Recent advances in clinical practice
Gut: first published as 10.1136/gutjnl-2017-315866 on 18 May 2018. Downloaded from http://gut.bmj.com/ on August 30, 2021 at University of Maastricht Consortia. Protected by copyright.
1
Pediatric Gastroenterology and
Nutrition Unit, Edith Wolfson
Medical Center, Holon, Israel
2
Tel Aviv University, Tel Aviv,
Israel
3
Department of Pediatrics,
University of Alberta, Edmonton,
Alberta, Canada
Correspondence to
Professor Arie Levine, Paediatric
Gastroenterology and Nutrition
Unit, Wolfson Medical Center,
Holon 58100 Israel; ​arie.​levine.​
dr@g​ mail.​com
Received 2 January 2018
Revised 16 April 2018
Accepted 17 April 2018
Published Online First
18 May 2018
To cite: Levine A, Sigall
Boneh R, Wine E. Gut
2018;67:1726–1738.
1726   Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866
Evolving role of diet in the pathogenesis and
treatment of inflammatory bowel diseases
Arie Levine,1,2 Rotem Sigall Boneh,1,2 Eytan Wine3
Abstract
Recent advances in basic and clinical science over the
last 3 years have dramatically altered our appreciation
of the role of diet in inflammatory bowel diseases
(IBD). The marked increase in incidence of these
diseases along with the important role of non-genetic
susceptibility among patients with IBD has highlighted
that these diseases have a strong environmental
component. Progress in the field of microbiome and
IBD has demonstrated that microbiome appears to
play an important role in pathogenesis, and that diet
may in turn impact the composition and functionality
of the microbiome. Uncontrolled clinical studies have
demonstrated that various dietary therapies such as
exclusive enteral nutrition and newly developed exclusion
diets might be potent tools for induction of remission at
disease onset, for patients failing biologic therapy, as a
treatment for disease complications and in reducing the
need for surgery. We review these advances from bench
to bedside, along with the need for better clinical trials to
support these interventions.
Introduction
The basic understanding of how and why IBD
develop has been the focus of research of many
disciplines over the last few decades, especially
given the complex, multifactorial nature of these
conditions. The discovery of NOD2 as the first,
and most important, susceptibility gene1 2 was then
followed by identification of over 200 other loci,3 4
but these genetic contributions together likely only
explain 19%–26% of the hereditary variance of
IBD.5 Genetic studies have identified defects in
innate immunity in Crohn disease (CD) and altered
barrier function in Ulcerative Colitis (UC) as some
of the key players in disease susceptibility.6 7
The intestinal barrier comprises the mucous
layer, epithelial cells and the tight junctions between
cells, rendering the mucosa relatively imperme-
able to bacteria. Some of the early changes in the
sequence of events, leading to IBD are seen in the
epithelial and mucus layers,8–10 which is particu-
larly evident in patients with UC.11 12 The mucous
layer is a critical barrier separating commensal and
pathogenic bacteria from the epithelium, thereby
decreasing immune activation. Both CD and UC
are characterised by high penetration of the mucous
layer by bacteria and increased barrier permea-
bility.11 13 Increased barrier dysfunction during
remission has been associated with clinical relapse
of the disease.14 15
CD and UC are characterised by the presence of
mucosal bacteria16 that differs from healthy human
Significance of this study
What is already known?
►► Diet has been implicated in the pathogenesis
of Crohn disease (CD) and Ulcerative Colitis
(UC). Dietary factors may have a plausible role
in altering the microbiota, metabolome, host
barrier function and innate immunity.
What is new?
►► Exclusive enteral nutrition has demonstrated
efficacy for induction of remission, as well
as treatment of complications such as
inflammatory strictures, intrabdominal abscess
and enterocutaneous fistulae in Crohn disease.
Use or preoperative exclusive enteral nutrition
for ≥4 weeks may reduce the need for surgical
resections.
►► Preliminary reports from uncontrolled studies
suggest that specific exclusion diets based on
partial enteral nutrition and specific whole
foods may induce remission and can be used
as a salvage therapy after loss of response to
biologics or combination therapy.
How might it impact on clinical practice?
►► Dietary interventions ranging from dietary
education of patients to exclusive enteral
nutrition and newer elimination diets may have
the potential to better control disease or avoid
complications, pending better clinical trials.
There are insufficient data at the present time
to suggest that dietary therapy may be useful in
UC; this is an important research gap.
hosts, in which bacteria for the most part do not
reside adjacent to the mucosal epithelium (figure 1A,
B).13 In fact, increased epithelial cell shedding, high
vascular flow, depletion of the small bowel mucus
layer and presence of mucosa-associated bacteria
have been demonstrated in non-inflamed duodenum
and ileum of children with UC.17–19 Both CD and UC
appear to involve translocation of bacteria through
the epithelium.20 Thus, impaired barrier function,
defects in innate immunity, changes in microbial
composition and the presence of mucosa-associated
and translocating bacteria have all been described
in IBD. However, differences do exist between CD
(figure 1A) and UC (figure 1B).
Dysbiosis is more prominent in CD.21 The
predominance of Proteobacteria, specifically indi-
vidual Escherichia coli strains, especially in CD, has
been known for many years22 23; however, whether
or not this reflects a true role in driving disease

Figure 1  Western diet and pathogenesis of IBD. (A) Proposed pathogenesis of Crohn disease and effects of western diet. (B) Proposed pathogenesis
of UC and effects of western diet observations that can be associated with western diet appear in the marked boxes. Tregs, regulatory T cells.
or just a change in the gut setting (eg, due to higher oxygen
tension, related to inflammation) remains controversial; it is safe
to say that both processes are likely and that the diversity of
disease presentation and course likely represent different levels
of microbial involvement in different individuals.24 The pres-
ence or decline in specific mucosal genera have been identified
in children and adults with IBD.21 25 26 Several researchers have
demonstrated that patients with UC appear to have diminished
ability to produce short chain fatty acids (SCFA), even with an
abundant supply of substrates,27 28 suggesting that microbial
metabolic dysfunction may play an important role in UC.
