Effects of obesity, and of weight loss following bariatric surgery, on methylation of DNA from the rectal mucosa and in cell-free DNA from blood.

BACKGROUND: DNA methylation is an epigenetic mechanism through which environmental factors including nutrition and inflammation influence health. Obesity is a major modifiable risk factor for many common diseases including cardiovascular diseases and cancer. In particular, obesity-induced inflammation resulting from aberrantly-methylated inflammatory genes may drive risk of several non-communicable diseases including colorectal cancer (CRC). This study is the first to investigate the effects of weight loss induced by bariatric surgery (BS) on DNA methylation in the rectum and in cell-free DNA (cfDNA) from blood. SUBJECTS AND METHODS: DNA methylation was quantified in rectal mucosal biopsies and cfDNA from serum of 28 participants with obesity before and 6 months after BS, as well as in 12 participants without obesity (control group) matched for age and sex from the Biomarkers Of Colorectal cancer After Bariatric Surgery (BOCABS) Study. DNA methylation of LEP, IL6, POMC, LINE1, MAPK7 and COX2 was quantified by pyrosequencing. RESULTS: BMI decreased significantly from 41.8 kg/m2 pre-surgery to 32.3 kg/m2 at 6 months after BS. Compared with the control group, obesity was associated with lower LEP methylation in both the rectal mucosa and in cfDNA from serum. BS normalised LEP methylation in DNA from the rectal mucosa but not in cfDNA. BS decreased methylation of some CpG sites of LINE1 in the rectal mucosal DNA and in cfDNA to levels comparable with those in participants without obesity. Methylation of POMC in rectal mucosal DNA was normalised at 6 months after BS. CONCLUSION: BS reversed LINE1, POMC and LEP methylation in the rectal mucosa of patients with obesity to levels similar to those in individuals without obesity. These findings support current evidence of effects of BS-induced weight loss on reversibility of DNA methylation in other tissues. The DNA methylation changes in the rectal mucosa shows promise as a biomarker for objective assessment of effects of weight loss interventions on risk of cancer and other diseases.

Obesity and Roux-en-Y gastric bypass drive changes in miR-31 and miR-215 expression in the human rectal mucosa.

BACKGROUND/OBJECTIVES: Obesity increases colorectal cancer (CRC) risk. However, the effects of weight loss on CRC risk are unclear. Epigenetic mechanisms involving microRNAs that lead to dysregulated gene expression may mediate the effects of obesity and weight loss on CRC risk. We examined the effects of obesity and weight loss following Roux-en-Y gastric bypass (RYGB) on microRNA expression in the human rectal mucosa. SUBJECTS/METHODS: We collected rectal mucosal biopsies from obese patients (n = 22) listed for RYGB and age- and sex-matched healthy non-obese Controls (n = 20), at baseline and six months post-surgery. We quantified microRNA expression in rectal mucosal biopsies using Next Generation Sequencing and bioinformatics analysis to investigate the likely functional consequences of these epigenetic changes. RESULTS: Compared with non-obese individuals, obese individuals showed differential expression of 112 microRNAs (p < 0.05). At six-months post-RYGB, when mean body mass had fallen by 27 kg, 60 microRNAs were differentially expressed, compared with baseline (p < 0.05). The expression of 36 microRNAs differed significantly between both i) obese and non-obese individuals and ii) obese individuals pre- and post-RYGB. Quantitative polymerase chain reaction (qPCR) demonstrated that expression of miR-31 and miR-215 was significantly (p < 0.05) higher, 143-fold and 15-fold respectively, in obese than in non-obese individuals. Weight loss, following RYGB, reduced expression of miR-31 and miR-215 to levels comparable with Controls. These differentially expressed microRNAs are implicated in pathways linked with inflammation, obesity and cancer. CONCLUSION: Our findings show, for the first time, that obesity is associated with dysregulated microRNA expression in the human rectal mucosa. Further, surgically-induced weight loss may normalise microRNA expression in this tissue.

The role of damage control surgery in the treatment of perforated colonic diverticulitis: a systematic review and meta-analysis.

