarized previously, the main dietary risk factors for the development of CD appear to be low dietary fiber intake as well as a high nutrient-dense diet associated with obesity. For the treatment of flares, however, it is the complex antigens that appear to play a role. Most of the evidence for the association of diet with gut permeability comes from studies in the field of obesity and the effects of high-fat diets. Modulation of the gut bacteria by a highfat diet greatly increases gut permeability by reducing expression of genes that code for tight junction proteins. Additionally, obese and high-fat–fed diabetic mice treated with an antibiotic, recover normal gut permeability, thus highlighting the
involvement of gut bacteria [61,62]. Previous work has demonstrated an association between BMI and FC [45]. Additionally, dietary fat can indirectly affect gut permeability through the activation of mast cells in the intestinal mucosa [63]. Mast cells are directly related to the regulation of transcellular and paracellular gut permeability through the secretion of mediators, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1 b, IL-4, and IL-13, as well as tryptase via protease activation receptor-2 [64]. Other mechanisms that could lead a high-fat intake to be associated with increased gut permeability relate to increased ileal and proximal colonic exposure to bile acids. It is of interest that these are precisely the sites where CD is most common. Bile acids are toxic to gut epithelium and are raised by increased dietary fat intake [65]. Bile has potent antimicrobial properties that can contribute to the selection or exclusion of many potential gut microbiota. Several intestinal pathogens, however, are not only bile resistant, but are highly favored in the presence of bile, possibly through suppression of symbiotic commensal microorganisms, allowing pathogens to establish a niche in the gut. Once established, the byproducts of these bacteria can serve to infiltrate the gut mucosa, allowing for increased immune cell infiltration and tissue damage [66]. One such byproduct is hydrogen sulphide, which is a potentially mucosal toxin. In addition to its direct toxic effects, it is thought to contribute to gut inflammation through a variety of mechanisms including impaired use of short-chain fatty acids (SCFAs) [67,68].
Fig. 3. Summary of the various mechanisms in which diet affects the gut barrier and intestinal permeability.
D. Chan et al. / Nutrition 31 (2015) 1195–1203
1201
Fiber
Vitamin D
Fiber intake was linked in a population-based study to reduced levels of FC, providing evidence that fiber can affect gut inflammation and permeability [45]. Dietary fiber is fermented in the colon by specific bacteria to SCFAs, including acetate, propionate, valerate, and butyrate; with butyrate being one of the major products from this process. Butyrate regulates gene expression as a histone deacetylase inhibitor. It plays an important role in maintaining the health of the intestinal mucosa and immune regulation, by controlling the balance between epithelial cell proliferation, differentiation, and programmed cell death. Animal studies have indicated that butyrate may have antiinflammatory and antineoplastic properties [69]. In vitro studies have shown that butyrate decreases proinflammatory cytokine expression by lamina propria mononuclear cells of patients with CD via inhibition of transcription factor, nuclear factor-k degradation [70]. Lymphocyte and IL-2 production is also reduced. This work points to a possible protective effect of fiber [71]. Therefore, it has been suggested that diets low in fiber, which result in low production of SCFAs may explain the high occurrence of colonic disorders in the Western world [72]. As well as SCFAs, it is thought that the microbiota regulates inflammatory response through a number of pathways. Some commensal bacteria have been found to use fiber to produce a glycan, polysaccharide A, which has strong anti-inflammatory properties against experimental IBD in mouse models. Pepidoglycan (PGN) is another microbiota-derived product that can modulate the immune system, promoting the killing of certain bacterial pathogens. Depletion of the microbiota in mice models resulted in lower systemic PGN levels [73].
Vitamin D deficiency has been implicated as a risk factor for CD, as well as other unrelated conditions. Animal models have reported that vitamin D increases tight junction proteins and enhances healing after injury to the intestinal epithelium [78]. Very recently, the effect of vitamin D supplementation and intestinal permeability has been investigated in patients with CD, with some evidence suggesting that vitamin D plays a role in supporting gut barrier functioning [79].
Fatty acids Other fatty acids have also been implicated in changes in gut permeability. u-3 PUFAs have been found to be associated with increased expression of the epithelial tight junction protein ZO-1 in colonic tissue in mouse models. This has been shown to correlate with reduced epithelial permeability [74]. Specific u-3 PUFAs, DHA and eicosapentaenoic acid (EPA), are known to inhibit genes that activate the inflammatory process and alter the composition of cell membranes, influencing cell signaling and inflammation [11,75]. Studies on human intestinal cells have shown the long-chain PUFAs: DHA, EPA, arachidonic acid, and dihomo-g-linolenic acid are particularly effective in supporting gut barrier integrity by improving resistance and reducing IL-4–mediated permeability [76]. Food additives A recent review examined previous studies for dietary clues into the pathogenesis of CD. In addition to the traditional dietary components comprising proteins, fat, fiber, carbohydrates, vitamins, and minerals, they reviewed several studies of epidemiologic data, as well as data from animal models, on food additives and intestinal function. The authors noted that a Western diet resulted in increased exposure to emulsifiers and food preservatives and concluded that the rise in CD could be due to these additives damaging the intestinal epithelium and gut permeability [77].
Food antigens and CD It seems unlikely that changes in gut permeability can explain the response to exclusion of complex dietary antigens in active CD. It would seem more likely that in some way dietary antigens are perpetuating the inflammatory response. Immunoglobulins directed against food antigens have previously been detected in patients with CD. Early evidence of the association of food antigens in CD comes from a study examining the antibody to Saccharomyces cerevisiae (baker’s yeast), a common dietary antigen, in patients with IBD and healthy controls. It was found that IgG and IgA levels to S. cerevisiae were significantly higher in patients with CD. Anti-S. cerevisiae antibodies (ASCA) have now been established as an aid to the diagnosis of CD [80,81]. It has been found that treatment with the new anti–TNF-a agents in patients with CD, is associated with a significantly decreased ASCA IgG and IgA levels [81]. That food antigens can initiate mucosal immune responses has been demonstrated in food-sensitive IBS, where instillation of food substances to which individuals were sensitive into the duodenum induced evidence of a mucosal immune response [82]. Intraepithelial lymphocytes increased, epithelial leaks and gaps formed, and intervillous spaces widened. How this relates to CD, where the site of disease is more distal, is uncertain, but it would seem likely that at least some partially digested food antigens persist into the lower GI tract, particularly as food digestion is likely to be impaired by a number of mechanisms in active CD [82]. Furthermore, because there is improvement of CD with elemental diets, it may be the complex antigenic proteins in food that are a contributary factor in the inflammatory process of CD. To our knowledge, we were the first to look at IgG4-targeted exclusion diets in patients with CD. In the initial pilot study, 29 individuals with CD were tested for IgG4 antibodies to 14 specific food antigens. Each individual’s four most reactive foods were then excluded for a 4-wk period (see Table 2 for tested foodstuffs). Disease activity was assessed using a modified CD activity index score (mCDAI) and inflammatory markers. Twenty-six patients reported improvement in their symptoms, with a reduction in mCDAI and blood inflammatory marker [83]. It has been found that in mouse models of CD, intestinal inflammation via CD4 T-cell activation was induced by food antigens associated with high serum IgG4 levels and was improved by elimination of food antigens. The pathology for why IgG is detected in patients with CD, however, remains unclear [84]. Table 2 IgG4 Exclusion Diet Tested Foodstuffs Ig, immunoglobulin Egg white Egg yolk
