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Role of Diet and Faecal Microbiota Transplantation following Bowel Cancer Surgery

ABSTRACT: Interventions: Following bowel resection due to cancer, up to 80% patients will experience variable and unpredictable bowel function and symptoms termed as Low Anterior Resection Syndrome (LARS). The exact mechanism of LARS remains unclear and currently there is no standard treatment. This program of research will investigate if Faecal Microbiota Transplantation (FMT) can improve the bowel function and patient’s quality of life (QoL). Phase 1- Dose-finding-study. Group 1: FMT at one year post Ultra Low Anterior Resection (ULAR)/LAR via lower route (colonoscopy). Dose includes 4 x BiomeBoostTM FMT syringes, containing a total of 50 g of faecal matter as the active ingredient. Group 2: FMT at one year post ULAR/LAR via lower route (colonoscopy). Dose includes 6 x BiomeBoostTM FMT syringes, containing a total of 75 g of faecal matter as the active ingredient. FMT dose will be administered at one time, by the specialist conducting the colonoscopy (gastroenterologist/surgeon). The procedure of delivering FMT will only add 5 minutes to the routine colonoscopy being performed. Adherence will be monitored by: 1. Dietetic phone follow up How well did you follow the intervention in a non judgmental format. Primary outcome(s): Bowel function assessed via Low Anterior Resection Syndrome (LARS) questionnaire [At baseline (week 0) and week 4 post intervention commencement.];General quality of life (QoL) assessed via Cancer Quality of Life-general post cancer questionnaire (EORTC QLQ-C30) [At baseline (week 0) and week 4 post intervention commencement.];Colorectal specific quality of life (QoL) assessed via Colorectal specific QoL (EORTC QLQ-C30) questionnaire [At baseline (week 0) and week 4 post intervention commencement.] Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Open (masking not used);Assignment: Parallel;Type of endpoint: Efficacy

DISEASE(S): Oral And Gastrointestinal-other Diseases Of The Mouth, Teeth, Oesophagus, Digestive System Including Liver And Colon,Bowel Cancer,Surgery-other Surgery,Diet And Nutrition-other Diet And Nutrition Disorders,Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Low Anterior Resection Syndrome,Low Anterior Resection

PROVIDER: 2472786 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Interventions: This is a prospective randomised controlled study comparing colesevelam therapy with placebo in a two-period cross-over design, where patients will act as their own controls. Radiological testing for Bile acid malabsorption (BAM) will be performed in a subset of participants prior to the intervention being administered. We aim to test at least half of the participants, but this will be determined by funding and access to radiology. We anticipate that 3-15 patients will undergo this test. Selection will be based on the test being available when the individual is recruited. The SeHCAT test involves administering 75Se 23-selena-25-homocholic acid and glycocholic acid as an oral capsule to a fasting patient. The initial count rate of 75Se will be measured three hours after the intake of the isotope. On day 7 following administration, there will be further imaging, and the net count rate of 75Se will be expressed as a percentage of the net count rate at day 0. The % retention of 75Se will be recorded. While a positive test is one that shows a retention <15%, the actual levels of 75Se will also be compared to changes in the LARS score. A 2-sequence, 2-period design will be used with a six-week washout between interventions to account for first-order carryover effects. Participants will be randomised to one of the following sequences: AB|BA, where A=colesevelam therapy and B=placebo. The intervention will be presented as 312mg capsules. The participant will start by taking two capsules (approximately 625mg) three times a day for three days, and if there are no side effects will then increase to four capsules (1.25g) three times a day. Side effects will be monitored by use of a daily patient diary and telephone interviews on days one and three. Patients will Primary outcome(s): Low Anterior Resection Syndrome (LARS) Score, from a validated questionnaire. This questionnaire will be administered in Dunedin Hospital by a research assistant before and after each treatment. [LARS score will be measured prior to commencement of the first treatment, at the end of the first 5-week treatment phase, prior to commencement of the second treatment (approximately 11 weeks post-enrollment), and at the end of the second 5-week treatment phase.];Short-form 12 Health Survey, a quality of life questionnaire. This questionnaire will be administered in Dunedin Hospital by a research assistant before and after each treatment. [Quality of life will be measured prior to commencement of the first treatment, at the end of the first 5-week treatment phase, prior to commencement of the second treatment (approximately 11 weeks post-enrollment), and at the end of the second 5-week treatment phase.];Faecal Incontinence Quality of Life Score. This will be administered at Dunedin Hospital by a research assistant.[Quality of life will be measured prior to commencement of the first treatment, at the end of the first 5-week treatment phase, prior to commencement of the second treatment (approximately 11 weeks post-enrollment), and at the end of the second 5-week treatment phase.] Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Crossover;Type of endpoint: Safety/efficacy