INTRODUCTION: Damage control surgery (DCS) is the classic approach to manage severe trauma and has recently also been considered an appropriate approach to the treatment of critically ill patients with severe intra-abdominal sepsis. The purpose of the present review is to evaluate the outcomes following DCS for Hinchey II-IV complicated acute diverticulitis (CAD). METHODS: A comprehensive systematic search was undertaken to identify all randomized clinical trials (RCTs) and observational studies, irrespectively of their size, publication status, and language. Adults who have undergone DCS for CAD Hinchey II, III, or IV were included in this review. DCS is compared with the immediate and definitive surgical treatment in the form of HP, colonic resection, and primary anastomosis (RPA) with or without covering stoma or laparoscopic lavage. We searched the following electronic databases: PubMed MEDLINE, Scopus, and ISI Web of Knowledge. The protocol of this systematic review and meta-analysis was published on Prospero (CRD42020144953). RESULTS: Nine studies with 318 patients, undergoing DCS, were included. The presence of septic shock at the presentation in the emergency department was heterogeneous, and the weighted mean rate of septic shock across the studies was shown to be 35.1% [95% CI 8.4 to 78.6%]. The majority of the patients had Hinchey III (68.3%) disease. The remainder had either Hinchey IV (28.9%) or Hinchey II (2.8%). Phase I is similarly described in most of the studies as lavage, limited resection with closed blind colonic ends. In a few studies, resection and anastomosis (9.1%) or suture of the perforation site (0.9%) were performed in phase I of DCS. In those patients who underwent DCS, the most common method of temporary abdominal closure (TAC) was the negative pressure wound therapy (NPWT) (97.8%). The RPA was performed in 62.1% [95% CI 40.8 to 83.3%] and the 22.7% [95% CI 15.1 to 30.3%]: 12.8% during phase I and 87.2% during phase III. A covering ileostomy was performed in 6.9% [95% CI 1.5 to 12.2%]. In patients with RPA, the overall leak was 7.3% [95% CI 4.3 to 10.4%] and the major anastomotic leaks were 4.7% [95% CI 2.0 to 7.4%]; the rate of postoperative mortality was estimated to be 9.2% [95% CI 6.0 to 12.4%]. CONCLUSIONS: The present meta-analysis revealed an approximately 62.1% weighted rate of achieving GI continuity with the DCS approach to generalized peritonitis in Hinchey III and IV with major leaks of 4.7% and overall mortality of 9.2%. Despite the promising results, we are aware of the limitations related to the significant heterogeneity of inclusion criteria. Importantly, the low rate of reported septic shock may point toward selection bias. Further studies are needed to evaluate the clinical advantages and cost-effectiveness of the DCS approach.

Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations.

Inherited mitochondrial DNA (mtDNA) mutations cause mitochondrial disease, but mtDNA mutations also occur somatically and accumulate during ageing. Studies have shown that the mutation load of some inherited mtDNA mutations decreases over time in blood, suggesting selection against the mutation. However, it is unknown whether such selection occurs in other mitotic tissues, and where it occurs within the tissue. Gastrointestinal epithelium is a canonical mitotic tissue rapidly renewed by stem cells. Intestinal crypts (epithelium) undergo monoclonal conversion with a single stem cell taking over the niche and producing progeny. We show: (1) that there is a significantly lower mtDNA mutation load in the mitotic epithelium of the gastrointestinal tract when compared to the smooth muscle in the same tissue in patients with the pathogenic m.3243A>G and m.8344A>G mutations; (2) that there is considerable variation seen in individual crypts, suggesting changes in the stem cell population; (3) that this lower mutation load is reflected in the absence of a defect in oxidative phosphorylation in the epithelium. This suggests that there is selection against inherited mtDNA mutations in the gastrointestinal stem cells that is in marked contrast to the somatic mtDNA mutations that accumulate with age in epithelial stem cells leading to a biochemical defect. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Perforated sigmoid diverticulitis: Hartmann's procedure or resection with primary anastomosis-a systematic review and meta-analysis of randomised control trials.