Lamb Pork
Yeast Chicken
Rice Wheat
Beef Peanut
Potato Soya
Cheddar cheese Tomato
1202
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Conclusion The influence of diet on the risk for CD and on disease behavior remains poorly understood. Mechanisms by which diet can influence the risk for disease are different from the mechanisms through which diet influences disease behavior. Effects on gut permeability are likely to mediate diet-related risk for disease, with effects on microbiota being the likely mechanism. When gut permeability is already disturbed in patients with CD, immune recognition of complex food antigens plays an additional role. The current contradictory state of much of the evidence for disease risk calls for the establishment of a biomarker for increased CD risk, which would allow better evaluation of the role of different dietary factors. This would permit sense checking and exploration of mechanisms of the wide range of dietary constituents that have been implicated. Formal measures of gut permeability are too cumbersome for large scale use. As yet, there is little data on the link between gut dysbiosis and levels of FC, and this is an area which requires further exploration. References [1] Sands BE. Inflammatory bowel disease: past, present, and future. J Gastroenterol 2007;42:16–25. [2] Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012;13:R79. [3] Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46–54. [4] Ng SC, Tang W, Ching JY, Wong M, Chow CM, Hui AJ, et al. Incidence and phenotype of inflammatory bowel disease based on results from the AsiaPacific Crohn’s and colitis epidemiology study. Gastroenterology 2013;145: 158–65. [5] Li X, Sundquist J, Hemminki K, Sundquist K. Risk of inflammatory bowel disease in first- and second-generation immigrants in Sweden: a nationwide follow-up study. Inflamm Bowel Dis 2011;17:1784–91. [6] Tsironi E, Feakins RM, Probert CS, Rampton DS, Phil D. Incidence of inflammatory bowel disease is rising and abdominal tuberculosis is falling in Bangladeshis in East London, United Kingdom. Am J Gastroenterol 2004;99:1749–55. [7] Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:119–24. [8] Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol 2011;106:563–73. [9] Spooren CE, Pierik MJ, Zeegers MP, Feskens EJ, Masclee AA, Jonkers DM. Review article: the association of diet with onset and relapse in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;38: 1172–87. [10] Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, De Silva P, Korzenik JR, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 2013;145:970–7. [11] Chan SSM, Luben R, Olsen A, Tjonneland A, Kaaks R, Lindgren S, et al. Association between high dietary intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid and reduced risk of Crohn’s disease. Aliment Pharmacol Ther 2014;39:834–42. [12] Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, de Silva P, Fuchs CS, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut 2014;63:776–84. [13] Chan SS, Luben R, van Schaik F, Oldenburg B, Bueno-de-Mesquita HB, Hallmans G, et al. Carbohydrate intake in the etiology of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2014;20:2013. [14] Jantchou P, Morois S, Clavel-Chapelon F, Boutron-Ruault MC, Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: the E3 N prospective study. Am J Gastroenterol 2010;105:2195–201. [15] Mendall MA, Gunasekera AV, John BJ, Kumar D. Is obesity a risk factor for Crohn’s disease? Dig Dis Sci 2011;56:837–44. [16] Khalili H, Ananthakrishnan AN, Higuchi LM, Richter JM, Fuchs C, Chan AT. 222 measures of adiposity and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 2013;144. S-48.
[17] Harpsøe MC, Basit S, Andersson M, Nielsen NM, Frisch M, Wohlfahrt J, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol 2014;43:843–55. mann M, Feagan BG, Kamm MA, Cosnes J, et al. [18] D’Haens GR, Fedorak R, Le Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn’s disease. Inflamm Bowel Dis 2009;15: 1599–604. [19] Akobeng AK, Thomas AG. Enteral nutrition for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev; 2007:CD005984. [20] Takagi S, Utsunomiya K, Kuriyama S, Yokoyama H, Takahashi S, Iwabuchi M, et al. Effectiveness of an “half elemental diet” as maintenance therapy for Crohn’s disease: a randomized controlled trial. Aliment Pharmacol Ther 2006;24:1333–40. [21] Verma S, Holdsworth CD, Giaffer MH. Does adjuvant nutritional support diminish steroid dependency in Crohns disease? Scand J Gastroenterol 2001;36:383–8. [22] Hirakawa H, Fukuda Y, Tanida N, Hosomi M, Shimoyama T. Home elemental enteral hyperalimentation (HEEH) for the maintenance of remission in patients with Crohn’s disease. Gastroenterol Jpn 1993;28:379–84. [23] Wilschanski M, Sherman P, Pencharz P, Davis L, Corey M, Griffiths A. Supplementary enteral nutrition maintains remission in paediatric Crohn’s disease. Gut 1996;38:543–8. [24] Verma S, Kirkwood B, Brown S, Giaffer MH. Oral nutritional supplementation is effective in the maintenance of remission in Crohn’s disease. Dig Liver Dis 2000;32:769–74. [25] Esaki M, Matsumoto T, Nakamura S, Yada S, Fujisawa K, Jo Y, et al. Factors affecting recurrence in patients with Crohn’s disease under nutritional therapy. Dis Colon Rectum 2006;49(Suppl 10):S68–74. [26] Yamamoto T, Nakahigashi M, Saniabadi AR, Iwata T, Maruyama Y, Umegae S, et al. Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and mucosal cytokines during remission in patients with Crohn’s disease: a prospective study. Inflamm Bowel Dis 2007;13:1493–501. [27] Ikeuchi H, Yamamura T, Nakano H, Kosaka T, Shimoyama T, Fukuda Y. Efficacy of nutritional therapy for perforating and non-perforating Crohn’s disease. Hepatogastroenterology 2004;51:1050–2. [28] Yamamoto T, Nakahigashi M, Umegae S, Matsumoto K. Enteral nutrition for the maintenance of remission in Crohn’s disease: z systematic review. Eur J Gastroenterol Hepatol 2010;22:1–8. [29] Esaki M, Matsumoto T, Hizawa K, Nakamura S, Jo Y, Mibu R, et al. Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with reference to findings determined by intra-operative enteroscopy. Scand J Gastroenterol 2005;40:1431–7. [30] Yamamoto T, Nakahigashi M, Umegae S, Kitagawa T, Matsumoto K. Impact of long-term enteral nutrition on clinical and endoscopic recurrence after resection for Crohn’s disease: a prospective, non-randomized, parallel, controlled study. Aliment Pharmacol Ther 2007;25:67–72. [31] Spinelli A, Sacchi M, Fiorino G, Danese S, Montorsi M. Risk of postoperative recurrence and postoperative management of Crohn’s disease. World J Gastroenterol 2011;17:3213–9. [32] Borowiec AM, Fedorak RN. Predicting, treating and preventing postoperative recurrence of Crohn’s disease: the state of the field. Can J Gastroenterol 2011;25:140–6. [33] Hwang C, Ross V, Mahadevan U. Popular exclusionary diets for inflammatory bowel disease: the search for a dietary culprit. Inflamm Bowel Dis 2014;20:732–41. [34] Levenstein S, Prantera C, Luzi C, D’ubaldi A. Low residue or normal diet in crohn’s disease: a prospective controlled study in Italian patients. Gut 1985;26:989–93. [35] Gunasekera AV, Rajendran N, Mendall M, Kumar D. An IgG4 specific food exclusion diet improves both clinical disease activity and quality of life in Crohn’s disease; a aandomised sham diet controlled study. Gastroenterology; 2011. S-567. [36] Wedlake L, Slack N, Andreyev HJN, Whelan K. Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis 2014;20:576–86. [37] Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005;307:1920–5. [38] Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427–34. [39] Arnott ID, Kingstone K, Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol 2000;35:1163–9. R, De Leo V, Corrao G, Martines D, D’Odorico A, Mestriner C, et al. [40] D’Inca Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am J Gastroenterol 1999;4:2956–60. [41] Benjamin J, Makharia G, Ahuja V, Anand Rajan KD, Kalaivani M, Gupta SD, et al. Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn’s disease: a randomized controlled trial. Dig Dis Sci 2012;57:1000–12. [42] Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, et al. Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020 insC mutation? Gut 2006;55: 342–7.