Project description:Purpose: To determine whether previously observed behavioral differences in alcoholic human patients after fecal microbiota transplantation (FMT) could be transferred to mice. Methods: Fecal microbiota samples from a previously published phase 1, double-blind, randomized clinical trial of AUD-related cirrhosis patients were used to colonize germ-free mice. Fecal material was transferred to 10-15-week-old GF C57BL/6 male mice by daily gavage for 3 day. The mice were housed in sterile individually filtered cages for 15 days after which stool was collected and then they underwent the alcohol preference experiment using 2-bottle choice drinking (water and 20% ethanol v/v). Microbial DNA was isolated from stool samples by sequencing the V1 and V2 variable regions of the bacterial 16S rRNA gene were sequenced using Multitag fusion primers and sequenced on an Ion Torrent PGM next-generation sequencer. Intestinal mucosa, liver, and prefrontal cortex tissue was collected from mice at time of sacrifice. RNAseq was used to measure gene expression in pre-FMT and post-FMT samples. RNAseq data were aligned to the mouse genome (GRCm39) using STAR (version 2.7.9a) and counts were generated with HTSeq (version 0.13.5). Genes with very low counts across the study (defined as fewer than 10 counts in more than 2 samples) were eliminated before differential expression analysis. Low count genes were determined separately for each tissue type. The DESeq2 package for R was then used to measure differential expression between pre-FMT and post-FMT mice in the intestine, liver, and PFC. Benjamini and Hochberg False Discovery Rate (FDR) was used to correct for multiple testing with FDR ≤ 0.2 considered significant. Results: Mice colonized with post-FMT stool significantly reduced ethanol acceptance, intake and preference versus pre-FMT colonized mice. Microbial taxa that were higher in post-FMT humans were also associated with lower alcohol intake and preference in mice. RNAseq further showed that differential gene expression, post-FMT, occurred in the intestine rather than the liver and prefrontal cortex. Conclusions: FMT leads to significant change in gut microbiome population, which in turn alters gene expression in the intestine. FMT also significantly affects alcohol consumption. The microbiotal-intestinal interface may alter gut-liver-brain axis and reduce alcohol consumption in humans.

Project description:Background and study aims Colorectal cancer is the third most common cancer worldwide with 14,000 patients in the UK being diagnosed with rectal cancer per year. Over half of those patients will undergo major resectional surgery. Low anterior resection syndrome (LARS) is a consequence of this surgery and describes a constellation of bowel symptoms including urgency, faecal incontinence, stool clustering and incomplete evacuation. It has a significant adverse impact on quality of life (QoL). LARS symptoms are present in up to 75% of the patients in the first year after surgery and may persist in 25%, remaining in up to half of these patients for more than 10 years. There is poor evidence to support the various treatment options currently in use. As disease-free survival is regarded as the most important factor following curative rectal cancer surgery, QoL and potential ways to improve it may be overlooked. Patients are often not aware or not told that bowel function can change significantly following surgery and radiotherapy and may think any adverse effects will be short-term. It is not known when post-operative bowel dysfunction, which may occur after any colonic resection, can be defined as LARS and how the trajectory of LARS changes over time, especially in patients undergoing radiotherapy. An introductory cohort study aims to explore the natural history of LARS, identify predictors of major LARS and screen patients for recruitment to a randomised controlled trial (RCT) that will measure the effectiveness of the new intervention. The aims of the RCT are to evaluate the clinical and cost-effectiveness of transanal irrigation (TAI) or sacral neuromodulation (SNM) versus optimised conservative management (OCM) for people with major LARS. Who can participate? Adult participants aged over 18 years old who have undergone a high or low anterior resection for colorectal cancer in the last 10 years. Participants with major LARS symptoms, defined as a LARS score of 30+, will be eligible to be randomised to the randomised controlled trial element. What does the study involve? Participants who enter the cohort will be asked to complete questionnaires about their quality of life and bowel symptoms every 3 months for 24 months. Clinical study data will be collected at baseline and then at 12 and 24 months from registration from medical notes. Participants who enter the RCT will be randomised to receive either TAI, SNM or OCM and will then go on to receive their allocated treatment. Patients will attend the hospital at various times depending on the treatment they are receiving and will also be followed up for trial purposes at 3, 6, 9 and 12 months post-randomisation via a combination of clinic or telephone assessments. At 24 months clinical study data will be collected from medical notes.

Project description:Advances in rectal cancer management have significantly reduced morbidity and mortality. The most commonly performed operation for rectal cancer is restorative proctectomy (RP), leaving up to 70% with long-term bowel dysfunction called Low Anterior Resection Syndrome (LARS). LARS manifests as stool frequency, incontinence and difficult defecation. LARS, along with other functional impairments such as sexual and urinary dysfunction (SUD), can impact quality of life (QoL) and cause emotional distress. High-quality longitudinal data on these sequalae are lacking, leading to variable estimates of their prevalence, risk factors and prognosis. Most studies are European, cross-sectional, lack pre-treatment evaluation and long-term follow-up, and use inconsistent assessment measures. Thus, a North American study that evaluates patients longitudinally from diagnosis will provide quality data to fill this knowledge gap. The main aim of the proposed study is to contribute evidence regarding the impact of LARS, SUD, emotional/financial distress, and patient activation on long-term post-treatment QoL in North American rectal cancer after RP. This multicenter North American, observational, prospective cohort study relies on validated patient reported outcome measures (PROMs) at diagnosis, during and post-treatment. Patients from 20 sites will be recruited over 2 years and followed for 3 years. The primary endpoint is QoL as measured by the European Organization for Research & Treatment of Cancer QoL questionnaire. We anticipate accrual of 1200 patients. Factors associated with QoL will be explored. Impact of patient activation in relation to functional outcomes on QoL over time will be explored using a difference-in-differences approach. The study involves a multidisciplinary team who will provide expertise in research methodology, nursing, oncology and surgery. The main contributions of this study are 1) provision of reference baseline North American values for important rectal cancer PROMs for clinical and research use, 2) an understanding of the evolution of functional outcomes and QoL post-treatment to counsel patients peri-operatively and throughout survivorship, and 3) to provide the basis for future tailored programs to support rectal cancer survivors.

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Role of Diet and Faecal Microbiota Transplantation following Bowel Cancer Surgery

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