INTRODUCTION: The surgical management of perforated sigmoid diverticulitis and generalised peritonitis is challenging. Surgical resection is the established standard of care. However, there is debate as to whether a primary anastomosis (PA) or a Hartmann's procedure (HP) should be performed. The aim of the present study was to perform a review of the literature comparing HP to PA for the treatment of perforated sigmoid diverticulitis with generalised peritonitis. METHODS: A systematic literature search was performed for articles published up to March 2018. We considered only randomised control trials (RCTs) comparing the outcomes of sigmoidectomy with PA versus HP in adults with perforated sigmoid diverticulitis and generalised peritonitis (Hinchey III or IV). Primary outcomes were mortality and permanent stoma rate. Outcomes were pooled using a random-effects model to estimate the risk ratio and 95% confidence intervals. RESULTS: Of the 1,204 potentially relevant articles, 3 RCTs were included in the meta-analysis with 254 patients in total (116 and 138 in the PA and HP groups, respectively). All three RCTs had significant limitations including small size, lack of blinding and possible selection bias. There was no statistically significant difference in mortality or overall morbidity. Although 2 out of the 3 trials reported a lower permanent stoma rate in the PA arm, the difference in permanent stoma rates was not statistically significant (RR = 0.40, 95% CI 0.14-1.16). The incidence of anastomotic leaks, including leaks after stoma reversal, was not statistically different between PA and HP (RR = 1.42, 95% CI 0.41-4.87, p = 0.58) while risk of a postoperative intra-abdominal abscess was lower after PA than after HP (RR = 0.34, 95% CI 0.12-0.96, p = 0.04). CONCLUSIONS: PA and HP appear to be equivalent in terms of most outcomes of interest, except for a lower intra-abdominal abscess risk after PA. The latter finding needs further investigation as it was not reported in any of the individual trials. However, given the limitations of the included RCTs, no firm conclusion can be drawn on which is the best surgical option in patients with generalised peritonitis due to diverticular perforation.

Biomarkers of Colorectal Cancer Risk Decrease 6 months After Roux-en-Y Gastric Bypass Surgery.

PURPOSE: The impact of weight loss on obesity-related colorectal cancer (CRC) risk is not well defined. Previous studies have suggested that Roux-en-Y gastric bypass (RYGB) surgery may have an unexpected adverse impact on CRC risk. This study aimed to investigate the impact of RYGB on biomarkers of CRC risk. MATERIALS AND METHODS: Rectal mucosal biopsies and blood were obtained from patients undergoing RYGB (n = 22) and non-obese control participants (n = 20) at baseline and at a median of 6.5 months after surgery. Markers of systemic inflammation and glucose homeostasis were measured. Expression of pro-inflammatory genes and proto-oncogenes in the rectal mucosa was quantified using qPCR. Crypt cell proliferation state of the rectal mucosa was assessed by counting mitotic figures in whole micro-dissected crypts. RESULTS: At 6.5 months post-surgery, participants had lost 29 kg body mass and showed improvements in markers of glucose homeostasis and in systemic inflammation. Expression of pro-inflammatory genes in the rectal mucosa did not increase and COX-1 expression fell significantly (P = 0.019). The mean number of mitoses per crypt decreased from 6.5 to 4.3 (P = 0.028) after RYGB. CONCLUSION: RYGB in obese adults led to lower rectal crypt cell proliferation, reduced systemic and mucosal markers of inflammation and improvements in glucose regulation. These consistent findings of reduced markers of tumourigenic potential suggest that surgically induced weight loss may lower CRC risk.

A historical review of surgery for peritonitis secondary to acute colonic diverticulitis: from Lockhart-Mummery to evidence-based medicine.

The management of patients with colonic diverticular perforation is still evolving. Initial lavage with or without simple suture and drainage was suggested in the late 19th century, replaced progressively by the three-stage Mayo Clinic or the two-stage Mickulicz procedures. Fears of inadequate source control prompted the implementation of the resection of the affected segment of colon with formation of a colostomy (Hartman procedure) in the 1970's. Ensuing development of the treatment strategies was driven by the recognition of the high morbidity and mortality and low reversal rates associated with the Hartman procedure. This led to the wider use of resection and primary anastomosis during the 1990's. The technique of lavage and drainage regained popularity during the 1990's. This procedure can also be performed laparoscopically with the advantage of faster recovery and shorter hospital stay. This strategy allows resectional surgery to be postponed or avoided altogether in many patients; and higher rates of primary resection and anastomosis can be achieved avoiding the need for a stoma. The three recent randomized controlled trials comparing laparoscopic peritoneal lavage alone to resectional surgery reported inconsistent outcomes. The aim of this review is to review the historical evolution and future reflections of surgical treatment modalities for diffuse purulent and feculent peritonitis. In this review we classified the various surgical strategies according to Krukowski et al. and Vermeulen et al. and reviewed the literature related to surgical treatment separately for each period.

