Insights into the pathogenesis of inflammatory bowel diseases (IBDs) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are increased in inflamed intestinal tissues of patients with IBD. Loss-of-function variants of the IL23-receptor gene (IL23R) protect against IBD, and, in animals, blocking IL23 reduces the severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for the treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms also are emerging for the treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

Recent genome-wide association studies have identified more than 200 regions that affect susceptibility to inflammatory bowel disease (IBD). However, identified common variants account for only a fraction of IBD heritability and largely have been identified in populations of European ancestry. We performed a genome-wide association study of susceptibility loci in Korean individuals, comprising a total of 1505 IBD patients and 4041 controls. We identified 2 new susceptibility loci for IBD at genome-wide significance: rs3766920 near PYGO2-SHC1 at 1q21 and rs16953946 in CDYL2 at 16q23. In addition, we confirmed associations, in Koreans, with 28 established IBD loci (P < 2.16 × 10-4). Our findings support the complementary value of genetic studies in different populations.

Few treatments have demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). A phase 3, randomized, double-blind, placebo-controlled trial was performed to evaluate the safety and efficacy of repeat treatment with the nonsystemic antibiotic rifaximin.

Proximal or 'downhill' esophageal varices are a rare cause of upper gastrointestinal hemorrhage. Unlike the much more common distal esophageal varices, which are most commonly a result of portal hypertension, downhill esophageal varices result from vascular obstruction of the superior vena cava (SVC). While SVC obstruction is most commonly secondary to malignant causes, our review of the literature suggests that benign causes of SVC obstruction are the most common cause actual bleeding from downhill varices. Given the alternative pathophysiology of downhill varices, they require a unique approach to management. Variceal band ligation may be used to temporize acute variceal bleeding, and should be applied on the proximal end of the varix. Relief of the underlying SVC obstruction is the cornerstone of definitive treatment of downhill varices.

Transforming growth factor (TGF)-β cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-β family member signaling. We review how TGF-β family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.

Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin.

Endoscopy is an integral part of the investigation and management of gastrointestinal disease. We aimed to examine outcomes of pregnancies for women who underwent endoscopy during their pregnancy.

Technologies such as genome sequencing, gene expression profiling, proteomic and metabolomic analyses, electronic medical records, and patient-reported health information have produced large amounts of data from various populations, cell types, and disorders (big data). However, these data must be integrated and analyzed if they are to produce models or concepts about physiological function or mechanisms of pathogenesis. Many of these data are available to the public, allowing researchers anywhere to search for markers of specific biological processes or therapeutic targets for specific diseases or patient types. We review recent advances in the fields of computational and systems biology and highlight opportunities for researchers to use big data sets in the fields of gastroenterology and hepatology to complement traditional means of diagnostic and therapeutic discovery.

Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (>4 weeks in duration) are more elusive. We review the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extraepithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in the assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.

The combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve patients without cirrhosis and a baseline level of HCV RNA <6 million IU/mL. We analyzed data from a multicenter, prospective, observational study to determine real-world sustained virologic responses 12 weeks after treatment (SVR12) with regimens containing ledipasvir and sofosbuvir and identify factors associated with treatment failure.

Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.

The management of the pregnant patient with inflammatory bowel disease is complicated by multiple providers, misinformation, and a disease entity that, particularly when active, can adversely affect pregnancy outcomes. This article seeks to frame the debate on medication safety in pregnancy and lactation using the US Food and Drug Administration's new Pregnancy and Lactation Labeling Rule and the most up-to-date safety information to discuss the risks and benefits of using each class of inflammatory bowel disease medication.

The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed.

Nonalcoholic fatty liver disease (NAFLD) is associated with increased risk of hepatic, cardiovascular, and metabolic diseases. High-protein diets, rich in methionine and branched chain amino acids (BCAAs), apparently reduce liver fat, but can induce insulin resistance. We investigated the effects of diets high in animal protein (AP) vs plant protein (PP), which differ in levels of methionine and BCAAs, in patients with type 2 diabetes and NAFLD. We examined levels of liver fat, lipogenic indices, markers of inflammation, serum levels of fibroblast growth factor 21 (FGF21), and activation of signaling pathways in adipose tissue.

This review chronicles the evolution of dysplasia detection and management in inflammatory bowel disease since 1925, the year the first case report of colitis-related colorectal cancer was published. We conclude that colorectal cancer prevention and dysplasia management for patients with inflammatory bowel disease has changed since this first case report, from somewhat hopeless to hopeful.

Crohn's disease and ulcerative colitis are heterogeneous inflammatory bowel diseases, and therapeutic requirements vary among patients. We have a limited capacity to predict disease progression for individual patients, therefore it is important that they are evaluated for the presence of active disease when symptoms are mild or even absent, when patients are more likely to respond to new treatment interventions. It then is important to monitor responses to treatment, to quickly identify those therapies that are ineffective, modify or change therapy, and avoid disease complications. Studies are underway to assess the effects of different monitoring strategies. Because of the heavy burden of severe inflammatory bowel disease on patients' health and quality of life, and the association between intestinal healing and disease progression in high-risk patients, a treat-to-target strategy (based on tissue healing) is likely to be optimal.

Poorly digested, fermentable carbohydrates may induce symptoms of irritable bowel syndrome (IBS) via unclear mechanisms. We performed a randomized trial with magnetic resonance imaging (MRI) analysis to investigate correlations between symptoms and changes in small- and large-bowel contents after oral challenge.