Cyclic dietary calorie and protein restriction for induction of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a multifactorial inflammatory disease of
the gut, which is comprised of two main disease entities; Ulcerative colitis
(UC) and Crohn*s disease (CD). IBD arises from an exaggerated immune response
against the intestinal microbiome in genetically susceptible individuals. IBD
and associated symptoms are influenced by environmental factors, with a higher
incidence of IBD in Westernised countries compared to less developed countries.
These differences in global incidence are thought to result from differences in
hygienic conditions, genetics and diet, and the resulting modulation thereby of
the gut microbiome. Western diets in particular are thought to be involved as a
trigger during initiation and continuation of the abnormal immune response in
IBD. Treatment of patients suffering from active IBD is aimed at controlling
the inflammatory response in the bowel, and includes the use of steroids and
immunosuppressive or immunomodulatory drugs. Although treatment of acute
symptoms is often adequate, steroids used to induce remission have side-effects
and steroid dependency sometimes occurs. Furthermore, inducing long-term
remission without flare-ups and/or side-effects of drugs remains a challenge.
With the rising incidence of IBD, the need for more effective, safe and
preferably less expensive therapies for IBD is increasing. Even in this era of
biologicals, approximately 40% of patients on infliximab (IFX) therapy will
eventually lose their response to treatment.
One of the most commonly asked questions of IBD patients is how diet might
positively influence their disease and symptoms. A recent survey in our centre
indicates that 68% of IBD patients associate diet with complaints (preliminary
data). Although several dietary interventions have been investigated for
treatment of IBD, study results have been disappointing. Exclusive Enteral
Nutrition (EEN) is an effective induction strategy in paediatric Crohn*s
disease patients. However, this diet is less well characterised in adults.
Other studies focused on reductions of carbohydrate intake, including low
fermentable oligosaccharides, disaccharides, monosaccharides and polyols
(FODMAP) diet, but these studies show mixed results. Changes in diet are known
to modulate the microbiome. A dysbiosis of the intestinal microbiota, defined
as a disbalance in pathogenic versus beneficial bacteria (increased versus
decreased respectively), is assumed to contribute to disease, as altered gut
microbial composition has been shown in IBD. Furthermore, induction of colitis
in mouse models occurs more efficiently under conventional housing conditions,
i.e. in the presence of bacteria, as compared to germ-free conditions..
Interestingly, in mouse models, high fat and protein diets were associated with
an increased abundance of Bacteroides and invasive E. Coli species in the gut,
a microbial dysbiosis also often observed in IBD. In addition, animal-based
diets (in contrast to plant-based diets) reduce the amount of
butyrate-producing Roseburia, another feature observed in IBD. Thus, changing
dietary patterns may be beneficial for intestinal health. While it is known
that dietary changes affect the microbiome, short term and long term diets
differ in their microbial modulation. Changes in enterotypes were strongly
associated with long-term diets, with protein and animal fat associated with
the Bacteroides enterotype and carbohydrates associated with Prevotella.
Conversely, a controlled-feeding study showed that microbiome composition
changed within 24 hours of initiating a high-fat/low-fiber or
low-fat/high-fiber diet, but that enterotype identity remained stable at short
times.
Recently, a calorie restriction/protein restriction (CRPR) diet was described
which shows strong anti-inflammatory properties in preclinical settings of both
surgically induced traumatic inflammation and chemotherapy induced toxicity.
The feasibility and safety of short-term (5 day) CRPR has been shown previously
by the Erasmus MC Department of Surgery (METC number 2012-134) in patients
awaiting surgery, with patients exhibiting compliance rates of up to 71%.
Furthermore this diet is currently being tested in metastatic colorectal cancer
patients receiving irinotecan, to optimize anti-tumor effects and survival
(METC number 15-710), based on promising results in mouse studies showing that
CRPR has significant chemotherapy-enhancing capacity. Interestingly, the
anti-inflammatory effects of the CRPR diet include a reduction of
inflammation-induced IL6 and TNFα and a leptin dependent decrease in mTOR
signalling. As these pathways are important players in IBD pathology, and given
the fact that the anti-inflammatory effects of this diet were observed within 3
to 5 days in earlier studies, this diet may also be potentially beneficial for
induction of remission in the IBD patient population. In case of effectiveness
of the remission induction, a new study will follow to assess maintenance
therapy with the CRPR diet. This single center study will be performed as part
of a national effort to investigate the effect of diet in IBD, which includes
UMCG, MUMC, Gelderse Vallei, AMC, RadboudMC, Wageningen University,
Hagaziekenhuis, Jeroen Bosch Ziekenhuis, Gelre Ziekenhuis, in addition to
patient organizations for IBD (CCUVN) and PSC (PSCPatientsEurope). During the
first consortium meeting, collective evidence presented suggests that clinical
effects of add-on dietary interventions (e.g. Vitamin B12) are very rapid
(within 2 to 4 weeks). Anti-inflammatory effects of the CRPR diet, while not
tested in IBD patients, was already achieved within days. However, as this is
not an add-on diet, in contrast to previous studies, the intervention in the
current study will be given in a cyclic fashion, consisting of 4 constitutive
diet-days in week 1 and 3 constitutive diet-days in week 2, 3 and 4. Such a
cyclic diet has not been tried before in IBD patients, but might increase
compliance because it might be easier for patients to adhere to. As such, the
cyclic dietary intervention may pose less of a burden for patients and will
prevent malnutrition because of its cyclic character. To the best of our
knowledge, protein reduction has not yet been investigated in IBD, despite
epidemiological studies suggesting that high fat/high protein intake is
associated with developing IBD (9). In order to reduce heterogeneity, the
patient group will consist of CD patients only, for whom dietary influences
appear to have the largest impact. The results obtained by this study will
provide critical information on the feasibility for IBD patients to adhere to
this cyclic dietary intervention for four weeks, and the possibility for this
diet to induce microbial changes. Dietary interventions are not expected to
change the microbiome in all patients to a similar extent, which may explain
the mixed results of former dietary interventions tested in IBD patients.

Primary objective:
- To assess the efficacy of a calorie and protein restricted (CRPR) diet for
induction of remission in IBD.

Secondary objectives:
- To assess the feasibility of a CRPR diet in IBD patients.
- To assess the effect of a CRPR diet on disease biomarkers, including
molecular and microbial factors

This study is designed as a 4 week randomized prospective pilot study. 30 IBD
patients with mild to moderate disease according to endoscopic findings will
receive dietary intervention (15 patients) or budesonide 9mg induction therapy
(15 patients). The CRPR diet consists of an estimated 70% of the individual*s
required calories and 20% of the individual*s protein, based on the basal
metabolic rates and on the daily energy requirements (DER) as calculated with
the Harris-Benedict equation and with the BODPOD (the Gold Standard Body
Composition Tracking System is an air displacement plethysmograph which uses
whole-body densitometry to determine body composition (fat and fat-free mass)
in adults. The Harris-Benedict equation takes into account sex, height, age,
body weight and estimated activity level. Normal protein intake is set at 20%
of the total calories based on the DER. To facilitate the dietary requirements,
participants will receive calorie- and protein-restricted powder shakes
(Scandishake® Mix) as the main component of the diet, which can be supplemented
with a limited amount of protein-restricted products (mainly fruits and
vegetables) until the desired individual energy content of the diet is reached.
Calorie and protein restriction has been shown to results in an
anti-inflammatory response within 3 to 5 days, with longer times showing the
highest effect. Taking into account the fragile population (i.e. patients with
active CD) and in order to improve compliance, we opted for short time points.
Thus, dietary intervention consists of an induction phase of 4 days of diet at
week 1, followed by 3 days of diet at week , 3 days of diet at week 3 and
another 3 days of diet at week 4.

Compliance/ safety:
Every week, our contact person will have telephone contact with the patients in
the CRPR arm during the diet-period, to answer questions, stimulate patient
participation and to check compliance. Enrolled subjects will be asked to
collect the empty dietary sachets as proof of compliance to the diet. In
addition, after four weeks objective markers for the diet will be measured in
serum (i.e. (pro)-albumin, urea and retinol binding protein).

This study will investigate a (cyclic) calorie restriction/protein restriction
(CRPR) diet, consisting of 70% of the individual*s required calories and ~20%
of the individual*s protein requirement, based on basal metabolic rates and on
the daily energy requirement as an nduction regimen (4 days diet at week 1, 3
days at week 2, 3 days at week 3 and 3 days at week 4.)

Previous human intervention studies have shown no risks associated with the
diet and side effects are mild as only gastrointestinal discomfort has been
reported. Benefits of the diet include the potential anti-inflammatory effect
and potential beneficial change in microbiome.