Changes in physical activity after bariatric surgery: using objective and self-reported measures.

BACKGROUND: Many studies using self-reported physical activity (PA) assessment tools have suggested there is an increase in PA after bariatric surgery. OBJECTIVES: Our aim was to assess PA and sedentary behavior before bariatric surgery and at 6 months after, using subjective and objective tools. SETTING: Bariatric surgery candidates were recruited from a single center. METHODS: Demographic data, medical history, current medications, and anthropometric measurements were recorded. Participants were asked to complete a PA and lifestyle questionnaire and to wear an accelerometer on their nondominant wrist. Data were collected before and at 6 months after surgery. RESULTS: Twenty-two participants were included (17 gastric bypass; 4 sleeve gastrectomy; 1 intragastric balloon). Mean age was 46 years and the majority were female (72%). At a median of 6.3 months follow-up, there were significant reductions in measures of body fatness with a mean reduction of 27 kg in weight. The majority of daytime (12.5±1.1 out of 16 h) was spent in sedentary behavior presurgery with little change postsurgery (12.2±1.2; P = .186). Objectively measured mean moderate-vigorous PA did not change significantly from pre- to postsurgery (mean 11.5±13.9 and 11.6±13.1 min/d, respectively; P = .971). Self-reported total nonoccupational PA did not change significantly (P = .390). CONCLUSIONS: The majority of bariatric surgery candidates were physically inactive presurgery, and there was no significant change in either subjectively or objectively measured PA at follow-up. This patient group may benefit from objective PA assessment and interventions aimed at increasing PA.

The Effects of Bariatric Procedures on Bowel Habit.

BACKGROUND: Bariatric procedures are increasingly being used to combat the rising obesity epidemic. The aim of this study was to assess the effect of these interventions on bowel habit. METHODS: We recruited obese adults listed for a bariatric procedure. Demographic data, medical history, medications and anthropometric measurements were recorded. Bowel habit was characterized using a 7-day Bristol Stool Form Scale (BSFS) diary. A validated food frequency questionnaire (FFQ) was used to assess diet. RESULTS: Twenty-six patients were assessed pre-operatively and at a median of 6.4 months post-operatively. Nineteen had a Roux-en-Y gastric bypass (RYGB), five had a sleeve gastrectomy (SG) and two had an intra-gastric balloon (IGB) with median percentage excess weight loss (% EWL) of 67.9, 52.4 and 31.3 %, respectively. Dietary fibre intake decreased from 24.4 (±12.1) g/day pre-operatively to 17.5 (±7.3) g/day post-operatively (P = 0.008). Frequency of bowel motions decreased from 8.6 (±3.5) to 5.7 (±3.5) motions/week (P = 0.001). Mean usual BSFS score decreased (towards firmer stool) from 4.1 (±1.3) pre-operatively to 3.1 (±1.9) post-operatively (P = 0.016). Constipation increased from 8 to 27 %, but this did not reach statistical significance (P = 0.125). CONCLUSIONS: Constipation is a common problem after bariatric surgery. The decrease in bowel motion frequency and change towards firmer stools suggest prolonged intestinal transit time after bariatric procedures. Reduction in dietary fibre intake is likely to be a contributory factor.

Effect of vitamin C and vitamin E supplementation on endothelial function: a systematic review and meta-analysis of randomised controlled trials.