Background: diet and IBD
Diet is one of the key players in the normal gut microenvironment,
impacting microbial composition, function, the gut barrier and
host immunity. Alterations in single food groups have far ranging
implications. For example, depriving colonic microbes from fibre
in rodent models will favour taxa that can use alternative carbon
sources found within the colonic mucus; this then leads to depletion
of the mucus layer, disruption of the barrier, immune activation and
tissue damage.29 Changing from a plant-based to an animal-based
diet radically changes bacterial taxa and metabolism, leading to
alterations in bile acids and sulfide metabolism, both of which may
play a role in IBD.30 Recent data suggest that the most important
Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866
Recent advances in clinical practice
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factors regulating compositional changes are access to calorie,
carbohydrate and protein intake.31 Since diet has such an important
role in gut homeostasis, and interacts with the microbiome, host
barrier and immunity, we will explore the possible and plausible
role of dietary factors in the pathogenesis of IBD.
Clues from epidemiology
Numerous epidemiological studies with inconsistent methodolog-
ical quality have demonstrated associations between the intake
of specific dietary components or dietary patterns and the risk of
developing IBD.32–39 One of the earliest epidemiological associ-
ations with IBD is the strong protective role of breast feeding.
Although recall bias needs to be considered, almost all studies from
various regions support this dose-dependent association, which is
also demonstrated for other immune-mediated conditions.40 The
results from other epidemiological studies should be considered
with caution due to a recall bias and possible dietary modification
before the diagnosis of IBD.41 A statistical association between
specific dietary factors and disease does not necessarily imply
causation. In any complex disease with dietary triggers, it may be
difficult to unravel the role of individual dietary risk factors since
dietary patterns often involve exposures to clusters of foods. In
addition, certain dietary ingredients are likely to cluster together
due to industrial processing of food. For example, fat exposure
1727
 Recent advances in clinical practice
will likely be associated with emulsifier exposure, processed meats
with preservatives, dairy products with thickening agents and
emulsifiers, etc. In addition, food frequency questionnaires may
be insufficient to address longitudinal exposures.
D’Souza et al conducted a case-control study to assess the dietary
patterns of Canadian children and the risk of developing CD. They
evaluated multiple dietary patterns including western diet and a
prudent diet. A dietary pattern characterised by meats, fatty foods
and desserts (western diet) increased the risk for CD in females (OR
4.7, 95% CI 1.6 to 14.2), whereas the consumption of vegetables,
fruits, olive oil, fish, grains and nuts (prudent diet) was associated
with a decreased risk for developing CD in both males and females
(females: OR 0.3, 95% CI 0.1 to 0.9; males: OR 0.2, 95% CI 0.1
to 0.5).33 A recent Australian population-based study of environ-
mental risk factors demonstrated an increased risk for CD with
frequent consumption of fast food (western diet) before diagnosis.42
Several studies have associated protein with increased risk for
IBD.32 35 36 As part of the E3N prospective study, which included
67 581 French women, high animal protein was associated with
a significantly increased risk of IBD (OR 3.03, 95% CI 1.45 to
6.34), particularly with UC (OR 3.29, 95% CI 1.34 to 8.04).32
Vegetable protein intake was not associated with either disease.
However, other smaller studies have not confirmed this.43 In a
separate study evaluating dietary intake and relapse of UC, red
meat was found to have the strongest association (OR 5.19,
95% CI 2.09 to 12.9) with relapse.36
Data regarding the associations between increased intakes of
carbohydrates and the risk for IBD are inconsistent. The E3N
study did not identify carbohydrate intake as a risk factor for
IBD, CD or UC.32 Racine et al, evaluated 366 351 participants
with IBD from theEuropean Prospective Investigation into
Cancer and Nutrition (EPIC) study cohort and found no correla-
tion between dietary intake patterns and CD.34 They did find
an association between high-sugar and low-fibre intake and UC
(OR 1.68, 95% CI 1.00 to 2.82).
More recent data from the EPIC study found no associa-
tion between alcohol consumption and the risk for CD.44 This
contrasted with the study by Jowett et al,36 who tried to find
dietary products associated with the relapse of UC. High alcohol
consumption was associated with an increased risk of relapse
(OR 2.71, 95% CI 1.1 to 6.67).
Dietary fats are associated with an increase or decrease risk
for IBD, depending on the type of fat. Among 170 805 women
followed over 26 years, a high intake of dietary long-chain n-3
polyunsaturated fatty acids was associated with a reduced risk of
UC. In contrast, high intake of transunsaturated fats was associ-
ated with an increased risk of UC.37
Perhaps the dietary component with the greatest agreement in
epidemiological studies is dietary fibre, which is also represented
in the prudent dietary patterns mentioned above. Multiple
studies reported a negative association between dietary fibre
intake from fruits or fruits and vegetables and subsequent risk
for CD.33 37 Data from the Nurses’ Health Study among 170 776
participants showed that higher long-term intake of fruit was
associated with lower risk of CD but not UC.37
Several research gaps remain in this field, including more data
about exposure to industry-added ingredients, such as emulsi-
fiers, preservatives and thickening agents, including maltodex-
trins and carrageenans.
Diet and altered host immunity
Host factors that may play an important role in pathogenesis or
active inflammation include defects in barrier function, depletion
1728
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of the intact mucous layer, decreased regulatory T cells (Tregs) and
impaired bacterial clearance mechanisms (figure 1A, B). A major
limitation to date is that most of the evidence comes from animal
models and human cell lines, which makes extrapolation difficult.
Dietary factors that may affect host immunity are presented in
table 1 and figure 2. Western diet is characterised by alterations
in the amount of exposure to natural dietary ingredients such as
high fat (HF), high sugar (HS), high wheat and high dairy expo-
sure, accompanied by low fibre exposure, and by high exposure
to multiple food additives.45 46 We will focus our discussion on
the dietary products with the most evidence from animal models,
which include fibre, animal fat, wheat and food additives.