D. Chan et al. / Nutrition 31 (2015) 1195–1203 [43] Kucharzik T, Walsh SV, Chen J, Parkos CA, Nusrat A. Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol 2001;159:2001–9. [44] Berstad A, Arslan G, Folvik G. Relationship between intestinal permeability and calprotectin concentration in gut lavage fluid. Scand J Gastroenterol 2000;35:64–9. [45] Poullis A, Foster R, Shetty A, Fagerhol MK, Mendall MA. Bowel inflammation as measured by fecal calprotectin: a link between lifestyle factors and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2004;13:279–84. [46] Kelsen JR, Wu GD. The gut microbiota, environment and disease of modern society. Gut Microbe 2012;3:374–82. [47] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature 2012;486:222–7. [48] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022–3. [49] Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–103. [50] Hooper LV, Midtvedt T, Gordon JL. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002;22:283–307. [51] Kanauchi O, Mitsuyama K, Araki Y, Andoh A. Modification of intestinal flora in the treatment of inflammatory bowel disease. Curr Pharm Des 2003;9: 333–46. [52] D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262–7. [53] Rutgeerts P, Peeters M, Hiele M, Vantrappen G, Pennincx F, Aerts R, et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 1991;338:771–4. [54] Nuding S, Fellermann K, Wehkamp J, Stange EF. Reduced mucosal antimicrobial activity in Crohn’s disease of the colon. Gut 2007;56:1240–7. [55] Taurog JD, Maika SD, Simmons WA, Breban M, Hammer RE. Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. J Immunol 1993;150:4168–78. [56] Seksik P, Rigottier-Gois L, Gramet G, Sutren M, Pochart P, Marteau P, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut 2003;52:237–42. [57] Hedin CR, McCarthy NE, Louis P, Farquharson FM, McCartney S, Taylor K, et al. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn’s disease and their unaffected siblings. Gut 2014; 63:1578–86. [58] Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 2011;60:631–7. [59] Rajca S, Grondin V, Louis E, Vernier-Massouille G, Grimaud JC, Bouhnik Y, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn’s disease. Inflamm Bowel Dis 2014;20:978–86. [60] Tannock G. The bowel microbiotal and inflammatory bowel disease. Int J Inflamm 2010;10:4061–70. [61] Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81. [62] Shen W, Gaskins HR, McIntosh MK. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem 2014;25:270–80. [63] Ji Y, Sakata Y, Tso P. Nutrient-induced inflammation in the intestine. Curr Opin Clin Nutr Metab Care 2011;14:315–21. [64] Söderholm JD. The intestinal barrier and its regulation by neuroimmune factors. Neurogastroenterol Motil 2010;22:718–33.
1203
[65] Reddy BS, Hanson D, Mangat S, Mathews L, Sbaschnig M, Sharma C, et al. Effect of high-fat, high-beef diet and of mode of cooking of beef in the diet on fecal bacterial enzymes and fecal bile acids and neutral sterols. J Nutr 1980;110:1880–7. [66] Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/-mice. Nature 2012;487:104–8. [67] Medani M, Collins MD, Docherty NG, Baird AW, O’Connell PR, Winter DC. Emerging role of hydrogen sulfide in colonic physiology and pathophysiology. Inflamm Bowel Dis 2011;17:1620–5. [68] Hou JK, Lee D, Lewis J. Diet and inflammatory bowel disease: review of patient-targeted recommendations. Clin Gastroenterol Hepatol 2014;12: 1593–600. [69] Sabatino A, Morera R, Ciccocioppo R, Cazzola P, Gotti S, Tinozzi FP, et al. Oral butyrate for mildly to moderately active Crohn’s disease. Aliment Pharmacol Ther 2005;22:789–94. [70] Segain JP, De La Bletiere RD, Bourreille A, Leray V, Gervois N, Rosales C, et al. Butyrate inhibits inflammatory responses through NFkappaB inhibition: Implications for Crohn’s disease. Gut 2000;47:397–403. [71] Cavaglieri CR, Nishiyama A, Fernandes LC, Curi R, Miles EA, Calder PC. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci 2003;73:1683–90. [72] Scheppach W. Effects of short chain fatty acids on gut morphology and function. Gut 1994;35(Suppl 1):S35–8. [73] Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 2010;16:228–31. [74] Whiting CV, Bland PW, Tarlton JF. Dietary n3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis. Inflamm Bowel Dis 2005;11:340–9. [75] Novak TE, Babcock TA, Jho DH, Helton WS, Espat NJ. NF-kB inhibition by u-3 fatty acids modulates LPS-stimulated macrophage TNF-a transcription. Am J Physiol Lung Cell Mol Physiol 2003;284:L84–9. [76] Willemsen LE, Koetsier MA, Balvers M, Beermann C, Stahl B, van Tol EA. Polyunsaturated fatty acids support epithelial barrier integrity and reduce IL-4 mediated permeability in vitro. Eur J Nutr 2008;47:183–91. [77] Pfeffer-Gik T, Levine A. Dietary clues to the pathogenesis of Crohn’s disease. Dig Dis 2013;32:389–94. [78] Kong J, Zhang Z, Musch M, Ning G, Sun J, Hart J, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol 2008;294: G208–16. [79] Raftery T, Martineau A, Greiller C, Ghosh S, McNamara D, Bennett K, et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: results from a randomised double-blind placebo-controlled study. United European Gastroenterol J 2015;3:294–302. [80] Main J, McKenzie H, Yeaman GR, Kerr MA, Robson D, Pennington CR, et al. Antibody to Saccharomyces cerevisiae (bakers’ yeast) in Crohn’s disease. BMJ 1988;297:1105–6. [81] Frehn L, Jansen A, Bennek E, Mandic AD, Temizel I, Tischendorf S, et al. Distinct Patterns of IgG and IgA against food and microbial antigens in serum and feces of patients with inflammatory bowel diseases. PLoS One 2014;9:e106750. [82] Fritscher-Ravens A, Schuppan D, Ellrichmann M, Schoch S, Röcken C, Brasch J, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 2014;147:1012–20. [83] Rajendran N, Kumar D. Food specific IgG4-guided exclusion diets improve symptoms in Crohns disease da pilot study. Colorectal Dis 2010;13: 1009–13. [84] Kawaguchi T, Mori M, Saito K, Suga Y, Hashimoto M, Sako M, et al. Food antigen-induced immune responses in Crohn’s disease patients and experimental colitis mice. J Gastroenterol 2014;50:1–12.
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Review
What is known about the mechanisms of dietary influences in Crohn’s disease? Derek Chan M.B.B.S. a, Devinder Kumar Ph.D., F.R.C.S. a, *, Mike Mendall M.A., M.D., F.R.C.P. b a b
Department of Colorectal Surgery St George’s Hospital, London, UK Croydon University Hospital, London, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 February 2015 Accepted 16 April 2015
Much has been written about the role of diet and risk for Crohn’s disease (CD). However, the evidence is contradictory. Recent evidence has pointed to fiber playing an important role along with the possibility that dietary fat and overnutrition also have a role. Diet has a clearer place in disease modification, with some diets used in the treatment of CD. The lack of clarity stems from a poor understanding of the mechanisms underlying the relationship between diet and CD. Gut permeability is likely to play a key role in the risk for CD. Mechanisms whereby diet can affect gut permeability, including the effects of the gut microbiota, are reviewed. Modification of disease behavior is likely to be influenced by additional mechanisms, including recognition of complex food antigens. As with many other chronic diseases, a surrogate marker of CD risk would greatly aid evaluation of the dietary factors involved. Formal measures of gut permeability are too cumbersome for large-scale use, but fecal calprotectin may be a convenient measure of this. There are only preliminary data on the effect of diet and microbiota composition on fecal calprotectin and these require further investigation. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Inflammatory bowel disease Crohn’s disease Diet Fiber Gut permeability Microbiota
Introduction More than 250,000 individuals in the United Kingdom are affected by inflammatory bowel disease (IBD) and approximately 10,000 new cases are diagnosed every year. IBD comprises predominately two conditions: ulcerative colitis (UC) and Crohn’s disease (CD). CD is a chronic inflammatory disease of the gastrointestinal (GI) tract that can affect anywhere from the mouth to the anus. Individuals with this condition often experience periods of symptomatic relapse and remission. Although the etiology of IBD is not completely understood, both UC and CD are thought to occur through a combination of genetic, environmental, and immunologic factors. The current thinking is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in a genetically susceptible host, although the precise nature of this remains to be elucidated [1,2].
* Corresponding author. Tel.: þ44 208 725 1302; fax: þ44 208 725 1302. E-mail address: [email protected] (D. Kumar). http://dx.doi.org/10.1016/j.nut.2015.04.018 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.
These diseases were traditionally limited to the Western industrialized world, with a high incidence and prevelance in western Europe and North America [3]. Over the past decade, however, they are becoming more common in countries that have adopted a Western lifestyle [4] (Fig. 1). Additionally increasing numbers of first- and second-generation migrants to these Western countries are being diagnosed [5,6]. The reason for this is uncertain, however, diet is believed to play a key role in the pathogenesis. Increasing evidence supports the role of diet in the pathogenesis of CD, particularly with regard to dietary fiber intake, support for which has come from powerful prospective studies. Also, emerging studies suggest a role of overnutrition or obesity in the pathognesis of certain forms of CD. Genetic studies have identified more than 160 risk loci associated with IBD, most of which are asscoiated with both UC and CD [7]. Many of these are involved in gut epithelial barrier function and immune responses to foreign microbes and antigens. We will review the evidence to date that diet and, in particular the particular components of diet, play a role in CD pathogenesis and disease modification. Then we will explore the
1196
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Fig. 1. Worldwide Crohn’s disease incidence rates and/or prevalence for countries reporting data (A) before 1960, (B) from 1960 to 1979, and (C) after 1980. Incidence and prevalence values were ranked into quintiles representing low (dark and light blue) to intermediate (green) to high (yellow and red) occurrence of disease. Reprinted reference 3; Copyright 2012 by Elsevier. Reprinted with permission. (The color version of this figure is available online at www.nutritionjrnl.com.)
D. Chan et al. / Nutrition 31 (2015) 1195–1203
evidence for the interaction and mechanisms between diet, the gut microbiota, and gut permeability in the pathogenesis of CD. Diet and onset of CD: The evidence It has been proposed that the Western dietdhigh in fat and protein, but low in vegetables and fruitsdhas contributed to the increase of IBD in Europe and the United States. Additionally, it is thought that the spread of the Western diet has caused an increase in IBD in places previously thought to be uncommon (e.g., China, Korea, Puerto Rico) [8]. Case–control studies A systematic review of the literature from 1966 to 2010 looked at the association between pre-illness dietary intake and the risk for developing IBD. Nineteen studies were identified. An increased risk for developing CD with a diet high in polyunsaturated fatty acids (PUFAs), u-6 fatty acids, saturated fats, and meat was reported. Decreased risk for developing CD was associated with a high intake of dietary fiber. Specifically, this was statistically significant in individuals consuming >22.1 g/d of fiber. A high intake of fruit was also found to reduce the risk for developing CD by 73% to 80% [8]. A further recent sytematic review of the literature looked at the role of habitual diet in the onset and risk for relapse in IBD. Again, some studies had found an increased risk for CD onset with a high intake of carbohydrates and a decreased risk with a high intake of fruits and vegetables. Additionally, some studies found a high intake of grain-derived products was negatively associated with the onset of CD, pointing to a possible protective role of fiber. Despite the significant associations reported by several studies, further studies have not confirmed these associations and hence no firm conclusions can be made [9]. It is important to note that none of the studies reviewed were prospective and hence they suffer from associated problems of recall bias and reverse causation. Prospective studies Stronger prospective evidence comes from data from the Nurses’ Health Study. Long-term intake of dietary fiber, particularly from fruit, was associated with a lower risk for developing CD. The association was independent of carbohydrate, protein, and fat intake [10]. This prospective cohort study began in 1976 when 121,700 female nurses in the United States, between the ages of 30 and 55 y completed a lifestyle questionnaire. In 1989, a parallel cohort study enrolled an additional 116,686 nurses between the ages of 25 and 42 y into the Nurses’ Health Study II. This included questions about body proportions. The nurses were followed up with a repeat questionnaire every 2 y for 29 y. The strengths of this study were its prospective nature and the fact that it was assessed at a number of time points before the onset of disease. The limitations of this study, however, were that it only applied to white women, with predominantly late-onset disease. Some prospective studies also have looked at more specific dietary components. A multicenter European study of 229,702 participants was the first to look at the relationship between dietary intake of the PUFA, docosahexaenoic acid (DHA), and CD. A significant inverse relationship between the development of CD and dietary intake of DHA was found [11]. However the
1197
Nurses’ Health Study I and II did not find any association with long-term intake of total fat, saturated fats, or unsaturated fats with risk for CD [12]. Recent evidence from a large European multicenter prospective study recruiting 401 326 individuals, suggested that carbohydrate does not play any role in the risk for developing CD [13]. This is further supported by a recent French study comprising 67 581 women, which again showed no relationship between risk for developing CD and carbohydrate intake. The French study, however, did find a dose–effect relationship for total protein intake and risk for developing CD, although this relationship was not observed with animal protein intake [14]. In conclusion, regarding specific dietary components, there is little evidence to support the role of any macrodietary component other than dietary fiber and possibly protein.
Overnutrition and Crohn’s disease Additional supporting evidence of the role of diet in the pathogenesis of CD is based on studies that have suggested a link between a risk for CD and obesity, particularly later-age–onset disease. The first such study came from our research group. This case–control study of 524 patients found that patients presenting with CD were more likely to have an extremely high or extremely low body mass index (BMI) compared with individuals with UC and a sample of community controls [15]. Prospective data supporting this association has been reported, based on the Nurses’ Health Study. An increased risk for CD was associated with measures of increased adiposity, including BMI, waist-to-height ratio, and body shape many years before disease onset. The median age of diagnosis of CD was 54 y (range 29–82 y). Again, this association was not found with UC [16]. Further recent prospective data from the Danish National Registry explored the relationship between BMI and a range of autoimmune diseases, including CD and UC. Evidence was found of a U-shaped relationship with CD, with the risk for CD being highest in those of low BMI and very high BMI, but again not with UC. Overall, 75 008 women with a median age of 30.2 y were followed up for a median of 11.4 y. In all, 138 cases of CD were diagnosed and a 1.9 increased risk for CD in obese women was found. As with the Nurses’ Health study, the age at onset of disease was relatively older [17]. In summary, the only strong evidence for the role of diet in the pathogenesis of CD relates to fiber and possibly protein intake. Additionally, overnutrition may play a role, although whether certain components of the diet leading to overnutrition are important is uncertain.
Diet and disease modification Disease modification of CD is defined as reversal of mucosal and transmural inflammation, thereby preventing structural damage (strictures, fistulas, abscesses) and surgical resection, with the goal of preventing loss of intestinal function [18]. Disease modification presents a different issue to potential causes of disease. Various treatments are available for CD. These include glucocorticosteroids, immunosuppressive agents, and biologic agents. These are primarily directed against the inflammatory process of CD. Their role is to reduce inflammation, slow down disease progression, and maintain remission.
1198
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Additionally, dietary intervention has been used for both acute CD and for maintenance of remission, with varying degrees of success. Although some nutritional therapies have been shown to be efficacious, the specific mechanisms of action are not clear. Although a number of different diets have been tried to treat CD, only a few are routinely used in the clinical setting: enteral nutrition, low-residue diets, and exclusion diets. Enteral nutrition Two systematic reviews have been published in recent years examining the role of elemental and polymeric diets in maintaining remission in CD. The first, a Cochrane review, examined two randomized controlled trials. Both studies found elemental diet, polymeric diet, or a combination of the two were effective in maintaining remission of CD [19–21]. The second systematic review included 10 studies examining the efficacy of the elemental and polymeric diets and their dosages in preventing CD relapse and found them to be effective [20,22–28]. Similar dietary regimens in the postoperative setting also have been shown to be beneficial, although the specific component of the diet responsible for relapse has yet to be identified [29–32]. Low-residue diets Low-residue diets have sometimes been recommended during acute flares of stricturing CD. These diets provide foods that are easily digestible by reducing the intake of indigestible carbohydrates. Low-residue diets limit the individual to <10 to 15 g/d of fiber (generally insoluble fiber such as raw fruits and vegetables and whole grain). It is thought that this helps to reduce the frequency and volume of stools, and also reduce the risk for intestinal obstruction. There is, however, potential for deficiencies in folate, vitamins A and C, and potassium [33]. Despite the anecdotal improvements that have been seen, lowresidue diets in CD have been poorly studied. A prospective study in Italy randomized a group of 70 patients with CD to a low-residue or a normal diet for a mean period of 29 mo. The findings did not show any difference in outcome between the two groups based on symptoms, hospitalization, surgery, new complications, nutritional status, or postoperative recurrence [34].
red meat and other forms of animal protein appear to be beneficial [35]. Fiber Managing IBD with dietary fiber was first investigated >30 y ago. A recent review studied investigations on the efficacy and mechanisms of action of fiber in IBD. To 2012, 12 randomized control trials investigating fiber in CD were found. The studies recruited patients with varying stages of disease (active, remission, and mixed), with fiber being increased through supplementation or dietary advice. None of the studies found any significant health benefit of a high-versus low-fiber diet, with one study finding negative results for high-versus low-fiber diet [36]. In conclusion, although clear evidence exists that certain diets are effective in the treatment of CD, the precise components that are important are not well understood. This stems from a lack of understanding of the underlying pathogenic mechanisms. Diet in the pathogenesis of CD: Mechanisms There are a number of possibilities as to how diet could affect the risk for developing CD and modify disease behavior. It is likely that different aspects of diet are important in these contexts. Evidence from genetic and clinical studies point to the importance of gut barrier function and handling of gut bacteria in the pathogenesis of CD. Possible mechanisms therefore could be related to the effects of diet on gut barrier function, either directly or indirectly, such as through alterations in gut microbiota for which there is emerging evidence of the importance in CD pathogenesis. Impaired gut barrier function leads to exposure of foreign food and microbial antigens, which likely play a role in perpetuating the mucosal inflammation found in CD. After a description of the defects in gut barrier function and alterations in gut microbiota found in CD, we will consider the evidence that diet can alter gut barrier function, whether through direct mechanisms or through effects mediated by the gut microbiota. Much of the evidence comes from animal studies, but special attention will be paid to studies in humans. Gut permeability and the intestinal barrier
Exclusion diet Therapeutic dietary regimens have involved elemental diet alone for a specified period of time. This is followed by reintroducing food types one at a time and assessing clinical response. This process is complex, time-consuming, and has poor patient compliance. Exclusion diets also have been administered by restricting foods that the patient recalls as triggers of disease exacerbation. IgG4-directed exclusion diets Recently trials of more targeted exclusion diets have been designed, guided by immunoglobulin (Ig)G4 activity to a set of food types. IgG4 is a regulatory antibody that is produced in response to chronic exposure to an antigenic stimulus. Results have shown benefit for patients with CD, based on clinical disease activity and quality-of-life scores. In particular, exclusion of
The gut epithelial cell barrier is composed of a single layer of gut epithelial cells. Each cell’s role is to maintain close association with its ajoining neighbors, sealing the surface of the gut with tight junctions (Fig. 2). In the proximal and mid small intestine, the bulk of gut antigen exposure comes from dietary intake, whereas in the ileum and large intestine, further antigen load comes from the complex gut microbiota. The other major antigenic challenge facing the gut comes from ingested food antigens [37]. The integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, and epithelial cell integrity, as well as the production of mucus. Genetic polymorphisms related to the functioning of all of these elements have been associated with CD. Impairment of one or all of these functions led to intestinal inflammation in a range of animal models, through the presence of antigen or microbes, in and beyond the epithelial layer and
D. Chan et al. / Nutrition 31 (2015) 1195–1203
1199
FC and hence gut permeability in a healthy middle-aged population. The main dietary determinant of FC was dietary fiber intake, agreeing with the findings from epidemiologic studies. Significantly, fat and protein intake were not related [45]. It is therefore likely that dietary fiber may be an important determinant of gut permeability in humans, but the question remains as to by what mechanisms. The gut microbiota: What is it and what is the dysbiosis in CD?
Fig. 2. Anatomy of the mucosal barrier. The human intestinal mucosa is composed of a simple layer of columnar epithelial cells, as well as the underlying lamina propria and muscular mucosa. Goblet cells, which synthesize and release mucin, as well as other differentiated epithelial cell types, are present. The unstirred layer, which cannot be seen histologically, is located immediately above the epithelial cells. The tight junction, a component of the apical junctional complex, seals the paracellular space between epithelial cells. Intraepithelial lymphocytes are located above the basement membrane, but are subjacent to the tight junction. The lamina propria is located beneath the basement membrane and contains immune cells. Reprinted from “Intestinal mucosal barrier function in health and disease,” by Turner JR 2009, Nature Reviews Immunology, vol 9(1), p.799 to 809. Copyright 2009 by Nature Publishing Group. Adapted with permission.
due to the inability of the innate immune system to deal effectively with them [38]. Increased gut permeability is increased in 30% to 65% of patients with CD. Many of the genetic loci associated with CD code for genes that regulate gut permeability. Abnormal gut permeability has been seen with early replase of CD; with a sevenfold increase in the relapse rates in patients with increased gut permeability compared with normal permeability. This increased permeability can predict relapses by up to 1 y [39,40]. Additionally, alteration in gut permeability correlates with disease activity, such that improvement in the disease activity corresponds with improvement in gut permeability [41]. Also, first-degree relatives of those with CD have significantly increased gut permeability compared with healthy controls [42]. Altered expression of tight junction proteins has also been observed in patients with CD and their relatives [43]. In healthy humans, measures of gut permeability correlate closely with the presence of inflammation. The clearest evidence for this comes from studies comparing gut permeability with fecal levels of calprotectin; a calcium-binding protein found only in cells from a myelmonocytic lineage. The two correlate closely and also with Indium-labeled white cell excretion studies [44]. It is important to note that it is therefore likely that both gut permeability and fecal calprotectin (FC) are affected by the same factors. To our knowledge, our research group conducted the only cross-sectional population-based study into the determinants of
Growing evidence implicates the human microbiota in a variety of diseases, including diabetes, atherosclerosis, asthma, and colon cancer, as well as IBD [46]. Major shifts of bacterial taxa in the gut microbiota have been observed with changes in diet. The gut microbiota from children in Africa and Europe have been found to have significant differences, perhaps reflecting the dietary disparities in fiber, fat, and protein intake. African children had a greater abundance of Bacteroidetes and a lower abundance of Firmicutes compared with the European cohort, with a significant enrichment of bacteria from the Prevotella and Xylanibacter genera, highlighting the effect of diet on gut microbial composition [46]. This geographic change in population and gut microbiota has been reproduced in subsequent studies [47]. Additionally, changes in diet have been shown to influence the gut microbiota within the same individual. Obese individuals assigned to a fat-restricted or to a carbohydrate-restricted diet experienced an increase in the ratio of firmicutes to bacteroides [48]. Evidence of the effect of diet on the gut microbiota and gut permeability has been shown in mouse models, with a selective change in gut microbiota with prebiotics, causing improvement in gut barrier function [49]. In CD, there is various reasoning implicating bacteria in its pathogenesis. The sites of highest concentrations of bacteria in the gut correspond to the areas of the most frequent disease; namely the distal small bowel and colon. Additionally, this inflammation may be improved with antibiotics [50,51]. Diversion of the fecal stream, which contains a high content of microbiota, away from inflamed bowel is associated with disease improvement and relapse on restoration or exposure to fecal material, although this could equally support the importance of diet-related antigens [52,53]. Tissue biopsies taken from colons affected by CD have a reduced functional antimicrobial activity compared with normal tissues [54]. Finally, animal models of IBD have shown that inflammation does not occur in a microbial-free environment [55]. Many studies have observed changes in the composition of the microbiota in patients with IBD, particularly in those with CD, compared with healthy individuals. There is a decrease in general bacterial biodiversity. At the group-specific level, several studies have shown lower numbers of members of the Firmicutes phylum and of the Clostridium cluster IV. Several studies have also shown increase in mucosa-associated Escherhia coli. At the species-specific level, the bacterium Faecalibacterium prausnitzii has been consistently shown to be reduced in patients with CD compared with healthy individuals. Additionally, Bifidobacteria and Lactobacillus have been found to be reduced in individuals with CD [56–59]. It is still not clear whether the dysbiosis observed in patients with CD is a cause or consequence of the disease. Several hypotheses have been put forward as to how the microbiota could be linked to CD [60] (Table 1).
