Phenotyping of Adult Crohn's Focusing on Sarcopenia

Plain-language summary

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.

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