Low dietary fibre, identified through epidemiological studies
as a possible risk factor,33 37 could affect host immunity via
multiple pathways. Fibres and starches found in fruits and vege-
tables are a vital substrate for the production of butyrate and
other SCFAs. Butyrate plays an important role in downregulating
inflammation by suppressing transcription of cytokines and
increasing differentiation and the population of lamina propria
Tregs.47 48 Butyrate can also enhance innate immunity by upreg-
ulating defensins and cathelicidins in animal models.47 48 Low
dietary fibre may cause catabolism of the mucous layer, leading
to increased permeability of the mucous layer, and allowing
increased contact between luminal bacteria and the epithelium.29
HF or HF/HS diets may act synergistically to a low fibre diet
as they may exert many of the same effects described above for
low fibre exposure. An HF/HS diet in a CEACAM 10 rodent
model has been shown to decrease MUC2 expression and goblet
cell mucous while increasing intestinal permeability.49 These
diets have been demonstrated to decrease both butyrate produc-
tion and expression of the butyrate GPR43 receptor, which is
underexpressed in CD.49 Finally, HF diets (without HS) have
been shown to increase tumour necrosis factor (TNF)-α and
interferon-γ expression and decrease levels of colonic Tregs.50
Exposure to gluten may promote an inflammatory state, impair
innate immunity or increase intestinal permeability. Dietary
gluten significantly decreased intestinal Tregs in non-obese
diabetic mice fed gluten compared with standard chow.51 Dietary
gluten was also shown to induce ileitis in TNFΔARE/WT mice
via an increase in intestinal permeability,52 which has been iden-
tified as a factor associated with relapse in CD.14
Alpha-amylase/trypsin inhibitors, found in wheat, may have a
pro-inflammatory role. They are activators of human dendritic cells
and macrophages, driving intestinal inflammation in rodents.53 54
Multiple food additives, commonly present in western diet,
may affect host barrier function or immunity. Chassaing et al,
demonstrated that IL-10−/− mice exposed to two common emul-
sifiers, carboxymethylcellulose and polysorbate-80, developed
increased intestinal permeability and significant thinning of the
mucous layer, leading to increased proximity of the microbiota
to the intestinal epithelium.55 Maltodextrins, used as thickeners
and sweeteners, have demonstrated the ability to affect mucosal
proximity (by a presumed effect on mucous layer thickness)
and to impair clearance of intracellular Salmonella.56 57 Carra-
geenans, used for texture and as thickening agents in the dairy
and sauce industry, may induce intestinal permeability.58 59 Other
factors, which may promote intestinal permeability are listed in
table 1 and are beyond the scope of this paper.
Diet and microbiota
Dietary components linked to changes in the microbiome that
have been associated with IBD appear in table 2 and figure 3. For
example, adherent invasive E. coli (AIEC) strains cannot induce
inflammation under normal conditions. Pathogenicity may arise
Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866
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Table 1  Dietary factors potentially affecting host barrier and immunity
Dietary component Reference Model Effect
Natural components
 High fat+high sugar diet Martinez-Medina. Gut, CEABAC 10 mice ►► Decreased MUC2 expression
201449 ►► Depleted Goblet cells
►► Increased intestinal permeability
►► Increased TNF-α secretion
 High fat+high sugar diet Agus. Sci Rep, 201660 CEABAC 10 mice ►► Decreased FoxP3 Tregs in mesenteric lymph nodes
►► Decreased butyrate production
►► Reducedexpression of the butyrate GPR43 receptor
►► Dysbiosis
►► Significantly decreased SCFA concentrations
 High fat diet Ma. Clin Exp Immunol, WT C57BL/6 mice ►► Higher numbers of non-CD1d-restricted natural killer T cells in the colonic
200850 IEL
►► Increased TNF-α and IFN-γ expression
►► Decreased levels of colonic Tregs
 High fat diet Suzuki. Nutri & Metab, LETO and ►► Increased intestinal permeability
2010101 OLETF rats (mutant obese Long-Evans) ►► Decreased tight junction proteins expression (claudin-1, claudin-3, occludin
Human intestinal Caco-2 cells and junctional adhesion molecule-1)
 High fat diet Gruber. PLoS One, 2013102 TNFΔARE/WT mouse and WT C57BL/6 ►► Aggravation of ileal inflammation
►► Reduced expression of occludin
►► Increasedtranslocation of endotoxin
►► Increased pro-inflammatory markers
►► Recruitment of dendritic cells and Th17-biased lymphocyte into the lamina
propria
 Sodium caprate Söderholm. Dig Dis Sci, Rat ileum ►► Increased tight junction permeability
(constituent of milk fat) 1998103
Söderholm. Gut, 2002104 Specimens from the distal ileum of ►► Rapid increased in paracellular permeability
patients with CD
 Gluten Ejsing-Duun. Scand J NOD and BALB/c mice ►► Decreased the occurrence of Tregs by 10%–15% (p<0.05)
Immunol, 200851
 Gluten Wagner. Inflamm Bowel TNFΔARE/WT mouse ►► Increased intestinal permeability
Dis, 201352 ►► Reduced occludin expression
►► Induced chronic ileitis
 Gluten (gliadin) Lammers. Human intestinal epithelial cell, Caco2 ►► Zonulin released, causedtight junction disassembly
Gastroenterology, 2008105 cells
IEC6 cells
 Gluten (gliadin) Hollon. Nutrients, 2015106 Ex vivo human duodenal biopsies ►► Increased intestinal permeability
►► Higher concentration of IL-10 in controls compared with coeliac disease in
remission or gluten sensitivity
