Gastrointest. Disord., Volume 1, Issue 1 (March 2019) – 18 articles

Vitamin D has a complex role in the pathogenesis of inflammatory bowel disease (IBD), which is still under investigation. We conducted a literature search using PubMed through December 2018 through the use of relevant search terms. We found an abundance of evidence to support the role of vitamin D in regulating the innate and adaptive arms of the immune system. The pathogenesis of IBD implicates the immune dysregulation of these immune system components. Proof of concept of the vitamin’s role in the pathogenesis of IBD is the mapping of the vitamin D receptor in a region of chromosome 12, where IBD is also mapped, and specific VDR polymorphisms’ link to IBD phenotypes. Further research is needed to better delineate vitamin D’s role in preventing IBD and its potential as a therapeutic target for this disease. Full article

Approximately half of patients with eosinophilic esophagitis (EoE) respond clinically and histologically to proton pump inhibitor (PPI) therapy. Although recent guidelines suggest that PPI-responders and non-responders were included in EoE, it is important to investigate the predictive factors of PPI- responsiveness. This study aimed to determine the rate of PPI- responders and compare the characteristics of PPI-responders and non-responders. Fifty-nine patients with esophageal eosinophilia received PPI therapy for eight weeks, and its efficacy was assessed. PPI- responsiveness was diagnosed based on the relief in symptoms and reduction of intraepithelial eosinophilic infiltration to <15 per high-power field (hpf) after PPI therapy. Multivariate analysis was performed to identify factors associated with PPI-responders. Of the 59 patients, 41 (69.5%) were diagnosed with PPI-responders. The rate of gastrointestinal (GI) screening in the indications for endoscopy was significantly higher in patients with PPI- responders than in those with non-responders. On multivariate analysis, GI screening and presence of reflux esophagitis was associated with an increased odds ratio (OR) of PPI-responders, but presence of rings with a decreased OR of PPI-responders. Presence of reflux esophagitis and absence of rings on endoscopy especially during GI screening might be significant predictive factors for PPI response in patients with EoE. Full article

Differentiation between rectal and sigmoid carcinomas is a diagnostic challenge with important implications for further treatment. Depending on the tumor stage, treatment for rectal carcinoma consists of preoperative (chemo)radiotherapy and surgery. Sigmoid carcinomas are treated with surgery alone. We established the diagnostic accuracy of flexible endoscopy, MRI and/or CT scan, and both modalities combined as reflected by the conclusion of our multidisciplinary team (MDT). Furthermore, we assessed the treatment consequences of misdiagnosis. Consecutive patients were included who underwent surgery from January 2012 to January 2017 for colorectal carcinoma located ≤20 cm from the anal verge as determined by flexible colonoscopy. Diagnostic accuracy of MRI/CT, flexible endoscopy and the final MDT conclusion were analyzed as index test. The location of the tumor during surgery and the type of surgery was the reference standard. We included 293 patients. Flexible endoscopy had a diagnostic accuracy of 90% and for MRI/CT scanning this was 86–87%. Combination of both modalities improved diagnostic accuracy to 96%. Due to misdiagnosis during initial staging, three patients (1%) erroneously underwent neoadjuvant treatment and in two patients neoadjuvant treatment was potentially erroneously omitted. In conclusion, the combination of both flexible endoscopy and MRI/CT (the MDT conclusion) improves diagnostic accuracy. Erroneous clinical diagnosis can lead to under- and overtreatment. Full article

Sarcopenia is as an important prognostic factor in inflammatory bowel disease. In patients with Crohn’s disease (CD), sarcopenia has impact on morbidity after surgical resection. Aim: Evaluate sarcopenia impact on prognosis of patients with CD and assess CD sarcopenia prevalence. An retrospective study of 58 CD patients diagnosed histologically and imagiologically at the Hospital de Braga between 1 January 2009 and 31 December 2017. In order to obtain the Skeletal Muscle Index (SMI), it was calculated the muscle area at L3 level, from computed tomography. The t-test was used for independent samples, Mann-Whitney test, chi-square test and Fisher’s exact test for comparison between groups with and without sarcopenia. Sarcopenia prevalence was 41.4% (24 patients). Patients with sarcopenia presented a muscle area with a mean value of 119.88 cm² (±28.10), significantly lower than that of the group of patients without sarcopenia (t(56) = 2.191, p = 0.033, d = 0.60), and values of SMI with median 42.86 cm²/m², significantly lower than patients without sarcopenia (t(56) = 2.815, p = 0.007, d = 0.08). Regarding postoperative complications, significant differences were observed between the two groups (p = 0.000). In this study, sarcopenia was significantly associated with postoperative morbidity, as reported in the literature. Full article

Unsaturated fatty acids are critical in promoting colon tumorigenesis and its stemness. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipid desaturase associated with colon cancer cell proliferation and metastasis control. This study aims to evaluate the effects of SCD1 inhibition on colon cancer spheroid growth in a three-dimensional cell culture system. An analysis of clinical data showed that increased SCD1 gene expression in colon tumors was negatively correlated with the prognosis. A chemical inhibitor of SCD1, CAY10566, inhibited the growth of colon cancer cells in both monolayer and sphere cultures. In addition, oleic acid administration—a monounsaturated fatty acid generated by the action of SCD1—prevented the suppression of sphere formation by CAY10566. RNA-sequencing data from 382 colon tumor patient samples obtained from the Cancer Genome Atlas database showed that 806 genes were SCD1-associated genes in human colon cancer. Correlation analysis identified the master regulator of lipid homeostasis sterol regulatory element-binding protein 2 (SREBP2) as a prominent transcription factor, whose expression was positively correlated with SCD1 in human colon cancer. SCD1 knockdown using siRNA in colon cancer samples, suppressed SREBP2 gene expression, providing direct evidence that SREBP signaling is under the control of SCD1 in these cells. Pathway analysis in the Ingenuity Pathways Analysis platform showed that SCD1 expression positively correlated with genes involved in multiple pathways, including lipid synthesis and incorporation, cell proliferation, and tissue tumorigenesis. Further network analysis revealed a central role for Myc in the network hierarchy of the SCD1-correlated genes. These findings suggested that SCD1 inhibition would be an effective strategy for suppressing colon cancer spheroid growth, partly through downregulating SREBP-mediated lipid and cholesterol metabolism and Myc signaling. Full article

Although not required to establish the diagnosis, endoscopy with mucosal biopsy is commonly performed in the evaluation of children with dyspepsia. Traditionally, esophagogastroduodenoscopy (EGD) has been performed in children with abdominal pain to identify pathology or conversely, to “rule-out” organic disease in order to establish a diagnosis of FD. In this review, we discuss the current diagnostic yield of endoscopically-obtained biopsies in identifying disease in children and adolescents with dyspepsia including an expanded discussion of common histologic diagnoses where clinical significance has not been definitively established. In turn, we discuss the transition of endoscopy from a search for disease to a search for biologic contributors to symptom generation, while considering the growing evidence linking non-diagnostic mucosal inflammation to FD, specifically mast cells and eosinophils. Full article

Beneficial effects of pyloric botulinum toxin injection have been described in a subgroup of gastroparesis patients. Our aim is to evaluate whether clinical, manometric and/or scintigraphic parameters are able to predict treatment outcome. Forty patients (67% female, age 49 (36–56) years) with decompensated gastroparesis treated with botulinum toxin were included in this retrospective analysis. Objective parameters were high-resolution antroduodenal manometry, gastric emptying rate (scintigraphy), and weight change. Subjective treatment outcome was assessed with a Global Physician Assessment Scale. Binary logistic regression analysis was performed to identify predictors for treatment outcome. Fourteen patients (35%) were symptom-responders, and 65% of patients were short-term weight-responders. For both subjective and objective treatment outcome, no differences were found in manometric and scintigraphic variables between responders and non-responders. Neither clinical nor manometric or scintigraphic variables could predict subjective and objective treatment outcome. In conclusion, symptom improvement is achieved in a subgroup of gastroparesis patients treated with endoscopic pyloric botulinum toxin. Although the majority of patients were able to maintain their baseline weight at short-term follow-up, a substantial group of patients needed nutritional interventions on long-term follow-up. However, none of the demographic, clinical, scintigraphic, or antroduodenal manometry variables were able to predict either subjective or objective treatment outcome. Full article

Esophageal adenocarcinoma carries a very poor prognosis. For this reason, it is critical to have cost-effective surveillance and prevention strategies and early and accurate diagnosis, as well as evidence-based treatment guidelines. Barrett’s esophagus is the most important precursor lesion for esophageal adenocarcinoma, which follows a defined metaplasia–dysplasia–carcinoma sequence. Accurate recognition of dysplasia in Barrett’s esophagus is crucial due to its pivotal prognostic value. For early-stage esophageal adenocarcinoma, depth of submucosal invasion is a key prognostic factor. Our systematic review of all published data demonstrates a “rule of doubling” for the frequency of lymph node metastases: tumor invasion into each progressively deeper third of submucosal layer corresponds with a twofold increase in the risk of nodal metastases (9.9% in the superficial third of submucosa (sm1) group, 22.0% in the middle third of submucosa (sm2) group, and 40.7% in deep third of submucosa (sm3) group). Other important risk factors include lymphovascular invasion, tumor differentiation, and the recently reported tumor budding. In this review, we provide a concise update on the histopathological features, ancillary studies, molecular signatures, and surveillance/management guidelines along the natural history from Barrett’s esophagus to early stage invasive adenocarcinoma for practicing pathologists. Full article

Major advances in the last few decades have favored the view of inflammatory bowel disease (IBD) as a disease of hyper- or, more often, paradoxical hyporesponsiveness of the gut-associated immune system. The relevant pivot seems to be the loss of the balance between gut-associated pro-inflammatory lymphocytes and the indwelling microbiome species, with inner regulatory circuits (regulatory T-lymphocytes, T-reg) and outer factors (such as drugs, tobacco, diet components) contributing to complicate the matter. Light might be shed by the observation of the real-world IBD epidemiology, which may help unveil the factors that tend to cluster IBD cases to certain geographical areas. A transitional mind frame between bench and real-world gastroenterology could hopefully contribute to restrain the mounting epidemic of IBD in the Western world and to halt the more recent increases seen in many Eastern countries. Full article

Anti-tumor necrosis factor-α (anti-TNFα) agents are used for induction and maintenance of remission in patients with inflammatory bowel diseases (IBD). However, biologic drugs present a large economic burden on health insurance systems. We aimed to estimate the mean annual health care cost per patient with IBD and cost contribution of anti-TNFα agents. We performed an analysis of patients with Crohn’s disease (CD) and ulcerative colitis (UC) based on a large-scale administrative claims database constructed by Japan Medical Data Center (JMDC) Co. Ltd., comprising inpatient, outpatient, and pharmacy claims data. We evaluated all claims from 1 April 2013 through 31 March 2016. Descriptive statistics were used to measure median health care costs paid per member per year (PMPY) and the relative cost contribution of anti-TNFα agents. A total 1405 patients with CD and 5771 with UC were included. Median costs PMPY were approximately six times higher for CD than UC (JPY 1,957,320 and JPY 278,760, respectively). Medication cost for anti-TNFα agents was the main cost driver, accounting for 59.9% and 17.8% of the total costs for CD and UC, respectively. In Japan, costs for anti-TNFα agents have resulted in drug costs exceeding inpatient costs for IBD. Optimized use of anti-TNFα agents and introduction of biosimilars for anti-TNFα agents can be expected to substantially reduce the health care costs of IBD. Full article

Pancreatic cancer (PC), a leading cause of cancer-related deaths in the United States, is typically diagnosed at an advanced stage. To improve survival, there is an unmet need to detect pre-malignant lesions and early invasive disease. Prime populations to study for early detection efforts include cohorts of high risk individuals (HRI): those with increased risk to develop pre-malignant pancreatic cysts and PC because of a familial or hereditary predisposition to the disease and those in the general population of sporadic cases who are incidentally found to harbor a pre-malignant pancreatic cyst. The objective of this study was to describe the characteristics and clinical outcomes of cohorts of HRI identified at Moffitt Cancer Center. We set out to determine the uptake of screening, the prevalence and characteristics of solid and cystic pancreatic lesions detected via screening or as incidental findings, and the age at which lesions were detected. Of a total of 329 HRI, roughly one-third were found to have pancreatic lesions, most of which constituted pre-malignant cysts known as intraductal papillary mucinous neoplasms. Individuals with the highest genetic risk for PC were found to have smaller cysts at a much earlier age than sporadic cases with incidental findings; however, many individuals at high genetic risk did not have abdominal imaging reports on file. We also identified a subset of HRI at moderate genetic risk for PC that were found to have cystic and solid pancreatic lesions as part of a diagnostic work-up rather than a screening protocol. These findings suggest the pancreatic research community should consider expanding criteria for who should be offered screening. We also emphasize the importance of continuity of care between cancer genetics and gastrointestinal oncology clinics so that HRI are made aware of the opportunities related to genetic counseling, genetic testing, and screening. Full article

The gastrointestinal system where inflammatory bowel disease occurs is central to the immune system where the innate and the adaptive/acquired immune systems are balanced in interactions with gut microbes under homeostasis conditions. This article overviews the high-throughput research screening on multifactorial interplay between genetic risk factors, the intestinal microbiota, urbanization, modernization, Westernization, the environmental influences and immune responses in the etiopathogenesis of inflammatory bowel disease in humans. Inflammatory bowel disease is an expensive multifactorial debilitating disease that affects thousands new people annually worldwide with no known etiology or cure. The conservative therapeutics focus on the established pathology where the immune dysfunction and gut injury have already happened but do not preclude or delay the progression. Inflammatory bowel disease is evolving globally and has become a global emergence disease. It is largely known to be a disease in industrial-urbanized societies attributed to modernization and Westernized lifestyle associated with environmental factors to genetically susceptible individuals with determined failure to process certain commensal antigens. In the developing nations, increasing incidence and prevalence of inflammatory bowel disease (IBD) has been associated with rapid urbanization, modernization and Westernization of the population. In summary, there are identified multiple associations to host exposures potentiating the landscape risk hazards of inflammatory bowel disease trigger, that include: Western life-style and diet, host genetics, altered innate and/or acquired/adaptive host immune responses, early-life microbiota exposure, change in microbiome symbiotic relationship (dysbiosis/dysbacteriosis), pollution, changing hygiene status, socioeconomic status and several other environmental factors have long-standing effects/influence tolerance. The ongoing multipronged robotic studies on gut microbiota composition disparate patterns between the rural vs. urban locations may help elucidate and better understand the contribution of microbiome disciplines/ecology and evolutionary biology in potentially protecting against the development of inflammatory bowel disease. Full article

CC chemokine receptor 6 (CCR6) and its specific partner CC chemokine ligand 20 (CCL20) are known to play a pivotal role in intestinal inflammation. CCR6-associated inflammatory bowel disease (IBD) is already at the forefront of experimental inflammatory disease models, being the subject of numerous analytical studies. IBD is associated with two sub phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC). Both these disease entities produce potent immune dysregulation followed by intense tissue damage within the gut mucosal system, initiating symptoms that are severely debilitating. Multiple causative factors are said to be responsible for IBD, but direct immune dysfunction is kindled by overplay of innate and adaptive immune responses produced against the luminal contents through the weakened or leaky gut epithelial barrier. Once immune homeostasis is not achieved by endogenous protective mechanisms, the self-assertive adaptive immunity mobilizes its various T and B cell cohorts, initializing their immune mechanisms by deploying the immune cells towards the site of infection. CCR6 and its unique solitary ligand CCL20 are small protein molecules that are abundantly expressed by T and B lymphocytes and act as chemotactic immune-modulatory envoys that help in the deployment of the effector lymphocyte arm of the immune system and produce two directly opposing outcomes in IBD. This dichotomous immunity consists of either immune tolerance or inflammation which then develops into a chronic state, remaining unresponsive to inherent immunity or targeted clinical therapy. In this review, we have identified large numbers of experimental studies that have employed both mouse models and clinical subjects spanning a period of nearly two decades and we have clustered these into 13 different groups. This review will provide greater understanding of the CCR6–CCL20 axis in IBD and identify gaps in the literature that can be filled in the future. Full article

Heat shock proteins (HSPs) are essential mediators of cellular homeostasis by maintaining protein functionality and stability, and activating appropriate immune cells. HSP activity is influenced by a variety of factors including diet, microbial stimuli, environment and host immunity. The overexpression and down-regulation of HSPs is associated with various disease phenotypes, including the inflammatory bowel diseases (IBD) such as Crohn’s disease (CD). While the precise etiology of CD remains unclear, many of the putative triggers also influence HSP activity. The development of different CD phenotypes therefore may be a result of the disease-modifying behavior of the environmentally-regulated HSPs. Understanding the role of bacterial and endogenous HSPs in host homeostasis and disease will help elucidate the complex interplay of factors. Furthermore, discerning the function of HSPs in CD may lead to therapeutic developments that better reflect and respond to the gut environment. Full article

Previous studies have suggested that carbonated beverages may cause gastro-oesophageal reflux. Pepsin (the major enzyme secreted by the stomach) has been suggested to be an objective, acute marker of a reflux event. This pilot study aimed to investigate whether intake of carbonated beverages could affect pepsin concentration in saliva or reflux symptoms. This was assessed by a randomised, crossover trial where participants consumed 330 mL of beverage (carbonated cola, degassed cola or water) at separate visits. Saliva samples and symptom questionnaires were collected at baseline and over the 30 min postprandial period. Pepsin was detected in all saliva samples. No difference was found in the salivary pepsin concentrations between treatments at all time points. There were significantly higher scores (p > 0.05) for feelings of fullness, heartburn, urge to belch and frequency of belches after ingestion of carbonated cola than degassed cola and water. The ingestion of carbonated beverages did not appear to increase postprandial pepsin concentration in saliva compared to other beverages but did evoke higher levels of reflux-related symptoms such as fullness, heartburn and belching. This suggests carbonated beverages may cause symptoms associated with reflux but do not drive detectable levels of gastric juice to reach the oral cavity. Full article

Inflammatory bowel disease (IBD) has evoked significant interest in human immunobiology given its tactical immune evasion methodologies resulting in acute immune destabilization. IBD comprising Crohn’s disease and Ulcerative colitis manifests as chronic inflammation in the gut mucosa, leading to complexities involving immune dysregulation in the T helper lymphocyte arm, effecting disease pathogenicity. The mucosa of the alimentary canal is constantly exposed to a myriad of food antigens and luminal microorganisms for which a consistent host-protective mechanism is operative in healthy people. Lowered mucosal immune expression which allows penetration of the epithelial barrier by infective pathogenic microbes elicits both innate and adaptive immune responses in the gut, culminating in aberrant intestinal inflammation. Interestingly, the IBD leukocyte repertoire is significantly entwined with chemokine-assisted chemotactic navigation into the sites of inflammation, which is also thought to generate favorable immune-suppressive responses. The functions of the cognate chemokine receptor, CCR6, which binds with its unique ligand CCL20, are expected to tilt the balance between upregulation of homeostatic tolerance and inflammatory pathophysiology. This review aims to critically examine the CCR6-driven immune pathways: T_H1/T_H2, T_H1/T_H17, T_H17/T_reg, IL-23/IL-17, Akt/ERK-1/2, ILC3, and T_H9/T_H2 for systematic investigation of its underlying mechanisms in the future and to underpin its importance in resolving IBD pathology. Thus, CCR6 occupies an exclusive position in gut immunology which renders it an invaluable therapeutic tool for the production of novel medicaments to treat IBD. Full article

Eosinophilic esophagitis is characterized by dysphagia with esophageal eosinophilia. We sought to determine if intrabolus pressure measurements on high-resolution manometry had any correlation with dysphagia improvement following standard therapy for patients with fibrostenotic eosinophilic esophagitis. Consecutive patients were prospectively enrolled at our swallowing center. Dysphagia scores, esophageal eosinophil counts, endoscopic reference scores, and intrabolus pressure measurements were compared at baseline and following therapy with 8 weeks of a proton-pump inhibitor and serial bougie dilation to a luminal diameter of 17 mm. Five patients were included in the study. The median age was 38 years. The average endoscopic reference score improved from 5.0 to 2.4 (p = 0.007). The mean esophageal diameter improved from 10.8 mm to 17.2 mm (p = 0.001). Dysphagia severity scores improved from a mean value of 34.2 to 10.8 (p = 0.004). Mucosal eosinophilia had no correlation with dysphagia severity. Mean intrabolus pressure improved from 21.8 mmHg to 11 mmHg (p = 0.001). There was strong correlation between a decrease in intrabolus pressure and improvement in dysphagia severity; however, this was not significant (p = 0.108). Intrabolus pressure has strong correlation with dysphagia severity following therapy for fibrostenotic eosinophilic esophagitis. Bougie dilation provides improvement in dysphagia despite persistent mucosal eosinophilia. Full article