Phenotyping of Adult Crohn's Focusing on Sarcopenia

University of Nottingham35 enrolled

Overview

Inflammatory bowel disease (IBD) includes two idiopathic chronic relapsing and remitting inflammatory conditions affecting the gastrointestinal (GI) tract: Crohn's disease (CD) and ulcerative colitis (UC)Malnutrition and significant alteration of body composition are common in inflammatory bowel disease patients, whereby the prevalence of malnutrition may be up to 82.8% in CD patients with active disease, and up to 38.9% in CD patients in remission. Many CD patients have low muscle mass and function (sarcopenia) with drivers of such pathophysiology unknown. 41.6% of CD patients with sarcopenia require surgery, with the surgical trauma and resulting inactivity leading to further muscle mass loss such that the chronic inflammatory insult associated with refractory disease may be linked to advanced muscle mass depletion. The majority of adult CD patients have low muscle mass even in clinical remission indicating the poorly reversible nature of this phenomenon. Chronic disease burden may therefore be important in the accentuation of muscle loss. Muscle mass is maintained through the daily balance of MPS and muscle protein breakdown (MPB), with the essential amino acid (EAA) components of a meal and muscle contraction being the primary stimulators of MPS. Patients with active CD show a significant decrease in the expression of proteins in hypertrophic signalling pathways (Akt, P70S6K1) with no change in the expression of atrophic signalling (MAFbx, MuRF1). Also, adult CD patients with established disease consume less protein compared to matched healthy volunteers (HV). Furthermore, the intestinal motility, measured using cine-MRI, is reduced in active CD, possibly further decreasing intestinal digestion and absorption of dietary peptides. In general, the malabsorption is a major contributing factor to malnourishment in CD. It has been shown that in male paediatric patients with long-term CD, muscle metabolism is perturbed by a negative branched-chain amino acid balance in the forearm, with this variable linked to lower appendicular muscle mass, higher muscle fatigue and reduced protein intake, CD may have a significant effect on protein digestion and absorption, and blunt the MPS response to feeding, leading to a chronic muscle mass reduction that may persist even when in remission. The EAA components of a protein meal are crucial for the stimulation of muscle protein synthesis (MPS), and all the EAA/leucine play a key role in driving MPS. Low serum levels EAA/leucine have been reported in CD but their role in the aetiology of sarcopenia in CD is unknown. Further, how CD affects the protein digestion/absorption and how this contributes to low EAA/leucine unclear. Recent advances in stable isotope tracer techniques using a dual tracer methodology now enable a more accurate determination of protein digestibility. By following the appearance of intrinsically labelled AAs into the blood upon digestion of the intrinsically labelled protein, alongside the appearance of label-free AAs, protein digestibility can be accurately determined. Further, by collecting a muscle biopsy postprandially, the direct incorporation of AA from the digested protein into the muscle can be determined- providing a gold standard method for investigating anabolic resistance. Project aim is to use an intrinsically labelled casein to investigate protein digestion, absorption and MPS responses in CD patients. To achieve this, investigators will investigate protein digestion, absorption and muscle protein synthesis responses in Crohn's disease patients and healthy volunteers by utilising intrinsically labelled protein.

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria for Healthy group 1. Aged 18 years or older 2. BMI \<30 kg/m2/ 3. No previous known bowel disease 4. Be able to provide written informed consent \& participate fully in all aspects of the study. Inclusion Criteria for Crohn's group: 1. Aged 18 years or older. 2. BMI \<30 kg/m2 3. Documented diagnosis of CD previously confirmed by endoscopy and histology at least 2 years prior to enrolment. 4. Active CD defined as HBI \>4 and CRP \>5g/l or FCP \>250ug/g or as deemed through endoscopy or cross sectional imaging. 5. Previous biologic or immunosuppressant exposure 6. Previous CD-related intestinal surgery 7. Able to participate fully in all aspects of the study 8. Written informed consent obtained and documented Exclusion Criteria for Healthy group 1. Aged 18 years or older 2. BMI \<30 kg/m2/ 3. No previous known bowel disease 4. Be able to provide written informed consent \& participate fully in all aspects of the study. Exclusion Criteria for Crohn's group 1. A current diagnosis of ulcerative colitis, indeterminate colitis, microscopic colitis, or diverticular disease-associated colitis 2. A diagnosis of short-bowel syndrome 3. Use of systemic corticosteroids for CD (2 continuous weeks or more) within 3 months prior to enrolment, or use of any medications for HVs and CD, in the opinion of the investigator, may interfere with the subject's ability to participate fully in the study. 4. Serious underlying disease other than CD that, in the opinion of the investigator, may interfere with the subject's ability to participate fully in the study. 5. History of active alcohol or drug abuse that, in the opinion of the investigator, may interfere with the subject's ability to comply with the study procedures. 6. Pregnancy or breastfeeding. 7. Contraindications for DEXAscanning e.g. x-ray within last 7 days. 8. Allergy to milk, , or casein

Outcomes

Primary Outcomes

Postprandial muscle protein synthesis.