1200
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Table 1 Proposed mechanisms for the direct role of the gut microbiota in CD The microbiota as a whole could act as a surrogate pathogen Specific members of the microbiota could be overt pathogens and cause gut inflammation Changes in the proportions of different bacterial groups could initiate or perpetuate the inflammation by providing pathogenic antigens CD, Crohn’s disease
Diet, gut microbiota, and gut permeability: The evidence (Fig. 3) High fat diets, obesity, and western diets As summarized previously, the main dietary risk factors for the development of CD appear to be low dietary fiber intake as well as a high nutrient-dense diet associated with obesity. For the treatment of flares, however, it is the complex antigens that appear to play a role. Most of the evidence for the association of diet with gut permeability comes from studies in the field of obesity and the effects of high-fat diets. Modulation of the gut bacteria by a highfat diet greatly increases gut permeability by reducing expression of genes that code for tight junction proteins. Additionally, obese and high-fat–fed diabetic mice treated with an antibiotic, recover normal gut permeability, thus highlighting the
involvement of gut bacteria [61,62]. Previous work has demonstrated an association between BMI and FC [45]. Additionally, dietary fat can indirectly affect gut permeability through the activation of mast cells in the intestinal mucosa [63]. Mast cells are directly related to the regulation of transcellular and paracellular gut permeability through the secretion of mediators, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1 b, IL-4, and IL-13, as well as tryptase via protease activation receptor-2 [64]. Other mechanisms that could lead a high-fat intake to be associated with increased gut permeability relate to increased ileal and proximal colonic exposure to bile acids. It is of interest that these are precisely the sites where CD is most common. Bile acids are toxic to gut epithelium and are raised by increased dietary fat intake [65]. Bile has potent antimicrobial properties that can contribute to the selection or exclusion of many potential gut microbiota. Several intestinal pathogens, however, are not only bile resistant, but are highly favored in the presence of bile, possibly through suppression of symbiotic commensal microorganisms, allowing pathogens to establish a niche in the gut. Once established, the byproducts of these bacteria can serve to infiltrate the gut mucosa, allowing for increased immune cell infiltration and tissue damage [66]. One such byproduct is hydrogen sulphide, which is a potentially mucosal toxin. In addition to its direct toxic effects, it is thought to contribute to gut inflammation through a variety of mechanisms including impaired use of short-chain fatty acids (SCFAs) [67,68].
Fig. 3. Summary of the various mechanisms in which diet affects the gut barrier and intestinal permeability.
D. Chan et al. / Nutrition 31 (2015) 1195–1203
1201
Fiber
Vitamin D
Fiber intake was linked in a population-based study to reduced levels of FC, providing evidence that fiber can affect gut inflammation and permeability [45]. Dietary fiber is fermented in the colon by specific bacteria to SCFAs, including acetate, propionate, valerate, and butyrate; with butyrate being one of the major products from this process. Butyrate regulates gene expression as a histone deacetylase inhibitor. It plays an important role in maintaining the health of the intestinal mucosa and immune regulation, by controlling the balance between epithelial cell proliferation, differentiation, and programmed cell death. Animal studies have indicated that butyrate may have antiinflammatory and antineoplastic properties [69]. In vitro studies have shown that butyrate decreases proinflammatory cytokine expression by lamina propria mononuclear cells of patients with CD via inhibition of transcription factor, nuclear factor-k degradation [70]. Lymphocyte and IL-2 production is also reduced. This work points to a possible protective effect of fiber [71]. Therefore, it has been suggested that diets low in fiber, which result in low production of SCFAs may explain the high occurrence of colonic disorders in the Western world [72]. As well as SCFAs, it is thought that the microbiota regulates inflammatory response through a number of pathways. Some commensal bacteria have been found to use fiber to produce a glycan, polysaccharide A, which has strong anti-inflammatory properties against experimental IBD in mouse models. Pepidoglycan (PGN) is another microbiota-derived product that can modulate the immune system, promoting the killing of certain bacterial pathogens. Depletion of the microbiota in mice models resulted in lower systemic PGN levels [73].
Vitamin D deficiency has been implicated as a risk factor for CD, as well as other unrelated conditions. Animal models have reported that vitamin D increases tight junction proteins and enhances healing after injury to the intestinal epithelium [78]. Very recently, the effect of vitamin D supplementation and intestinal permeability has been investigated in patients with CD, with some evidence suggesting that vitamin D plays a role in supporting gut barrier functioning [79].
Fatty acids Other fatty acids have also been implicated in changes in gut permeability. u-3 PUFAs have been found to be associated with increased expression of the epithelial tight junction protein ZO-1 in colonic tissue in mouse models. This has been shown to correlate with reduced epithelial permeability [74]. Specific u-3 PUFAs, DHA and eicosapentaenoic acid (EPA), are known to inhibit genes that activate the inflammatory process and alter the composition of cell membranes, influencing cell signaling and inflammation [11,75]. Studies on human intestinal cells have shown the long-chain PUFAs: DHA, EPA, arachidonic acid, and dihomo-g-linolenic acid are particularly effective in supporting gut barrier integrity by improving resistance and reducing IL-4–mediated permeability [76]. Food additives A recent review examined previous studies for dietary clues into the pathogenesis of CD. In addition to the traditional dietary components comprising proteins, fat, fiber, carbohydrates, vitamins, and minerals, they reviewed several studies of epidemiologic data, as well as data from animal models, on food additives and intestinal function. The authors noted that a Western diet resulted in increased exposure to emulsifiers and food preservatives and concluded that the rise in CD could be due to these additives damaging the intestinal epithelium and gut permeability [77].
Food antigens and CD It seems unlikely that changes in gut permeability can explain the response to exclusion of complex dietary antigens in active CD. It would seem more likely that in some way dietary antigens are perpetuating the inflammatory response. Immunoglobulins directed against food antigens have previously been detected in patients with CD. Early evidence of the association of food antigens in CD comes from a study examining the antibody to Saccharomyces cerevisiae (baker’s yeast), a common dietary antigen, in patients with IBD and healthy controls. It was found that IgG and IgA levels to S. cerevisiae were significantly higher in patients with CD. Anti-S. cerevisiae antibodies (ASCA) have now been established as an aid to the diagnosis of CD [80,81]. It has been found that treatment with the new anti–TNF-a agents in patients with CD, is associated with a significantly decreased ASCA IgG and IgA levels [81]. That food antigens can initiate mucosal immune responses has been demonstrated in food-sensitive IBS, where instillation of food substances to which individuals were sensitive into the duodenum induced evidence of a mucosal immune response [82]. Intraepithelial lymphocytes increased, epithelial leaks and gaps formed, and intervillous spaces widened. How this relates to CD, where the site of disease is more distal, is uncertain, but it would seem likely that at least some partially digested food antigens persist into the lower GI tract, particularly as food digestion is likely to be impaired by a number of mechanisms in active CD [82]. Furthermore, because there is improvement of CD with elemental diets, it may be the complex antigenic proteins in food that are a contributary factor in the inflammatory process of CD. To our knowledge, we were the first to look at IgG4-targeted exclusion diets in patients with CD. In the initial pilot study, 29 individuals with CD were tested for IgG4 antibodies to 14 specific food antigens. Each individual’s four most reactive foods were then excluded for a 4-wk period (see Table 2 for tested foodstuffs). Disease activity was assessed using a modified CD activity index score (mCDAI) and inflammatory markers. Twenty-six patients reported improvement in their symptoms, with a reduction in mCDAI and blood inflammatory marker [83]. It has been found that in mouse models of CD, intestinal inflammation via CD4 T-cell activation was induced by food antigens associated with high serum IgG4 levels and was improved by elimination of food antigens. The pathology for why IgG is detected in patients with CD, however, remains unclear [84]. Table 2 IgG4 Exclusion Diet Tested Foodstuffs Ig, immunoglobulin Egg white Egg yolk
Lamb Pork
Yeast Chicken
Rice Wheat
Beef Peanut
Potato Soya
Cheddar cheese Tomato
1202
D. Chan et al. / Nutrition 31 (2015) 1195–1203
Conclusion The influence of diet on the risk for CD and on disease behavior remains poorly understood. Mechanisms by which diet can influence the risk for disease are different from the mechanisms through which diet influences disease behavior. Effects on gut permeability are likely to mediate diet-related risk for disease, with effects on microbiota being the likely mechanism. When gut permeability is already disturbed in patients with CD, immune recognition of complex food antigens plays an additional role. The current contradictory state of much of the evidence for disease risk calls for the establishment of a biomarker for increased CD risk, which would allow better evaluation of the role of different dietary factors. This would permit sense checking and exploration of mechanisms of the wide range of dietary constituents that have been implicated. Formal measures of gut permeability are too cumbersome for large scale use. As yet, there is little data on the link between gut dysbiosis and levels of FC, and this is an area which requires further exploration. References [1] Sands BE. Inflammatory bowel disease: past, present, and future. J Gastroenterol 2007;42:16–25. [2] Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012;13:R79. [3] Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46–54. [4] Ng SC, Tang W, Ching JY, Wong M, Chow CM, Hui AJ, et al. Incidence and phenotype of inflammatory bowel disease based on results from the AsiaPacific Crohn’s and colitis epidemiology study. Gastroenterology 2013;145: 158–65. [5] Li X, Sundquist J, Hemminki K, Sundquist K. Risk of inflammatory bowel disease in first- and second-generation immigrants in Sweden: a nationwide follow-up study. Inflamm Bowel Dis 2011;17:1784–91. [6] Tsironi E, Feakins RM, Probert CS, Rampton DS, Phil D. Incidence of inflammatory bowel disease is rising and abdominal tuberculosis is falling in Bangladeshis in East London, United Kingdom. Am J Gastroenterol 2004;99:1749–55. [7] Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:119–24. [8] Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol 2011;106:563–73. [9] Spooren CE, Pierik MJ, Zeegers MP, Feskens EJ, Masclee AA, Jonkers DM. Review article: the association of diet with onset and relapse in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;38: 1172–87. [10] Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, De Silva P, Korzenik JR, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 2013;145:970–7. [11] Chan SSM, Luben R, Olsen A, Tjonneland A, Kaaks R, Lindgren S, et al. Association between high dietary intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid and reduced risk of Crohn’s disease. Aliment Pharmacol Ther 2014;39:834–42. [12] Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, de Silva P, Fuchs CS, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut 2014;63:776–84. [13] Chan SS, Luben R, van Schaik F, Oldenburg B, Bueno-de-Mesquita HB, Hallmans G, et al. Carbohydrate intake in the etiology of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2014;20:2013. [14] Jantchou P, Morois S, Clavel-Chapelon F, Boutron-Ruault MC, Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: the E3 N prospective study. Am J Gastroenterol 2010;105:2195–201. [15] Mendall MA, Gunasekera AV, John BJ, Kumar D. Is obesity a risk factor for Crohn’s disease? Dig Dis Sci 2011;56:837–44. [16] Khalili H, Ananthakrishnan AN, Higuchi LM, Richter JM, Fuchs C, Chan AT. 222 measures of adiposity and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 2013;144. S-48.
[17] Harpsøe MC, Basit S, Andersson M, Nielsen NM, Frisch M, Wohlfahrt J, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol 2014;43:843–55. mann M, Feagan BG, Kamm MA, Cosnes J, et al. [18] D’Haens GR, Fedorak R, Le Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn’s disease. Inflamm Bowel Dis 2009;15: 1599–604. [19] Akobeng AK, Thomas AG. Enteral nutrition for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev; 2007:CD005984. [20] Takagi S, Utsunomiya K, Kuriyama S, Yokoyama H, Takahashi S, Iwabuchi M, et al. Effectiveness of an “half elemental diet” as maintenance therapy for Crohn’s disease: a randomized controlled trial. Aliment Pharmacol Ther 2006;24:1333–40. [21] Verma S, Holdsworth CD, Giaffer MH. Does adjuvant nutritional support diminish steroid dependency in Crohns disease? Scand J Gastroenterol 2001;36:383–8. [22] Hirakawa H, Fukuda Y, Tanida N, Hosomi M, Shimoyama T. Home elemental enteral hyperalimentation (HEEH) for the maintenance of remission in patients with Crohn’s disease. Gastroenterol Jpn 1993;28:379–84. [23] Wilschanski M, Sherman P, Pencharz P, Davis L, Corey M, Griffiths A. Supplementary enteral nutrition maintains remission in paediatric Crohn’s disease. Gut 1996;38:543–8. [24] Verma S, Kirkwood B, Brown S, Giaffer MH. Oral nutritional supplementation is effective in the maintenance of remission in Crohn’s disease. Dig Liver Dis 2000;32:769–74. [25] Esaki M, Matsumoto T, Nakamura S, Yada S, Fujisawa K, Jo Y, et al. Factors affecting recurrence in patients with Crohn’s disease under nutritional therapy. Dis Colon Rectum 2006;49(Suppl 10):S68–74. [26] Yamamoto T, Nakahigashi M, Saniabadi AR, Iwata T, Maruyama Y, Umegae S, et al. Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and mucosal cytokines during remission in patients with Crohn’s disease: a prospective study. Inflamm Bowel Dis 2007;13:1493–501. [27] Ikeuchi H, Yamamura T, Nakano H, Kosaka T, Shimoyama T, Fukuda Y. Efficacy of nutritional therapy for perforating and non-perforating Crohn’s disease. Hepatogastroenterology 2004;51:1050–2. [28] Yamamoto T, Nakahigashi M, Umegae S, Matsumoto K. Enteral nutrition for the maintenance of remission in Crohn’s disease: z systematic review. Eur J Gastroenterol Hepatol 2010;22:1–8. [29] Esaki M, Matsumoto T, Hizawa K, Nakamura S, Jo Y, Mibu R, et al. Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with reference to findings determined by intra-operative enteroscopy. Scand J Gastroenterol 2005;40:1431–7. [30] Yamamoto T, Nakahigashi M, Umegae S, Kitagawa T, Matsumoto K. Impact of long-term enteral nutrition on clinical and endoscopic recurrence after resection for Crohn’s disease: a prospective, non-randomized, parallel, controlled study. Aliment Pharmacol Ther 2007;25:67–72. [31] Spinelli A, Sacchi M, Fiorino G, Danese S, Montorsi M. Risk of postoperative recurrence and postoperative management of Crohn’s disease. World J Gastroenterol 2011;17:3213–9. [32] Borowiec AM, Fedorak RN. Predicting, treating and preventing postoperative recurrence of Crohn’s disease: the state of the field. Can J Gastroenterol 2011;25:140–6. [33] Hwang C, Ross V, Mahadevan U. Popular exclusionary diets for inflammatory bowel disease: the search for a dietary culprit. Inflamm Bowel Dis 2014;20:732–41. [34] Levenstein S, Prantera C, Luzi C, D’ubaldi A. Low residue or normal diet in crohn’s disease: a prospective controlled study in Italian patients. Gut 1985;26:989–93. [35] Gunasekera AV, Rajendran N, Mendall M, Kumar D. An IgG4 specific food exclusion diet improves both clinical disease activity and quality of life in Crohn’s disease; a aandomised sham diet controlled study. Gastroenterology; 2011. S-567. [36] Wedlake L, Slack N, Andreyev HJN, Whelan K. Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis 2014;20:576–86. [37] Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005;307:1920–5. [38] Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427–34. [39] Arnott ID, Kingstone K, Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol 2000;35:1163–9. R, De Leo V, Corrao G, Martines D, D’Odorico A, Mestriner C, et al. [40] D’Inca Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am J Gastroenterol 1999;4:2956–60. [41] Benjamin J, Makharia G, Ahuja V, Anand Rajan KD, Kalaivani M, Gupta SD, et al. Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn’s disease: a randomized controlled trial. Dig Dis Sci 2012;57:1000–12. [42] Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, et al. Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020 insC mutation? Gut 2006;55: 342–7.