 Wheat (ATIs) Junkers. J Exp Med, Human cells and biopsies ►► ATIs are potent activators of human innate immune responses in
201254 monocytes, macrophages and dendritic cells
 Wheat (ATIs) Zevallos. TLR4-responsive mouse and human ►► Activation of dendritic cells in mesenteric lymph nodes
Gastroenterology, 201753 cell lines ►► Released inflammatory mediators
 Soluble fibres and resistant Bassaganya-Riera. J Nutr, C57BL/6J WT mice ►► Decreased ileal and colonic inflammatory lesions
starch 2011107 IL-10−/− mice ►► Decreased IFN-γ production by effector CD4+ T cells from Peyer’s patches
►► Resistant starch increased the IL-10-expressing cells
►► Suppressed gut inflammation
 Dietary pectin Ye. J Agric Food Chem, IL-10−/− mice ►► Reduced expression of TNF-R and GATA-3
2010108 ►► Lower levels of IgE, IgG and IgM expression
►► Modulation of production of pro-inflammatory cytokines and
immunoglobulins
 Fermentable fibre (guar Hung. J Nutr, 2016109 BALB/c mice aged 7 weeks ►► Increased expression of occludin and claudin-3, claudin-4 and claudin-7
gum, partially hydrolysed (reduced permeability)
GG) ►► Greater total faecal SCFA concentrations
►► Reduced inflammation score
 Multifibre mix diet Wang. JCC, 201647 IL-10−/− mice ►► Reduced disease activity index score
►► Decreased CD4+CD45+ lymphocytes, IFN-γ/IL-17A, TNF-α/TNF-R2 mRNA
expression
►► Increased Tregs and SCFA production
►► Increased epithelial expression and correct localisation of tight junction
proteins
 Alcohol Forsyth. Alcohol Clin Exp Mice ►► Colonic (but not small intestinal) hyperpermeability
Res, 2017110 ►► Decreased butyrate/total SCFA ratio in stool
 Dietary salt Tubbs. J Immunol, 2017111 IL-10−/− murine model of colitis ►► Exacerbation of inflammatory pathology
►► Enhanced expression of numerous pro-inflammatory cytokines
►► TLR4 activation

Continued
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Table 1  Continued 
Dietary component Reference Model Effect
Food additives
 Carboxymethylcellulose Chassaing. Nature, IL-10−/− mice ►► Increased intestinal permeability
(E466) and polysorbate-80 201555 ►► Mucous layer depletion led to increased proximity of the microbiota to the
(E433) intestinal epithelium
 Carboxymethylcellulose Swidsinski. Inflamm IL-10−/− mice ►► Distension of spaces between villi, with bacteria filling these spaces
(E466) Bowel Dis, 2009112
 Maltodextrin Miyazato. Biosci BALB/c mice ►► Increasedtotal IgA levels in the intestinal tract
Microbiota Food Health,
2016113
 Carrageenan (E407) Choi. Toxicol Lett, 201259 HCT-8, HT-29 and Caco-2 cells ►► Lowered transepithelial resistance
►► Discontinuous and irregular ZO-1 expression
Fahoum. Mol Nutr Food Caco-2 cell model ►► Redistribution of the tight-junction protein ZO-1
Res, 201758 ►► Increased intestinal permeability
 Titanium dioxide (TiO2) Ruiz. Gut, 2017114 WT and NLRP3−/− mice with DSS ►► Oral administration of TiO2 worsened acute colitis through a mechanism
involving the NLRP3 inflammasome
►► Induced reactive oxygen species generation
►► Increased epithelial permeability in IEC monolayers
ATI, α-a mylase/trypsin inhibitors; CD, Crohn disease; IFN, interferon; IL, interleukin; SCFA, short chain fatty acids; Th, T helper; TNF, tumour necrosis factor; Tregs, T regulatory cells;
WT, wild-type; ZO, zonula occludens. IEL (intrepithelial lymphocyes), DSS (dextran sulfate sodium).

if the ligand CEACAM 6 is presented by intestinal epithelial and
M cells. Under these conditions, AIEC may form small intestinal
biofilms, adhere and translocate via M cells, and then invade the
associated epithelium. An HF/HS diet may promote colonisation
with IBD-associated pathobionts. CEABAC 10 mice, expressing
CEACAM 6, fed HF/HS but not standard chow were rapidly
colonised by mucosa-associated AIEC and presented higher
degrees of crypt abscesses when compared with the standard
chow group.49 Transplantation of faeces from HF/HS-treated
mice to germ free mice increased susceptibility to AIEC.60 A
study that compared HF with HS diet in a mouse model demon-
strated that HF but not HS induced dysbiosis, characterised
by an increase in Proteobacteria and a decrease in Firmicutes,
similar to that seen in CD.61 HF diets result in accumulation of
secondary bile acids, such as deoxycholic acid, which in turn can
inhibit the growth of members of the Bacteroidetes and Firmic-
utes phyla, characteristic of the dysbiosis found in CD.62
Maltodextrins have been shown to promote AIEC biofilm
formation independent of the presence of the ligand CEACAM 6,
while AIEC growth in medium was enhanced particularly with
polysaccharides used as thickening agents, such as maltodextrin
and xanthan gum, but not by glucose or sucrose.63
The source of dietary fat may play an important role in
promoting colitogenic bacteria. Devkota et al reported an

Figure 2  Possible effects of dietary factors on host barrier and immunity leading to IBD (based on cell lines and animal models). Tregs, regulatory T cells.
1730 Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866
 Recent advances in clinical practice

Table 2  Dietary factors potentially affecting the microbiota in IBD
Dietary component
Natural components
 High fat+high sugar diet
 High fat+high sugar diet
 High fat vs high sugar
 Milk fat (saturated fat)
 High fibre diet
 Fibre
 Animal vs plant diet
 Alcohol
Food additives
 Carboxymethylcellulose
(E466) and polysorbate-80
(E433)
 Carboxymethylcellulose
(E466)
 Polysorbate-80
 (E433)
 Plantain and broccoli fibre
 Maltodextrin
 Carrageenan (E407)
AIEC, adherent invasive E. coli ; SCFA, short chain fatty acids; Th, T helper.
Reference
Martinez-Medina. Gut, 201449
Agus. Sci Rep, 201660
Lai. Environ Pollut, 201661
Devkota. Nature, 201264
Silveira. Eur J Nutr, 2017115
James. GUT, 201528
David. Nature, 201430
Forsyth. Alcohol Clin Exp Res,
2017110
Chassaing. Nature, 201555
Chassaing. GUT, 201766
Swidsinski. Inflamm Bowel Dis,
2009112
Roberts. Gut, 201065
Nickerson. PLoS One, 201263
Nickerson. Gut Microbes, 201556
Munyaka. Front Microbiol,
2016116
Gut: first published as 10.1136/gutjnl-2017-315866 on 18 May 2018. Downloaded from http://gut.bmj.com/ on August 30, 2021 at University of Maastricht Consortia. Protected by copyright.
Model Effect
CEABAC 10 mice ►► AIEC Colonisation
►► Low diversity
►► Dysbiosis
►► Higher degree of crypt abscesses
CEABAC 10 mice ►► Intestinal mucosa dysbiosis
►► Decreased butyrate production
►► Reduced expression of the butyrate GPR43 receptor
►► Overgrowth of Escherichia coli
►► Significantly decreased SCFA concentrations
CD1 mice ►► High fat but not high sugar induced dysbiosis characterised by an increase
in Proteobacteria and a decrease in Firmicutes and Clostridia
►► Growth induction of the family Helicobacteraceae
IL-10−/− mice ►► Promoted expansion of sulfite-reducing pathobiont, Bilophila
wadsworthia
►► Induced pro-inflammatory Th1 immune response
►► Increased incidence of colitis
►► Low diversity
►► Dysbiosis
BALB/c female mice ►► High fibre diet protected from acute colitis
Patients with UC and ►► High fibre diet did not increased SCFA production in patients with UC
controls
Healthy volunteers ►► Animal-based diet increased the abundance of bile-
tolerant  microorganisms and decreased the levels of Firmicutes
Mice ►► Decreased butyrate/total SCFA ratio in stool
IL-10–/– mice ►► Increased mucosal-associated bacteria
Human intestinal microbial ►► Increased Flagellin expression
ecosystem (M-SHIME) ►► P-80 altered species composition
IL-10–/– mice ►► Bacterial overgrowth
►► Distension of spaces between villi, with bacteria filling these spaces
►► Adherence of bacteria to the mucosa
►► Migration of bacteria to the bottom of the crypts of Lieberkühn
M cells ►► Increasedtranslocation of E. coli across M cells
Caco-2 cells
Human Peyer’s patches ►► Reduction in translocation of E. coli across M cells
Human intestinal epithelial ►► Biofilm formation AIEC
cell monolayers ►► Enhanced E. coli adhesion independent of the cellular receptor CEACAM 6
Piglet model of IBD ►► Decreased bacterial species richness
►► Shifted community composition.
►► Bacterial dysbiosis

increase in colitis severity after exposure to milk fat diet but not
to isocaloric polyunsaturated fatty acid diet or a low fat diet in
IL-10−/− mice.64 Colitis was associated with the bloom of coli-
togenic Bilophila wadsworthia in the milk fat group, which was
dependent on milk fat, and induced taurine conjugated bile acids.
Interestingly, emulsifiers may affect the microbiome as well as the
host. The emulsifier polysorbate-80 was associated with increased
translocation of AIEC through M cells and the follicular associated
epithelium; this effect was suppressed by certain dietary fibres.65
Emulsifiers appear to affect compositional changes associated with
inflammation. Polysorbate-80 induced inflammation and flagellin
expression via alteration of microbial dysbiosis, whereas the emul-
sifier carboxymethylcellulose rapidly induced flagellin and alter-
ations in gene expression for flagellin in a model for gut dysbiosis.66
Exclusion of western diet by exclusive enteral nutrition (EEN) or an
exclusion diet in children with CD were shown to cause a marked
reduction in Proteobacteria and in taxa associated previously with
CD including Escherichia, Haemophilus, Veillonella and Fusobac-
teria  (Van Limbergen and Dunn, unpublished data).
Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866
The metabolic activity of the microbiota may be as important,
or even more important than compositional changes, especially in
UC. Both CD and UC are characterised by a decrease in SCFA-pro-
ducing genera, which are stimulated by the presence of dietary fibre.
However, UC seems to be characterised by deficient production of
SCFA, even when substrates such as resistant starch are provided.27 28
Sulfide-reducing bacteria and increased sulfide production have been
reported in UC.27 Animal protein-based diets favour production of
sulfide reductases and sulfide-reducing bacteria.30
In summary, high animal or dairy fat, animal protein, wheat,
emulsifiers and thickeners appear to top the list of candidate
foods associated with intestinal inflammation in animal models.
Diet as a therapeutic intervention
Recent studies have expanded our understanding of the possible
roles for dietary therapy, primarily in CD. Dietary therapies, such
as EEN, were traditionally and primarily used to induce remis-
sion in early or new-onset CD67 or as supportive therapy in chil-
dren and adults with malnutrition or in the preoperative setting.
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 Recent advances in clinical practice
Figure 3  Possible effects of dietary factors on microbiota leading to IBD (based on cell lines and animal models).
EEN involves the exclusive use of a liquid nutrition in the form
of medical formulas, without exposure to other foods, usually for
6–8 weeks (table 3). This effect does not depend on the protein
source (type of formula), but is very dependent on exclusion of
ordinary table food.68 69 Newer open-label studies have demon-
strated that existing and new dietary strategies may have a wider
role and can be employed to maintain remission, induce remission
in patients failing biologics and for patients with complicated disease
(figure 4). As data from randomised controlled trials (RCTs) are
absent or pending, we will confine ourselves to more recent studies
that have expanded our understanding beyond the use of EEN at
diagnosis for induction of remission, which is reviewed elsewhere.67
Induction of remission
Several recent paediatric studies have demonstrated and confirmed
that EEN may induce remission in 60%–86% of children accom-
panied by a significant decrease in inflammatory markers such as
erythrocyte sedimentation rate (ESR), C reactive protein (CRP)
and faecal calprotectin.69–73 This recent body of literature has
evaluated long-term benefits associated with use of EEN in mild-
to-moderate paediatric CD. In comparison to use of steroids and
corrected for disease severity, EEN was associated with higher
remission rates, better growth and longer steroid-free periods,71 72
but did not differ with regard to other outcomes such as relapse.
Cohen-Dolev et al demonstrated that EEN was superior to
corticosteroids for induction of remission and linear growth in
a multicentre prospective inception cohort of mild-to-moderate
CD at diagnosis. EEN was not superior with respect to other
outcomes such as time to relapse or complications over 2 years.72
Grover et al performed a prospective trial to assess mucosal
healing by performing colonoscopy before and after 8 weeks of
EEN with azathioprine. At the end of 8 weeks, complete mucosal
healing was observed in 33%, near complete in another 19% of
patients.73 Patients who achieved complete mucosal healing had
better sustained remission over 3 years of follow-up.
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Use of EEN poses challenges to physicians and patients
alike, as patients have to deal with monotony of food and
taste fatigue. Furthermore, up to 50% of patients may require
nasogastric tubes and many might refuse to start therapy
due to these issues.74 75 This limits access and availability of
the therapy. Therefore, it is no surprise that the last 3 years
have seen several attempts to achieve the effect of EEN while
allowing access to whole foods. Investigators from three
centres in the USA and Canada compared outcomes from three
cohorts treated with either: 1) high volume partial enteral
nutrition (PEN) using a mean of 77% of estimated energy
requirements from PEN with free access to food; 2) EEN and
3) infliximab. Clinical remission rates were similar between
infliximab and EEN (73%–76%) and lower (50%) in the PEN
group. Faecal calprotectin <250 g/dL as an inflammatory end
point was found only in 14% of patients treated with PEN
and ad libitum diet, compared with 45% with EEN and 62%
treated with infliximab at week 8. This suggests that high-
volume PEN with access to free diet is ineffective at improving
inflammation compared with EEN or infliximab, reaffirming
the principle of exclusivity.67 68
Other research groups have employed a different strategy based
on the combination of PEN with a specific exclusion diet that
allows access to whole foods. This review will be confined only to
studies that evaluated clinical remission and objective markers of
inflammation or mucosa healing. The Crohn’s disease exclusion
diet was developed based on the principles outlined in figures 1–3,
by excluding foods that have been associated with altered host
barrier or bacterial clearance, dysbiosis and virulence factors
that may allow bacteria to become mucosa-associated and enable
translocation, based on the bacterial penetration cycle hypothesis
for CD first proposed by the authors.76 The premise behind this
theory is that CD is caused by mucosal and translocating bacteria.
This diet was evaluated initially in 47 children and adults with
mild-to-moderate disease. Clinical remission was achieved in
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 Recent advances in clinical practice

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Table 3  Key studies and recent advances with EEN in children and adults
Duration of
Study design Population EEN Comparator Number of patients Outcome Key findings Reference
Randomised Adults 3–6 Weeks EEN vs CS and EEN: 51 pts Improvement in CDAI: Equal effectiveness of Malchow. Scand
controlled trial sulfasalazine Drugs: 44 pts EEN: 41% EEN compared with J Gastroenterol,
Drugs: 72% drugs per protocol 1990117
p<0.05
Randomised Adults 4–6 Weeks EEN vs CS and EEN: 52 pts Remission: Comparison to Lochs.
ccontrolled trial sulfasalazine Drugs: 55 pts EEN: 55% medications Gastroenterology,
Drugs: 74% 1991118
p<0.01
Randomised Adults 4 Weeks EEN: n-6 PUFA vs MUFA: 20 pts Remission rates (ITT): Composition of fat Gassull. Gut,
ccontrolled trial MUFA vs CS with PUFA: 23 pts MUFA EEN: 20% 2002119
ward diet CS: 19 pts PUFA EEN: 52%
CS: 79%
p=0.001
Randomised Paediatric CD 6 Weeks Elemental formula vs Elemental fomula: 16 pts Remission: Polymeric equivalent to Ludvigsson. Acta
ccontrolled trial polymeric formula Polymeric formula: 17 pts Elemental: 69% elemental Paediatr, 2004120
Polymeric: 82%
p=0.44
Randomised Paediatric CD 6 Weeks EEN vs 50% PEN EEN:24 pts Remission: Principle of exclusivity Johnson. GUT,
ccontrolled trial with free diet PEN: 26 pts PEN: 15% 200668
EEN: 42%
p=0.035
Randomised Newly diagnosed 10 Weeks Polymeric formula EEN: 19 pts Remission: Mucosal healing Borrelli. Clin
ccontrolled trial paediatric CD vs CS CS: 18 pts polymeric EEN: 79% comparing EEN with CS Gastroenterol
CS: 67% Hepatol, 2006121
p=0.4
Mucosal healing EEN: 74%
CS: 33%
p<0.05
Retrospective Paediatric CD 8 Weeks Oral vs continues Oral: 45 pts Remission: Oral equivalent to Rubio. Aliment
enteral feeding Enteral: 61 pts Oral EEN: 75% enteral feeding Pharmacol Ther,
Tube EEN: 85% 2011122
p=0.157
Prospective Adults 4 Weeks – EEN: 13 pts Significant improvement in Improvement of quality Gou. Nutr Clin
uncontrolled quality of life of life Pract, 2013123
Clinical remission: 84.6%
Prospective Newly diagnosed 6–8 Weeks EEN vs CS mild-to- 5-ASA: 29 pts CS-free remission week 12: EEN superior to CS Levine. IBD, 201470
inception cohort children moderate CD EEN: 43 pts EEN: 71% for reduction of
CS: 114 pts CS: 46% inflammation
5-ASA: 55%
p=0.0006
NCR:
EEN: 39%
CS: 25%
5-ASA: 24%
Prospective cohort Paediatric CD 6 Weeks EEN vs healthy EEN: 15 pts EEN: decreased butyrate, EEN mechanism Gerasimidis. IBD,
control HC: 21 pts decreased diversity, 2014124
Faecalibacterium prausnitzii
concentration decreased
Prospective cohort Newly diagnosed 6 Weeks Mild-to-moderate 34 Children Clinical remission: 84% Mucosal healing Grover. J
paediatric CD EEN with thiopurine Early good endoscopic Gastroenterol,
response: 58% 2014125
Complete transmural healing
ileal CD: 21%
Prospective cohort Paediatric CD 8 Weeks EEN vs anti-TNF vs Anti-TNF: 52 pts Clinical response: PEN- 64% Comparison with anti- Lee. IBD, 201569
PEN with ad libitum EEN: 22 pts EEN- 88% TNF
diet PEN: 16 pts Anti-TNF - 84% EEN reduced
p=0.08 FCP<250 mg/g: calprotectin
PEN: 14%
EEN -45%
Anti-TNF- 62%
p=0.001
Retrospective Newly diagnosed 8–16 Weeks EEN vs CS EEN:76 pts EEN: 86.6% remission vs CS: Reduced need for Connors. JCC,
paediatric CD CS 35 pts 58.1% steroids 201771
p<0.01 
Prospective Newly diagnosed 6–8 Weeks EEN vs CS EEN: 60 pts Remission: EEN superior to CS Cohen Dolev. JCC,
inception cohort children CS: 87 pts CS: 47% 201872
EEN: 63%
p=0.036 
5-ASA, 5-aminosalicylic acid; CD, Crohn disease; CDAI, Crohn’s Disease Activity Index; CS, corticosteroids; EEN, exclusion enteral nutrition; FCP, faecal calprotectin; ITT, intention to treat;
MUFA, monounsaturated fatty acids; NCR, normal C reactive protein remission; PEN, partial enteral nutrition; PUFA, polyunsaturated fatty acids.

Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866 1733

 Recent advances in clinical practice
Figure 4  New targets for dietary interventions in Crohn disease (CD).
70% of patients; this was accompanied by a significant drop in
ESR and CRP and was associated with mucosal healing among
patients who achieved remission and were evaluated during the
maintenance phase of the diet.77 The diet is low in animal fat,
rich in complex carbohydrates, with moderate exposure to soluble
fibre. It excludes wheat and dairy, emulsifiers, maltodextrins, cara-
geenans and sulfites. This diet was subsequently evaluated for
induction of remission in children and adults failing biologics.
Among 21 patients with active disease after loss of response to
biologics despite dose escalation or combination therapy, 61%
achieved clinical remission, again with a significant drop in inflam-
matory markers.78 While limited by design, these two retrospec-
tive studies reported remission with an exclusion diet at both ends
of the spectrum of clinical disease, suggesting that diet may be an
important tool for controlling active disease even in established
disease and among biologic unresponsive patients. These reports
should be viewed as preliminary data that need to be validated
in prospective controlled trials. Several RCTs using this method
are ongoing at the present time (NCT01728870, NCT02843100,
NCT02231814). The specific carbohydrate diet restricting carbo-
hydrates and processed foods has been advocated for CD and
UC. This was previously evaluated in 10 children with very mild
CD (mean Harvey Bradshaw Index (HBI) 3.3, mean ESR 9.7),
of whom 6 achieved clinical remission.79 However, another small
study published this year demonstrated that this diet was not asso-
ciated with mucosal healing.80 Clinical trials to assess this diet are
underway at the present time (NCT02213835, NCT01749813),
but randomised controlled studies evaluating patients with more
significant disease are required. Fibre and prebiotics supplements
have been evaluated as interventions in CD. A systematic review
including 10 eligible studies with clinical outcomes found no
evidence for use of fibre or prebiotics to induce or maintain remis-
sion in CD.81 Importantly, these papers concluded that there was
no evidence for restriction of fibre in the absence of obstructive
symptoms or stricturing disease.
Maintenance of remission
The idea of maintaining remission with diet is compelling and
challenging at the same time. On the one hand, once remission
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is established, it is certainly possible that diet will be sufficient to
maintain homeostasis and prevent the cascade of pro-inflamma-
tory events leading to flare; however, long-term studies are chal-
lenging to perform and adherence becomes a serious concern.
Nevertheless, several studies have assessed PEN for maintenance
of remission, some showing promising results.
One of the first studies to suggest the merit of PEN was
published in Gut in 1996. Wilschanski et al82 followed 28 children
who responded to EEN induction therapy for up to 12 months and
agreed to receive nightly nasogastric PEN; they were less likely to
flare than the 19 patients who chose not to receive PEN. A review,
which included 10 published studies, most of which were not
randomised, demonstrated some endoscopic improvement with
PEN, but the overall quality of these studies was limited, high-
lighting the need for large, prospective RCTs.83
A retrospective, single-centre study from Israel followed 42
children who responded to EEN and then went on PEN (50%
liquid formula, 50% free diet) for a median of 40 months.
Although a survival analysis was not included, median time for
remaining in remission was 6 months; however, the median time
in remission without need for additional therapy was 0 months
(0–16 months). Eighty-six percent of patients started on PEN as
maintenance therapy required additional therapy by 6 months.84
There is insufficient evidence to recommend PEN as the only
maintenance therapy in children based on existing data.
