Mechanism of constipation and response to diet: novel insights from manometry and magnetic resonance imaging

Constipation is a common condition in which an individual suffers with hard stools which are infrequent and difficult to pass. It has an estimated prevalence of 15-20% however the pathophysiology of symptoms remains poorly understood and treatment is often unsatisfactory for patients. In approximately 60% of patients their constipation is associated with abdominal pain, whilst in the remaining this appears in absence of pain. This thesis is split into three sections, in the first I will review the background and current investigation and treatment strategies in constipation. The second will look at two healthy volunteer studies performed looking at the effect of different foods on gut function and how these could be relevant to treatment of constipation. In the third I will describe our patient study into the pathophysiology of constipation that take advantage of two new techniques. These are Magnetic Resonance Imaging (MRI), which allows us to see the contractions of the colon and High-Resolution Manometry (HRM) which measures the contraction using pressure sensing catheters placed into the bowel. Using these techniques, we will identify patterns of contractions in each patient and compare to healthy controls to determine whether these could be used to predict different treatment respons

The MRI colonic function test: Reproducibility of the Macrogol stimulus challenge

Background Magnetic resonance imaging (MRI) of the colonic response to a macrogol challenge drink can be used to assess the mechanisms underlying severe constipation. We measured the intra-subject reproducibility of MRI measures of colonic function to aid their implementation as a possible clinical test. Methods Healthy participants attended for MRI on two occasions (identical protocols, minimum 1 week apart). They underwent a fasted scan then consumed the macrogol drink. Subjects were scanned at 60 and 120 minutes, with maximum value reached used for comparison. The colonic volume, water content, mixing of colonic content and the movement of the colon walls were measured. Coefficients of variation and intraclass correlation coefficients (ICC) were calculated. Results 12 participants completed the study: 9 female, mean age 26 years (SD 5) and body mass index 24.8kg/m2 (SD 3.2). All measures consistently increased above baseline following provocation with macrogol. The volume, water content and content mixing had good intra-subject reproducibility (ICC volume=0.84, water content=0.93, mixing=0.79,

Differential effects of FODMAPs (Fermentable Oligo-, Di-, Mono-Saccharides and Polyols) on small and large intestinal contents in healthy subjects shown by MRI

OBJECTIVES: The objective of this study was to investigate whether ingestion of fructose and fructans (such as inulin) can exacerbate irritable bowel syndrome (IBS) symptoms. The aim was to better understand the origin of these symptoms by magnetic resonance imaging (MRI) of the gut. METHODS: A total of 16 healthy volunteers participated in a four-way, randomized, single-blind, crossover study in which they consumed 500 ml of water containing 40 g of either glucose, fructose, inulin, or a 1:1 mixture of 40 g glucose and 40 g fructose. MRI scans were performed hourly for 5 h, assessing the volume of gastric contents, small bowel water content (SBWC), and colonic gas. Breath hydrogen (H 2) was measured and symptoms recorded after each scan. RESULTS: Data are reported as mean (s.d.) (95 % CI) when normally distributed and median (range) when not. Fructose increased area under the curve (AUC) from 0 – 5 h of SBWC to 71 (23) l / min, significantly greater than for glucose at 36 (11 – 132) l / min ( P < 0.001), whereas AUC SBWC after inulin, 33 (17 – 106) l / min, was no different from that after glucose. Adding glucose to fructose decreased AUC SBWC to 55 (28) l / min ( P = 0.08) vs. fructose. Inulin substantially increased AUC colonic gas to 33 (20) l / min, signifi cantly greater than glucose and glucose + fructose (both P < 0.05). Breath H 2 rose more with inulin than with fructose. Glucose when combined with fructose signifi cantly reduced breath H 2 by 7,700 (3,121 – 12,300) p.p.m. / min relative to fructose alone ( P < 0.01, n = 13). CONCLUSIONS: Fructose but not inulin distends the small bowel with water. Adding glucose to fructose reduces the effect of fructose on SBWC and breath hydrogen. Inulin distends the colon with gas more than fructose, but causes few symptoms in healthy volunteers

Towards More Predictive, Physiological and Animal-free In Vitro Models: Advances in Cell and Tissue Culture 2020 Conference Proceedings

Experimental systems that faithfully replicate human physiology at cellular, tissue and organ level are crucial to the development of efficacious and safe therapies with high success rates and low cost. The development of such systems is challenging and requires skills, expertise and inputs from a diverse range of experts, such as biologists, physicists, engineers, clinicians and regulatory bodies. Kirkstall Limited, a biotechnology company based in York, UK, organised the annual conference, Advances in Cell and Tissue Culture (ACTC), which brought together people having a variety of expertise and interests, to present and discuss the latest developments in the field of cell and tissue culture and in vitro modelling. The conference has also been influential in engaging animal welfare organisations in the promotion of research, collaborative projects and funding opportunities. This report describes the proceedings of the latest ACTC conference, which was held virtually on 30th September and 1st October 2020, and included sessions on in vitro models in the following areas: advanced skin and respiratory models, neurological disease, cancer research, advanced models including 3-D, fluid flow and co-cultures, diabetes and other age-related disorders, and animal-free research. The roundtable session on the second day was very interactive and drew huge interest, with intriguing discussion taking place among all participants on the theme of replacement of animal models of disease

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences. The utility of processes to predict replicability is their capacity to test scientific claims without the costs of full replication. Experimental data supports the validity of this process, with a validation study producing a classification accuracy of 84% and an Area Under the Curve of 0.94, meeting or exceeding the accuracy of other techniques used to predict replicability. The repliCATS process provides other benefits. It is highly scalable, able to be deployed for both rapid assessment of small numbers of claims, and assessment of high volumes of claims over an extended period through an online elicitation platform, having been used to assess 3000 research claims over an 18 month period. It is available to be implemented in a range of ways and we describe one such implementation. An important advantage of the repliCATS process is that it collects qualitative data that has the potential to provide insight in understanding the limits of generalizability of scientific claims. The primary limitation of the repliCATS process is its reliance on human-derived predictions with consequent costs in terms of participant fatigue although careful design can minimise these costs. The repliCATS process has potential applications in alternative peer review and in the allocation of effort for replication studies