Postprandial muscle bound \[ring-D5\]-Phenylalanine, \[5,5,5-D3\]-Leucine as measured through mass spectrometry

Time frame: Change from baseline 4 hours (Two time points)

Secondary Outcomes

Appearance/ digestibility of plasma Amino Acid in blood.

Postprandial plasma \[ring-D5\]-Phenylalanine, \[5,5,5-D3\]-Leucine as measured through mass spectrometry

Time frame: blood samples will be taken at regular intervals up to 240 minutes (max 120ml total blood draw post protein drink). 12-time points

Muscle mRNA expression of anabolic and catabolic

The mRNA expression of transcripts involved anabolic and catabolic signalling pathways as measured through RT-qPCR (Applied Biosystems).

Time frame: Change from baseline at 4 hours (Two time points).

Muscle protein expression of anabolic and catabolic pathway.

Muscle protein expression of anabolic and catabolic pathway signalling proteins

Time frame: Change from baseline at 4 hours (Two time points).

Serum Cytokines levels of IL-1

As measured using ELISAs

Time frame: Only at baseline.

Serum Cytokines levels of IL-6

As measured using ELISAs

Time frame: Only at baseline.

Serum Cytokines levels of IL-10

As measured using ELISAs

Time frame: Only at baseline.

Serum Cytokines levels of CRP

As measured using ELISAs (IBDQ)

Time frame: Only at baseline.

Serum Cytokines levels of TNF

Daily energy intake and dietary macronutrient composition

Time frame: Only at baseline.

Appendicular Lean Mass (ALM) to Height Ratio (Kg/Height2) through DEXA scan

\- It will be assessed via DEXA scan using a GE Lunar Prodigy DEXA scanner housed in the University of Nottingham's David Greenfield unit. The scan will be a whole-body scan for total body composition measurement including ALM to height. The scans will be analysed using the scanners inbuilt Corescan software. Regional measurements will be taken post scan using custom analysis functions within the Corescan software.

Time frame: Only at baseline

Appendicular skeletal muscle index (ASMI; kg/m2) through DEXA scan.

It will be assessed via DEXA scan using a GE Lunar Prodigy DEXA scanner housed in the University of Nottingham's David Greenfield unit. The scan will be a whole-body scan for total body composition measurement including ASMI. The scans will be analysed using the scanners inbuilt Corescan software. Regional measurements will be taken post scan using custom analysis functions within the Corescan software

Time frame: Only at baseline

Skeletal muscle index (SMI; kg/m2) through DEXA scan.

It will be assessed via DEXA scan using a GE Lunar Prodigy DEXA scanner housed in the University of Nottingham's David Greenfield unit. The scan will be a whole-body scan for total body composition measurement including SMI. The scans will be analysed using the scanners inbuilt Corescan software. Regional measurements will be taken post scan using custom analysis functions within the Corescan software.

Time frame: Only at baseline

Skeletal Muscle Mass Percentage (SMM; %) through DEXA scan.

It will be assessed via DEXA scan using a GE Lunar Prodigy DEXA scanner housed in the University of Nottingham's David Greenfield unit. The scans will be analysed using the scanners inbuilt Corescan software. Regional measurements will be taken post scan using custom analysis functions within the Corescan software.

Time frame: Only at baseline

Total Body Fat Percentage (BF; %) through DEXA scan.

Time frame: Only at baseline

Fat Mass Index (FMI; kg/m2) through DEXA scan.

Time frame: Only at baseline

Resting Metabolic Rate (RMR) through DEXA scan.

Time frame: Only at baseline

Muscle Strength through Handgrip

Handgrip Dynamometers are instruments for measuring the maximum isometric strength of the hand and forearm muscles

Time frame: Only at baseline

Muscle Strength through Cybex Dynamometer

A CYBEX Isokinetic Test is used to measure the maximum strength of a joint throughout its available range-of-motion (ROM).

Time frame: Only at baseline

Daily physical activity

Physical activity as measured with IPAQ

Time frame: Only at baseline

Quality of life for Crohn's disease patients

measured through the Short Quality of Life Questionnaire for Inflammatory Bowel Disease

Time frame: Only at baseline

Dietary intake of one day before the experiment day.

As analysed by using intake24 website; https://intake24.co.uk/info/output . The participant will be received email included the link to fill it by what they intake on this day.

Time frame: Only at baseline

Phenotyping of Adult Crohn's Focusing on Sarcopenia

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes