Emerging role of environmental pollutants in inflammatory bowel disease risk, outcomes and underlying mechanisms.

Epidemiological and translational data increasingly implicate environmental pollutants in inflammatory bowel disease (IBD). Indeed, the global incidence of IBD has been rising, particularly in developing countries, in parallel with the increased use of chemicals and synthetic materials in daily life and escalating pollution levels. Recent nationwide and ecological studies have reported associations between agricultural pesticides and IBD, particularly Crohn's disease. Exposure to other chemical categories has also been linked with an increased risk of IBD. To synthesise available data and identify knowledge gaps, we conducted a systematic review of human studies that reported on the impact of environmental pollutants on IBD risk and outcomes. Furthermore, we summarised in vitro data and animal studies investigating mechanisms underlying these associations. The 32 included human studies corroborate that heavy and transition metals, except zinc, air pollutants, per- and polyfluorinated substances, and pesticides are associated with an increased risk of IBD, with exposure to air pollutants being associated with disease-related adverse outcomes as well. The narrative review of preclinical studies suggests several overlapping mechanisms underlying these associations, including increased intestinal permeability, systemic inflammation and dysbiosis. A consolidated understanding of the impact of environmental exposures on IBD risk and outcomes is key to the identification of potentially modifiable risk factors and to inform strategies towards prediction, prevention and mitigation of IBD.

Preparation Regimens to Improve Capsule Endoscopy Visualization and Diagnostic Yield (PrepRICE): a multicenter randomized trial.

BACKGROUND AND AIMS: Current guidelines recommend bowel preparation before small-bowel capsule endoscopy (SBCE). However, the optimal protocol is yet to be defined. To determine the best timing for preparation in SBCE, we compared small-bowel visualization quality (SBVQ), diagnostic yield (DY), and patient-reported outcomes across 4 purgative regimens. METHODS: In this prospective, randomized (1:1:1:1), multicenter study, patients with suspected small-bowel bleeding were randomized into 4 arms: G1 (1 L of polyethylene glycol + ascorbic acid [Moviprep, Norgine, Amsterdam, Netherlands] the night before SBCE), G2 (1 L in the morning up to 2 hours before SBCE), G3 (0.5 L up to 2 hours before SBCE + 0.5 L after the capsule reached the duodenum), and G4 (1 L after the capsule reached the duodenum). To assess DY, lesions were categorized as having high (P2) or low (P0 or P1) bleeding potential. SBVQ was assessed using the Brotz score. Transit times were measured, and patient tolerability was scored from 0 to 5, with higher scores indicating better tolerability. RESULTS: A total of 387 patients were included, 59% female and with a median age of 73 years (interquartile range, 23). The examination completion rate was lower in G1 (90%, P < .001). Small-bowel transit time was shorter for patients receiving purgative during SBCE (G3 and G4, P = .001). SBVQ was better in patients receiving purgative after reaching the small bowel (P < .001): a median of 7 for G1, 8 for G2, and 9 for G3 and G4. The overall DY of patients receiving intraprocedure purgatives (G3 + G4) was superior (42.7 vs 31.3%, P = .02); significant differences were found in the second and third terciles. Likewise, G3 and G4 had higher angioectasia detection (P = .04). Patients' satisfaction was significantly superior for G4 (median, 4 points; interquartile range, 1). CONCLUSIONS: The group that received the bowel preparation the night before SBCE had poorer outcomes. Intraprocedure purgative regimens reduced SBTT, enhanced visualization, improved DY, and increased angioectasia detection. G4 was the best-tolerated regimen.

Lung abscess in a non-compliant patient with Crohn's disease.

A 66-year-old man was admitted to the emergency department due to malaise, fatigue and anorexia for the last 2 weeks. He presented no fever, no respiratory or gastrointestinal symptoms. The patient had been previously diagnosed with Crohn's Disease (CD) (A2L1L4B1 of Montreal Classification) 10 years before, when he presented complaints of watery diarrhea and unexplained weight loss. Despite refusing to start treatment, in the last staging exams performed 5 years before the admission (colonoscopy and magnetic resonance imaging) the patient was in deep remission. Nevertheless, he frequently missed his medical appointments and his disease had not been monitored since then. He denied previous use of corticosteroids, past abdominal surgery or previous CD related hospital admissions. He also denied smoking habits or chronic lung disease.

Dipeptidyl peptidase 4 (DPP4) in fecal samples: validation of the extraction methodology and stability in short-term storage conditions.

OBJECTIVES: This study assesses the clinical relevance of dipeptidyl peptidase 4 (DPP4) membrane exopeptidase as a biomarker of inflammatory bowel disease (IBD). A spike-and-recovery approach of DPP4 in fecal samples was used to compare two different methods for protein extraction, followed by a stability assessment. METHODS: Fecal samples of healthy volunteers spiked with known concentrations of recombinant DPP4 were processed using a standard manual extraction protocol and the CALEX® protocol. The two methods were compared by quantification of fecal DPP4 by ELISA, followed by Bland-Altman analysis. For the stability assays DPP4 was extracted from fecal samples and stored under different conditions of temperature and time after collection. RESULTS: In general, the levels of spiked DPP4 in stool samples were lower with the manual protocol than in those obtained with the CALEX® method; this trend was corroborated by Bland-Altman analysis. Nonetheless, variability was within the acceptable limits for both protocols. In the stability assessment, no statistically significant differences were found between the results obtained under the different storage conditions. CONCLUSIONS: Both manual and CALEX® protocols provided equal extraction ability of DPP4 from stool samples. In addition, DPP4 provided flexibility in terms of sample storage enabling the accurate assessment of samples delivered up to a week before analysis.

A full hemostatic repertoire in a complex cirrhotic patient.

A 55-year-old woman with cirrhosis was admitted for acute decompensation caused by portal vein thrombosis. Ten days later, the patient presented melena. Esophagogastroscopy revealed two gastric polyps, both with bleeding stigmata. One of the polyps was removed with a diathermic loop, after adrenalin injection, while in the other the "ligate and let go" technique was applied, after biopsy. A "metallic tulip-bundle" technique, combining through the scope and over-the-scope clips, was applied for hemostasis. This case underlines how the combination of various endoscopic techniques may be useful to manage upper gastrointestinal bleeding, especially in patients with important comorbidities.

Hemostasis of a bleeding inverted colonic diverticulum.

The authors report a case of a 62-year-old male presenting to the emergency department with hematochezia. Urgent colonoscopy revealed numerous diverticula in the sigmoid colon, two of them inverted. Oozing bleeding from a visible vessel was identified on the top of the most distal inverted diverticulum. An over-the-scope clip was released after suction into the transparent cap and successful hemostasis was achieved.

Closure of a perforated endoscopic submucosal dissection eschar using three over-the-scope clips.

We report the use of three partially overlapping over-the-scope clips to close a perforated ESD eschar. This case illustrates the relevance of prompt acting to ensure ESD safety and reinforces the feasibility of endoscopic treatment for challenging iatrogenic perforations, reducing the need for urgent surgery and its related morbidity and mortality.

Endoscopic "purse-string" to close a rectal endoscopic submucosal dissection eschar with intentional muscular sectioning.

This case demonstrates the utility of the "purse string" to close large defects and shows that optical diagnosis may have pitfalls in evaluating the invasion of neoplastic lesions, particularly large ones.

Effective submucosal tunneling endoscopic resection (STER) of a giant esophageal leiomyoma.

We report the successful removal of a giant esophageal leiomyoma using submucosal tunneling endoscopic resection in a 37-year-old woman with significant dysphagia.

Multiple GIST and pheochromocytoma - A rare association in neurofibromatosis type 1.

We describe a case of coexistence of multiple gastrointestinal stromal tumors (GIST) and pheochromocytoma in a 32-year-old patient with neurofibromatosis type 1. The coexistence of these two conditions in patients with this syndrome is extremely rare.

Forecast models to predict the demand for endoscopic procedures in a tertiary unit: a prospective validation.

Over the past few decades, there has been an exponential increase in the utilization of endoscopic procedures. Accurately predicting the demand is crucial for effective capacity planning and resource allocation in the endoscopic unit. However, predictive models are not integrated into current endoscopy software. To overcome this limitation, our group used data on the demand in our tertiary unit from 2015 to 2021 (83 months) to develop forecast models using exponential smoothing techniques adjusted for trend and seasonality (derivation phase). These models were recently published at the Revista Española de Enfermedades Digestivas.

Predicting the future: introducing business analytics to endoscopy units.

BACKGROUND AND AIMS: currently, most endoscopy software only provides limited statistics of past procedures, while none allows patterns to be extrapolated. To overcome this need, the authors applied business analytic models to predict future demand and the need for endoscopists in a tertiary hospital Endoscopy Unit. METHODS: a query to the endoscopy database was performed to retrieve demand from 2015 to 2021. The graphical inspection allowed inferring of trends and seasonality, perceiving the impact of the COVID-19 pandemic, and selecting the best forecasting models. Considering COVID-19's impact in the second quarter of 2020, data for esophagogastroduodenoscopy (EGD) and colonoscopy was estimated using linear regression of historical data. The actual demand in the first two quarters of 2022 was used to validate the models. RESULTS: during the study period, 53,886 procedures were requested. The best forecasting models were: a) simple seasonal exponential smoothing for EGD, colonoscopy and percutaneous endoscopic gastrostomy (PEG); b) double exponential smoothing for capsule endoscopy and deep enteroscopy; and c) simple exponential smoothing for endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS). The mean average percentage error ranged from 6.1 % (EGD) to 33.5 % (deep enteroscopy). Overall, 8,788 procedures were predicted for 2022. The actual demand in the first two quarters of 2022 was within the predicted range. Considering the usual time allocation for each technique, 3.2 full-time equivalent endoscopists (40 hours-dedication to endoscopy) will be required to perform all procedures in 2022. CONCLUSIONS: the incorporation of business analytics into the endoscopy software and clinical practice may enhance resource allocation, improving patient-focused decision-making and healthcare quality.

Are sarcopenia, frailty and malnutrition prognostic markers of liver disease decompensation in the ambulatory setting? - A prospective cohort study.

BACKGROUND: Sarcopenia, frailty and malnutrition are associated with adverse outcomes in liver cirrhosis. Studies assessing the prognostic value of these conditions in ambulatory patients with cirrhosis are scarce. METHODS: A prospective cohort study was conducted, with consecutive inclusion of all patients with cirrhosis observed in the Hepatology outpatient clinic of a Portuguese tertiary centre. At study enrolment, evaluation of muscle mass (ultrasound quadriceps femoris thickness), muscle strength (handgrip dynamometry) and nutritional status (Patient-Generated Subjective Global Assessment Short Form) was held. Follow-up ended upon the occurrence of a composite endpoint, comprising liver decompensation events and liver-related death, or last medical appointment/non-liver related death before the end of the study. The prognostic value of anthropometrical parameters and nutritional status in the composite endpoint was assessed using a multivariate Cox regression analysis, adjusted for several confounders. RESULTS: Ninety patients were enrolled (80% male), with a mean age of 63.5±10.5 years. The median follow-up was 30 (interquartile range 38) weeks, during which 12 patients reached the composite endpoint. These patients presented a lower mean handgrip strength [23.1±6.41 vs 30.3±10.4 Kg, p=0.04], compared to patients who did not reach the composite endpoint. On Cox regression multivariate analysis, however, no independent predictors of the composite endpoint were found, apart from previous decompensation episodes. CONCLUSION: In this study, muscle strength was lower in the group of patients with cirrhosis who presented a liver-related event. Handgrip strength might be a promising tool in the ambulatory setting to identify patients at risk of liver decompensation and liver-related death in the short term.

Diagnostic and therapeutic yields of early capsule endoscopy and device-assisted enteroscopy in the setting of overt GI bleeding: a systematic review with meta-analysis.

BACKGROUND AND AIMS: Small-bowel capsule endoscopy (SBCE) and device-assisted enteroscopy (DAE) are essential in obscure GI bleeding (OGIB) management. However, the best timing for such procedures remains unknown. This meta-analysis aimed to compare, for the first time, diagnostic and therapeutic yields, detection of active bleeding and vascular lesions, recurrent bleeding, and mortality of "early" versus "nonearly" SBCE and DAE. METHODS: MEDLINE, ScienceDirect, and Cochrane Central Register of Controlled Trials were searched to identify studies comparing early versus nonearly SBCE and DAE. Random-effects meta-analysis was performed; reporting quality was assessed. RESULTS: From 1974 records, 39 were included (4825 patients). Time intervals for the early approach varied, within 14 days in SBCE and 72 hours in DAE. The pooled diagnostic and therapeutic yields of early DAE were superior to those of SBCE (7.97% and 20.89%, respectively; P < .05). The odds for active bleeding (odds ratio [OR], 5.09; I2 = 53%), positive diagnosis (OR, 3.99; I2 = 45%), and therapeutic intervention (OR, 3.86; I2 = 67%) were higher in the early group for SBCE and DAE (P < .01). Subgroup effects in diagnostic yield were only identified for the early group sample size. Our study failed to identify differences when studies were classified according to time intervals for early DAE (I2 < 5%), but the analysis was limited because of a lack of data availability. Lower recurrent bleeding in early SBCE and DAE was observed (OR, .40; P < .01; I2 = 0%). CONCLUSIONS: The role of small-bowel studies in the early evaluation of OGIB is unquestionable, impacting diagnosis, therapeutic intervention, and prognosis. Comparative studies are still needed to identify optimal timing.

Potassium channels in intestinal epithelial cells and their pharmacological modulation: a systematic review.

Several potassium channels (KCs) have been described throughout the gastrointestinal tract. Notwithstanding, their contribution to both physiologic and pathophysiologic conditions, as inflammatory bowel disease (IBD), remains underexplored. Therefore, we aim to systematically review, for the first time, the evidence on the characteristics and modulation of KCs in intestinal epithelial cells (IECs). PubMed, Scopus, and Web of Science were searched to identify studies focusing on KCs and their modulation in IECs. The included studies were assessed using a reporting inclusiveness checklist. From the 745 identified records, 73 met the inclusion criteria; their reporting inclusiveness was moderate-high. Some studies described the physiological role of KCs, while others explored their importance in pathological settings. Globally, in IBD animal models, apical KCa1.1 channels, responsible for luminal secretion, were upregulated. In human colonocytes, basolateral KCa3.1 channels were downregulated. The pharmacological inhibition of K2P and Kv influenced intestinal barrier function, promoting inflammation. Evidence suggests a strong association between KCs expression and secretory mechanisms in human and animal IECs. Further research is warranted to explore the usefulness of KC pharmacological modulation as a therapeutic target.

Histologic Features of Colon Biopsies (Geboes Score) Associated With Progression of Ulcerative Colitis for the First 36 Months After Biopsy.

BACKGROUND & AIMS: In addition to findings from endoscopy, histologic features of colon biopsies have been associated with outcomes of patients with ulcerative colitis (UC). We investigated associations between Geboes scores (a system to quantify structural changes and inflammatory activity in colon biopsies) and UC progression, and the time period over which this association is valid. METHODS: We analyzed data from 399 asymptomatic patients with UC enrolled in the ACERTIVE study, followed at 13 inflammatory bowel disease (IBD) centers in Portugal through 31 December 2019. Blood and stool samples were collected and analyzed, and all patients underwent sigmoidoscopy within 24 h of sample collection. We assessed baseline endoscopic status (Mayo endoscopic subscore), histologic features of 2 sigmoid and 2 rectal biopsies (Geboes score), and concentration of fecal calprotectin (FC). The primary outcome was UC progression (surgical, pharmacologic, and clinical events). We generated survival curves for 36 months or less and more than 36 months after biopsy according to Geboes score using the Kaplan-Meier method and compared findings with those from a log rank test. Cox regression was adjusted for Mayo endoscopic subscore, Geboes score, and level of FC; results were expressed as adjusted hazard ratios (HR) with 95% CIs. RESULTS: Patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 had a higher frequency of, and a shorter time to UC progression, than patients with Geboes scores ≤2B.0, Geboes scores ≤3.0, or Geboes score ≤4.0 (P < .001). Disease progression occurred earlier in patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 compared with patients with Geboes scores ≤2B.0 (HR, 2.021; 95% CI, 1.158-3.526), Geboes scores ≤3.0 (HR, 2.007; 95% CI, 1.139-3.534), or Geboes scores ≤4.0 (HR, 2.349; 95% CI, 1.269-4.349), respectively, in the first 36 months after biopsy. Similar results were found for patients with concentrations of FC below 150 µg/g. CONCLUSIONS: We found histologic features of colon biopsies (Geboes score) to be an independent risk factor for progression of UC in the first 36 months after biopsy.

Timing of enteroscopy in overt-obscure gastrointestinal bleeding: a systematic review and meta-analysis.

BACKGROUND: the impact of early enteroscopy on the outcome of overt-obscure gastrointestinal bleeding (OGIB) is still unclear. Our aim was to evaluate the impact of early enteroscopy on overt-OGIB. METHODS: the PubMed-MEDLINE, Web of Science, and Scopus databases were systematically reviewed. Observational retrospective studies comparing early versus non-early enteroscopy in overt-OGIB were identified. Data on diagnosis, treatment, and rebleeding were extracted from each study, and a meta-analysis was performed. RESULTS: fifteen studies (comprising 1,907 patients) were included. Early enteroscopy was performed in 470 patients and non-early enteroscopy in 1,437 patients. Early enteroscopy was associated with a significantly higher diagnostic yield (odds ratio [OR] = 3.2, 95 % CI: 1.9-5.3; p = 0.002) and therapeutic yield (OR = 4.9, 95 % CI: 1.2-20.5; p = 0.03). However, moderate and high heterogeneity was observed in both analyses (DY I2 = 60.4 %; p = 0.002; TY I2 = 83.1 %; p < 0.001). When considering only studies where enteroscopy was performed during ongoing bleeding or within ≤ 24 h, ≤ 48 h, and ≤ 72 h of bleeding, heterogeneity was removed while the positive effect on diagnostic yield was maintained (OR = 4.7, 95 % CI: 3.4-6.6, p < 0.001, I2 = 0 %). Early enteroscopy did not significantly influence rebleeding rate (OR = 0.87, 95 % CI: 0.40-1.89, p = 0.72) in our analysis. CONCLUSIONS: in conclusion, early enteroscopy, especially when performed during ongoing bleeding or within 24 h, 48 h or 72 h of the bleeding episode, may increase diagnostic yield. Although an effect on therapeutic yield was observed, the value of early intervention has to be cautiously evaluated due to the high heterogeneity found among results. In our meta-analysis, early enteroscopy did not significantly influence rebleeding rate.

Features of Fecal and Colon Microbiomes Associate With Responses to Biologic Therapies for Inflammatory Bowel Diseases: A Systematic Review.

BACKGROUND & AIMS: We performed a systematic review of changes in fecal and colon microbiomes of patients with inflammatory bowel diseases (IBDs) receiving treatment with monoclonal antibodies against tumor necrosis factor, integrins, or cytokines. We explored associations among microbiome composition and functions (at baseline and throughout the treatment) and therapy-related outcomes to determine whether colon or fecal microbiomes might be used as biomarkers of response to therapy. METHODS: We searched the PubMed, Web of Science, and Science Direct databases through February 2019 for studies of associations among the microbiomes of fecal or colon samples, biologic therapies, and IBDs. We used the critical appraisal skills program checklist to assess the quality of the study methods. RESULTS: From the 787 citations identified, 10 studies met the inclusion criteria. Changes in microbiomes of fecal or colon samples after treatment did not differ significantly among biologic agents; all produced decreases in relative abundances of Escherichia and Enterococcus and increases in genera that produce short-chain fatty acids. Fecal or colon microbiomes of patients who responded to therapy with antagonists of tumor necrosis factor or interleukins had higher α-diversity and increased relative abundances of different genera (Faecalibacterium, Roseburia, or Clostridium) from the Clostridiales order, either at baseline or during follow-up evaluation. Patients in remission after treatment with antibodies against integrins had decreased abundances of Roseburia. CONCLUSIONS: In a systematic review of 10 studies, we found evidence for consistent changes in microbiomes of fecal and colon samples from patients with IBD who responded to treatment with biologic agents. Prospective studies are needed to determine what changes are associated significantly with treatment, whether these changes are causes or effects of response, or whether the composition of the intestinal microbiome can be used to select treatments for patients with IBD.

Inflammatory Bowel Disease - Non-biological treatment.

Nowadays, non-biological treatments remain valuable approaches among the therapeutic armamentarium of inflammatory bowel disease (IBD). Mesalamine is the core treatment of mild­to­moderate ulcerative colitis (UC) and corticosteroids are crucial for the induction of remission of moderate­to­severe flares in both UC and Crohn's disease (CD). Even approaches as cyclosporine, tacrolimus, azathioprine, methotrexate, and surgery still have a nuclear position as strategies to induce and/or maintain remission in IBD. Due to their particularities and to the accumulated evidence, each of these strategies conquered peculiar roles in the overall IBD strategy, all of them contributing to better outcomes. This review emphasizes the particular roles that non-biological treatments gained over time: recent mesalamine formulations to increase adhesion rates, higher doses of 5-ASA for high-risk patients, MMX technology to improve drug release and attain higher bowel concentrations, cyclosporine as a bridge to vedolizumab, tacrolimus as a potential alternative to thiopurines or infliximab, azathioprine in combination therapy with infliximab and dubious in monotherapy, and surgery as a mean to a "better end".