Randomised controlled trials (RCT) testing the effects of antioxidant supplements on endothelial function (EF) have reported conflicting results. We aimed to investigate the effects of supplementation with antioxidant vitamins C and E on EF and to explore factors that may provide explanations for the inconsistent results. We searched four databases (MEDLINE, Embase, Cochrane Library and Scopus) from inception until May 2014 for RCT involving adult participants aged ≥18 years who were supplemented with vitamins C and E alone or in combination for more than 2 weeks and reporting changes in EF measured using flow mediated dilation or forearm blood flow. Data were pooled as standardised mean difference (SMD) and analysed using a random-effects model. Significant improvements in EF were observed in trials supplementing with vitamin C alone (500-2000 mg/d) (SMD: 0·25, 95% CI 0·02, 0·49, P=0·043) and vitamin E alone (300-1800 IU/d; 1 IU vitamin E=0·67 mg natural vitamin E) (SMD: 0·48, 95% CI 0·23, 0·72, P=0·0001), whereas co-administration of both vitamins was ineffective (vitamin C: 500-2000 mg/d; vitamin E: 400-1200 IU/d) (SMD: 0·12, 95% CI-0·18, 0·42, P=0·428). The effect of vitamin C supplementation on EF increased significantly with age (ß 0·023, 95% CI 0·001, 0·05, P=0·042). There was a significant negative correlation between baseline plasma vitamin E concentration and the effect of vitamin E supplementation on EF (ß-0·03, 95% CI-0·06, -0·001, P=0·029). Supplementation with either vitamin C or vitamin E alone improves EF. However, subgroup analysis emphasises the importance of careful characterisation and selection of a population group which may benefit from such supplementation.

Transanal Endoscopic Microsurgery (TEM) for Rectal Cancer: University Hospital of North Tees Experience.

Transanal endoscopic microsurgery (TEM) is a minimally invasive technique that is increasingly being used to treat early rectal cancer (T1/T2). We studied the outcomes of TEM for rectal cancer at our institution looking at the indication, recurrence rate, need for further radical surgery, 30-day and 12-month mortality and complication rate. We performed a retrospective analysis of prospectively collected data of cases between 2008 and 2012: 110 TEM procedures were performed during this period: 40 were confirmed rectal cancers and 70 were benign. We analysed the data for the 40 patients with confirmed rectal cancer. Thirty (75 %) of the subjects were male with a mean age of 71 ± 10 years (range 49-90 years) and 19 (48 %) patients were ASA 3 and 4. Nineteen (48 %) of cancers were pT1, eighteen (45 %) were pT2, two (5 %) were pT3 and one was yPT0. Mean specimen size was 66 ± 20 mm (range 33-120 mm) with a mean polyp size of 41 ± 24 mm (range 18-110 mm). The mean cancer size was 24 ± 13 mm (range 2-50 mm). Average distance from the anal verge was 70 ± 37 mm (range 10-150 mm), and the mean operating time was 72 ± 22 min (range 40-120 min), with an average blood loss of 28 ± 15 ml (range 10-50ml). Median hospital stay was 2 ± 1 days (range 1-7 days). Complete excision (R0) was achieved in 37 (93 %) patients. Minor post-operative complications included urinary retention in two and pyrexia in three patients. There were no 30-day or 12-month mortalities. Mean follow-up was 13 ± 11 months, range (3-40 months) Local recurrence occurred in two (5 %) patients, both underwent redo TEM. Twelve (30 %) patients underwent laparoscopic radical resections (seven AR and five APER) post-TEM. Post-operative histology confirmed pT0N0 in 7/12 patients. Three were lymph node-positive (T0N1), one was pT3N1 and the fifth was pT3N2. TEM is associated with quicker recovery, shorter hospital stay and fewer complications than radical surgery. It is a good alternative to radical surgery in early rectal cancer, especially for high-risk patients. Recurrent tumours can be treated with redo TEM.

The effects of bariatric surgery on colorectal cancer risk: systematic review and meta-analysis.

Obesity is an established risk factor for colorectal cancer (CRC) but the effects of bariatric surgery on CRC incidence are uncertain. A systematic review of six electronic databases identified 3691 articles. Four observational studies met our inclusion criteria and results were pooled using a random effects model. Meta-analysis of these four studies revealed that bariatric surgery was associated with a significantly (p = 0.004) lower CRC incidence (RR = 0.73, 95 % confidence interval, 0.58 - 0.90) when compared with obese non-operated individuals, i.e., bariatric surgery is associated with a 27 % lower CRC risk. However the evidence base is limited and these findings should be confirmed by future studies with improved designs.