D. Chan et al. / Nutrition 31 (2015) 1195–1203 [43] Kucharzik T, Walsh SV, Chen J, Parkos CA, Nusrat A. Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol 2001;159:2001–9. [44] Berstad A, Arslan G, Folvik G. Relationship between intestinal permeability and calprotectin concentration in gut lavage fluid. Scand J Gastroenterol 2000;35:64–9. [45] Poullis A, Foster R, Shetty A, Fagerhol MK, Mendall MA. Bowel inflammation as measured by fecal calprotectin: a link between lifestyle factors and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2004;13:279–84. [46] Kelsen JR, Wu GD. The gut microbiota, environment and disease of modern society. Gut Microbe 2012;3:374–82. [47] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature 2012;486:222–7. [48] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022–3. [49] Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–103. [50] Hooper LV, Midtvedt T, Gordon JL. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002;22:283–307. [51] Kanauchi O, Mitsuyama K, Araki Y, Andoh A. Modification of intestinal flora in the treatment of inflammatory bowel disease. Curr Pharm Des 2003;9: 333–46. [52] D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262–7. [53] Rutgeerts P, Peeters M, Hiele M, Vantrappen G, Pennincx F, Aerts R, et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 1991;338:771–4. [54] Nuding S, Fellermann K, Wehkamp J, Stange EF. Reduced mucosal antimicrobial activity in Crohn’s disease of the colon. Gut 2007;56:1240–7. [55] Taurog JD, Maika SD, Simmons WA, Breban M, Hammer RE. Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. J Immunol 1993;150:4168–78. [56] Seksik P, Rigottier-Gois L, Gramet G, Sutren M, Pochart P, Marteau P, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut 2003;52:237–42. [57] Hedin CR, McCarthy NE, Louis P, Farquharson FM, McCartney S, Taylor K, et al. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn’s disease and their unaffected siblings. Gut 2014; 63:1578–86. [58] Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 2011;60:631–7. [59] Rajca S, Grondin V, Louis E, Vernier-Massouille G, Grimaud JC, Bouhnik Y, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn’s disease. Inflamm Bowel Dis 2014;20:978–86. [60] Tannock G. The bowel microbiotal and inflammatory bowel disease. Int J Inflamm 2010;10:4061–70. [61] Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81. [62] Shen W, Gaskins HR, McIntosh MK. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem 2014;25:270–80. [63] Ji Y, Sakata Y, Tso P. Nutrient-induced inflammation in the intestine. Curr Opin Clin Nutr Metab Care 2011;14:315–21. [64] Söderholm JD. The intestinal barrier and its regulation by neuroimmune factors. Neurogastroenterol Motil 2010;22:718–33.
1203
[65] Reddy BS, Hanson D, Mangat S, Mathews L, Sbaschnig M, Sharma C, et al. Effect of high-fat, high-beef diet and of mode of cooking of beef in the diet on fecal bacterial enzymes and fecal bile acids and neutral sterols. J Nutr 1980;110:1880–7. [66] Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/-mice. Nature 2012;487:104–8. [67] Medani M, Collins MD, Docherty NG, Baird AW, O’Connell PR, Winter DC. Emerging role of hydrogen sulfide in colonic physiology and pathophysiology. Inflamm Bowel Dis 2011;17:1620–5. [68] Hou JK, Lee D, Lewis J. Diet and inflammatory bowel disease: review of patient-targeted recommendations. Clin Gastroenterol Hepatol 2014;12: 1593–600. [69] Sabatino A, Morera R, Ciccocioppo R, Cazzola P, Gotti S, Tinozzi FP, et al. Oral butyrate for mildly to moderately active Crohn’s disease. Aliment Pharmacol Ther 2005;22:789–94. [70] Segain JP, De La Bletiere RD, Bourreille A, Leray V, Gervois N, Rosales C, et al. Butyrate inhibits inflammatory responses through NFkappaB inhibition: Implications for Crohn’s disease. Gut 2000;47:397–403. [71] Cavaglieri CR, Nishiyama A, Fernandes LC, Curi R, Miles EA, Calder PC. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci 2003;73:1683–90. [72] Scheppach W. Effects of short chain fatty acids on gut morphology and function. Gut 1994;35(Suppl 1):S35–8. [73] Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 2010;16:228–31. [74] Whiting CV, Bland PW, Tarlton JF. Dietary n3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis. Inflamm Bowel Dis 2005;11:340–9. [75] Novak TE, Babcock TA, Jho DH, Helton WS, Espat NJ. NF-kB inhibition by u-3 fatty acids modulates LPS-stimulated macrophage TNF-a transcription. Am J Physiol Lung Cell Mol Physiol 2003;284:L84–9. [76] Willemsen LE, Koetsier MA, Balvers M, Beermann C, Stahl B, van Tol EA. Polyunsaturated fatty acids support epithelial barrier integrity and reduce IL-4 mediated permeability in vitro. Eur J Nutr 2008;47:183–91. [77] Pfeffer-Gik T, Levine A. Dietary clues to the pathogenesis of Crohn’s disease. Dig Dis 2013;32:389–94. [78] Kong J, Zhang Z, Musch M, Ning G, Sun J, Hart J, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol 2008;294: G208–16. [79] Raftery T, Martineau A, Greiller C, Ghosh S, McNamara D, Bennett K, et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: results from a randomised double-blind placebo-controlled study. United European Gastroenterol J 2015;3:294–302. [80] Main J, McKenzie H, Yeaman GR, Kerr MA, Robson D, Pennington CR, et al. Antibody to Saccharomyces cerevisiae (bakers’ yeast) in Crohn’s disease. BMJ 1988;297:1105–6. [81] Frehn L, Jansen A, Bennek E, Mandic AD, Temizel I, Tischendorf S, et al. Distinct Patterns of IgG and IgA against food and microbial antigens in serum and feces of patients with inflammatory bowel diseases. PLoS One 2014;9:e106750. [82] Fritscher-Ravens A, Schuppan D, Ellrichmann M, Schoch S, Röcken C, Brasch J, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 2014;147:1012–20. [83] Rajendran N, Kumar D. Food specific IgG4-guided exclusion diets improve symptoms in Crohns disease da pilot study. Colorectal Dis 2010;13: 1009–13. [84] Kawaguchi T, Mori M, Saito K, Suga Y, Hashimoto M, Sako M, et al. Food antigen-induced immune responses in Crohn’s disease patients and experimental colitis mice. J Gastroenterol 2014;50:1–12.