Another approach, mainly based on studies in adults from
Japan, has focused on partial elemental diet (ED), providing a
minimum of 900 kcal/day combined with a free diet. An RCT
comparing this approach to a fully free diet showed lower relapse
rates at a mean follow-up of 1 year (34.6% vs 64%).85 More
recent retrospective studies have indicated a potential advan-
tage for partial ED in reducing loss of response to infliximab
and adalimumab.86 87 PEN has also been shown to be effective in
preventing postoperative recurrence of CD. Twenty adults who
were compliant to EN were treated with nightly ED and a low fat
diet during the day and were followed for 5 years; remarkably, 16
maintained the diet. Only two had disease recurrence (vs 9/20 in
a normal-diet control group; p=0.03) and 1 (vs 5) required addi-
tional surgery.88 Japanese researchers randomised adult patients
Levine A, et al. Gut 2018;67:1726–1738. doi:10.1136/gutjnl-2017-315866

with CD in remission on maintenance 5-aminosalicylic acid
(ASA) to additional 6-mercaptopurine (MP), PEN with 900 kcal/
day from an ED, or no additional therapy. At the end of 2 years,
sustained remission was present in 60% of patients on 6-MP, 47%
of patients on PEN and only 27% of patients on 5-ASA. Both
6-MP and PEN were significantly superior to 5-ASA.89 Fernán-
dez-Bañares et al demonstrated that combining fibre supplements
with mesalamine was more effective than mesalamine alone for
maintenance of remission.90 A systematic review found that there
was no evidence for an effect of dietary fibre on disease outcomes
in UC.81
Dietary therapy for complicated CD
CD is associated with several complications that eventually can
lead to surgery. Treatment of complicated disease, such as stric-
tures, abscesses and fistulae has traditionally been either medical
or surgical. Recent studies have demonstrated that dietary
therapy with EEN may have the potential to treat complications
and have a ‘surgery sparing effect’.
Two studies conducted by a group from China evaluated the
efficacy of EEN in complicated CD. Hu et al conducted a prospec-
tive, observational study to examine the effects of 12 weeks of
EEN on inflammatory bowel strictures. They performed cross-sec-
tional CT before and after therapy. Sixty-five per cent of patients
achieved clinical remission, while 54% achieved radiologic remis-
sion. This was accompanied by a significant increase in luminal
diameter and a significant decrease in bowel wall thickness.91 Yan
et al conducted a prospective study to identify the predictors of
response to 12 weeks of EEN in patients with CD who had entero-
cutaneous fistulae. They demonstrated that 30/48 (62.5%) had
a successfully closure of fistula after EEN therapy with average
closure time of 32.4±8.85 days. They found that decreased CRP
and elevated body mass index levels were associated with response
to EN in patients with CD with enterocutaneous fistulae.92
EEN has also been demonstrated to reduce the need for surgery
in complicated disease. Heerasing et al demonstrated in a retro-
spective case-control study that EEN for a period of 6 weeks could
lead to avoidance of surgery in (13/51) 25% of patients who were
scheduled for an elective surgical resection.93 They also showed by
multivariable logistic regression analysis that patients who went to
surgery without EEN had a ninefold increase in the incidence of
postoperative abscess and/or anastomotic leak (OR 9.1; 95% CI
1.2 to 71.2, p=0.04). An additional recent retrospective study
conducted by a group from China reported that patients with CD
with intra-abdominal abscesses who were treated with 4 weeks of
EEN and antibiotics were less likely to require surgical interven-
tion compared with those who did not use EEN (26.1% vs 56.3%,
p=0.01).94 Several studies have confirmed that perioperative EEN
can improve surgical outcomes, reduce complications and the need
for immune suppression.95 96 Use of preoperative EEN may have
long-lasting effects. Wang et al found that EEN prior to resection
was accompanied by a significant reduction of endoscopic recur-
rence rates after resection for CD after 6 months.96 In addition, a
large retrospective study demonstrated that administration of EEN
for approximately 4 weeks led to lower rates of stoma creation
(p<0.05), a decrease in urgent operation requirement (p<0.05)
and extended preoperative drug-free intervals (p<0.001).97
Diet for functional symptoms
Patients with IBD may experience GI symptoms even during
remission without underlying inflammation. Recent studies have
demonstrated that restriction of several groups of fermentable
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Recent advances in clinical practice
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carbohydrates (low fermentable oligosaccharides, disaccharides,
monosaccharides and polyols (FODMAP) diet) is effective in the
management of functional symptoms. Prince et al found that
78%, p<0.001 with IBD reported satisfactory relief of func-
tional symptoms after 6 weeks of low FODMAP diet.98 A recent
meta-analysis concluded that a low FODMAP diet is beneficial
for reducing GI symptoms in patients with quiescent IBD.99
Halmos et al100 showed that the low FODMAP diet had no effect
on the calprotectin results in patients with CD. Furthermore,
altering dietary FODMAP intake was associated with possible
detrimental changes in faecal microbiota and therefore is not
recommended for extended periods of time.
Summary
In summary, there seems to be a growing body of evidence to
suggest that dietary factors may play an important role in the patho-
genesis of CD. Use of EEN has expanded from a tool for induction
of remission in children at disease onset, to a tool with potential
to treat very complicated long duration disease in adults (figure 4).
Use of perioperative EEN has the potential to avoid the need for
surgery, reduce poor surgical outcomes and delay postoperative
recurrence in CD. Perhaps the most exciting development is the
potential to induce and maintain remission by use of exclusion diets
and PEN, which would enable wider use of dietary therapy across
the spectrum. However, the field still has insufficient high-quality
evidence due to the small number of well-designed trials performed
to date, but the future appears to be bright in CD. RCTs with newer
dietary interventions or indications are warranted. Perhaps the
largest research gaps at the present are in the field of UC. Although
there are emerging clues linking diet to UC as well, researchers have
yet to make the jump from bench to bedside in UC, and we still do
not know if dietary therapy would be effective in UC.
Contributors  All authors contributed to the writing of the manuscript.
Funding  This study was funded by grants from Nestle and the Azrieli Foundation.
Competing interests  None declared.
Patient consent  Not required.
Provenance and peer review  Commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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