Eating Behaviour in Crohn's Disease

Food intake is mainly controlled through interactions between the gut and brain (the homeostatic control) and through our environment, with food exposure, mood and past experiences (the hedonic control) playing a major role. The link between the gut and the brain is mainly controlled through enteroendocrine cells (EC). These cells in the bowel sense nutrients in the food and link with the brain to control how much we eat. They make a number of hormones that link with the brain to control one's eating habits.

Crohn's disease (CD) is an inflammatory disease of the bowel which can present with a number of symptoms including weight loss and loss of appetite. We thought some time ago that an increase in the number and function of these EC could play a central role. Since then we have carried out work which has shown that in CD these EC increase in number and produce more hormones after a meal. This finding could have a negative effect on food intake. This would be one explanation to the symptoms so commonly experienced by these patients.

In CD we thus feel that there might be an imbalance in the appetite control. We expect an increasingly sensitive gut to food intake and a subdued mood and perception to food reward and that this imbalance will lead to a decrease in food reward and consequently a decrease in food intake.

This study will be carried out using Healthy Volunteers and CD patients. We plan to measure food intake though telephone interviews and plan to analyse eating behaviour through 5 questionnaires.This study will help us to improve our understanding of what it is that controls food intake. This will be particularly important to patients with CD who routinely lose weight and appetite.

STUDY BACKGROUND INFORMATION AND RATIONALE

Crohn's disease (CD) patients can present with a variety of luminal and extra-luminal symptoms but nutritional abnormalities are a very common but poorly studied \[1\] problem in this disease \[2\]. Apart from disease burden and repeated surgery, reduced appetite \[3\] and associated symptoms such as nausea undoubtedly contribute, with a major impact on quality of life.

Appetite and satiation, the processes by which a meal is terminated, involve complex interactions of homeostatic and hedonic factors. While the hypothalamus is central in the homeostatic control of food intake, other neural circuits integrate environmental and emotional cues to constitute the hedonic drive of appetite regulation. The homeostatic control of food intake is governed by the enteroendocrine-gut brain axis. Enteroendocrine cells (EC) play a pivotal role in orchestrating physiological functions in the gastrointestinal (GI) tract. Sensing the nutrient content of the lumen, they secrete multiple peptides and amines that control gut secretory and motor functions. Gut hormones act on vagal afferents in the GI tract, directly relaying to key central nervous system (CNS) nuclei that interface within the hypothalamus and other cortical areas to regulate food intake. CD patients with active small bowel inflammation show significant up-regulation of EC cells with an increase in ileal expression of chromogranin A \[4, 5\], glucagon-like peptide-1 (GLP-1) \[4\], key transcription factors in the stem cell to EC differentiation pathway \[4\] , plasma polypeptide YY (PYY) \[3\], cholecystokinin (CCK) \[6\] levels and a reduction in the key enzyme dipeptidyl peptidase-4 expression \[7\]. This increase in plasma peptide levels is associated with the symptoms of nausea and anorexia, with both symptoms, and tissue and plasma EC-peptide expression decreasing to normality in remission \[3\].

An increase in EC expression at the tissue and plasma level might affect appetite regulation through an increase in CNS signalling.

Fatty-acids infused in the gut, lead to a CCK-dependent increase in CNS activity in areas related to homeostatic control of feeding such as the brainstem, the pons, hypothalamus, cerebellum and the motor cortical areas \[8\]. Glucose has been shown to decrease the response in the upper hypothalamus \[9\], possibly via a GLP-1-mediated pathway \[10\]. Ghrelin and PYY have known homeostatic CNS signalling properties but play a hedonic role in the control of food intake \[11\]. In effect, the increase in plasma PYY and GLP-1 seen after Roux-en-Y gastric bypass surgery in obese subjects or after parenteral administration \[12\] is associated with a lower activation in brain-hedonic food responses and a healthier eating behaviour \[13\]. In CD, we expect a subdued reward value of food, but postulate that this would be aversive, and inappropriately impairing appetite and food intake.

We hypothesize that in CD and small bowel inflammation we will observe a change in eating behaviour with loss of hedonic drives and food reward responses and an accentuated homeostatic response.

STUDY OBJECTIVES AND PURPOSE

PURPOSE The overall purpose of the study is to quantify food intake in patients with active Crohn's disease and compare it to when they are in remission and to healthy age, BMI and gender-matched healthy cohort of volunteers. We will quantify eating behaviour traits in the same patient cohort when in active disease and repeat when in remission. These data will be compared to that of healthy volunteers.

PRIMARY OBJECTIVE The primary objective is to quantify food intake in patients with active CD and compare this to HV.

SECONDARY OBJECTIVES The secondary objectives of this study are to a) quantify food intake in patients with active CD and compare that when in inactive disease. b) quantify changes in appetite and eating behaviour in patients with active CD and compare these to those in HV and inactive CD as measured by the appetite-related questionnaires

Eligibility Criteria:
Inclusion Criteria:

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We will study a cohort of CD patients with active disease as defined by:

1. Age 16-75 years
2. Ulceration seen at ileocolonoscopy, aiming for a simple endoscopic score for Crohn's disease (SES-CD) of 4-19, in the absence of stricturing disease or,
3. Intestinal inflammation or deep ulceration seen on CT or MR enterography, with the disease activity quantified via the MaRIA score or
4. Faecal calprotectin of \>250µg/g or
5. C-Reactive protein \>5mg/dl or,
6. Harvey-Bradshaw index score of 5-16
7. Body mass index (BMI) of 18-30.

For HV participants, inclusion criteria's 1 and 7 apply.

Exclusion Criteria:

1. Present or recent (within 12 weeks) corticosteroid usage
2. Malignant disease
3. BMI \<18 or \>30.
4. Significant cardiovascular or respiratory disease
5. Diabetes mellitus
6. Current Infection
7. Neurological or cognitive impairment; significant physical disability
8. Significant hepatic disease or renal failure
9. Abnormal blood results other than those explained by CD including bleeding diatheses (apart from in the case of HV where all unexplained blood results are an exclusion criteria) ,
10. Subjects currently participating in (or in the last three months) any other research project
11. pregnancy or breastfeeding or
12. Severe CD where a delay in a change in medical treatment for 1 weeks would not be clinically advisable

For HV participants, all exclusion criteria apply with the exception of criteria no.12