Current Opinion in Gastroenterology最新文献

Purpose of review: In the pathophysiological context of cholangiopathies and more broadly of hepatopathies, while it is conceptually clear that the maintenance of inter-cholangiocyte and inter-hepatocyte tight junction integrity would be crucial for liver protection, only scarce studies have been devoted to this topic. Indeed, in the liver, alteration of tight junctions, the intercellular adhesion complexes that control paracellular permeability would result in leaky bile ducts and bile canaliculi, allowing bile reflux towards hepatic parenchyma, contributing to injury during the disease process.

Recent findings: Last decades have provided a great deal of information regarding both tight junction structural organization and signaling pathways related to tight junctions, providing clues about potential intervention to modulate paracellular permeability during cholangiopathies pathogenesis. Interestingly, several liver diseases have been reported to be associated with abnormal expression of one or several tight junction proteins. However, the question remains unanswered if these alterations would be primarily involved in the disease pathogenesis or if they would occur secondarily in the pathological course.

Summary: In this review, we provide an overview of tight junction disruptions described in various biliary diseases that should pave the way for defining new therapeutic targets in this field.

Purpose of review: Primary sclerosing cholangitis is a chronic cholestatic liver disease for which no pharmacological treatment options are available. It is an immune-mediated disease and macrophages have been implicated in disease pathogenesis. However, which specific macrophage populations contribute to disease, and how we can apply this as therapeutic strategy is still unclear.

Recent findings: Recent studies have shown that fibrous tissue is characterized by osteopontin-positive macrophages, including in patients with primary sclerosing cholangitis. Experimental models indicate that intracellular osteopontin in macrophages confers protection, while secreted osteopontin contributes to disease. Serum osteopontin is increased in different liver diseases, including primary sclerosing cholangitis, and might thus serve as therapeutic target.

Summary: Although several studies report on the role of osteopontin in liver disease, only a minority of the studies have focused on isoform-specific functions, and the importance of the cellular source of secreted osteopontin. Future studies investigating these aspects, and how this can be translated to therapies for primary sclerosing cholangitis, and other chronic liver diseases, are required.

Purpose of review: Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed.

Recent findings: Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na + -taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes.

Summary: Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

Purpose of review: Colon polyps are potential precursors to colorectal cancer (CRC), which remains one of the most common causes of cancer-associated death. The proper identification and management of these colorectal polyps is an important quality measure for colonoscopy outcomes. Here, we review colon polyp epidemiology, their natural history, and updates in endoscopic classification and management.

Recent findings: Colon polyps that form from not only the adenoma, but also the serrated polyp pathway have significant risk for future progression to CRC. Therefore, correct identification and management of sessile serrated lesions can improve the quality of screening colonoscopy. Malignant polyp recognition continues to be heavily reliant on well established endoscopic classification systems and plays an important role in intraprocedural management decisions. Hot snare remains the gold standard for pedunculated polyp resection. Nonpedunculated noninvasive lesions can be effectively removed by large forceps if diminutive, but cold snare is preferred for colon polyps 3-20 mm in diameter. Larger lesions at least 20 mm require endoscopic mucosal resection. Polyps with the endoscopic appearance of submucosal invasion require surgical referral or advanced endoscopic resection in select cases. Advances in artificial intelligence may revolutionize endoscopic polyp classification and improve both patient and cost-related outcomes of colonoscopy.

Summary: Clinicians should be aware of the most recent updates in colon polyp classification and management to provide the best care to their patients initiating screening colonoscopy.

Purpose of review: Microscopic colitis is an inflammatory disease of the colon that presents as watery diarrhea with minimal to normal endoscopic changes on colonoscopy. It encompasses two common subtypes, lymphocytic colitis and collagenous colitis, which are both treated similarly.Immune checkpoint inhibitor colitis is among the most common immune-related adverse events. Endoscopic and histological findings range from normal colonic mucosa to inflammatory bowel like changes. This review article provides update in treatment and management of microscopic colitis and immune checkpoint inhibitor colitis (ICPi colitis).

Recent findings: Recent studies on microscopic colitis have focused on the successful use of immunomodulators such as biologics for treatment of budesonide refractory microscopic colitis cases. Microscopic colitis does not confer an added risk for colorectal cancer.With the increasing usage of immunotherapy agents, immune checkpoint inhibitor colitis is becoming more common. ICPi colitis can be successfully managed with steroids, with treatment stepped up to biologics for moderate to severe cases or for mild cases that do not respond to steroids. Immunotherapy agents can be carefully re-introduced in mild cases, after treatment of ICPi colitis.

Summary: Biologics can be used to treat budesonide refractory microscopic colitis. ICPi colitis can be managed with steroids and biologics in moderate to severe cases.

Purpose of review: As a significant cause of global morbidity and mortality, Clostridioides difficile infections (CDIs) are listed by the Centres for Disease Control and prevention as one of the top 5 urgent threats in the USA. CDI occurs from gut microbiome dysbiosis, typically through antibiotic-mediated disruption; however, antibiotics are the treatment of choice, which can result in recurrent infections. Here, we highlight new treatments available and provide a perspective on different classes of future treatments.

Recent findings: Due to the reduced risk of disease recurrence, the microbiome-sparing antibiotic Fidaxomicin has been recommended as the first-line treatment for C. difficile infection. Based on the success of faecal microbiota transplantations (FMT) in treating CDI recurrence, defined microbiome biotherapeutics offer a safer and more tightly controlled alterative as an adjunct to antibiotic therapy. Given the association between antibiotic-mediated dysbiosis of the intestinal microbiota and the recurrence of CDI, future prospective therapies aim to reduce the dependence on antibiotics for the treatment of CDI.

Summary: With current first-in-line antibiotic therapy options associated with high levels of recurrent CDI, the availability of new generation targeted therapeutics can really impact treatment success. There are still unknowns about the long-term implications of these new CDI therapeutics, but efforts to expand the CDI treatment toolbox can offer multiple solutions for clinicians to treat this multifaceted infectious disease to reduce patient suffering.

Purpose of review: This review aims to explore effective management of constipation, examine challenges in making a positive diagnosis, and highlights the significance of a positive patient-provider relationship and emerging treatments.

Recent findings: Less than one-fifth of patients feel satisfied with treatment of their constipation. Sixty percent of patients with functional dyspepsia and gastroparesis have severe to very severe constipation that correlates with their upper gastrointestinal symptom severity. Two gold kiwifruits are noninferior to 10 g of psyllium in the treatment of constipation. More than 40% of patients undergoing lumbar fusion continue to fill opioid prescriptions 90 days after surgery, contributing to 80 000 chronic opioid users annually. Most patients are using over-the-counter (OTC) treatments for constipation with greater than 60% dissatisfied. Pharmacologic management involves the use of GCC agonists and emerging drug classes such as bile acid transport inhibitors and sodium hydrogen exchanger isoform 3 (NHE3) inhibitors. Nonpharmacologic treatments, including neuromodulation and FDA-approved vibrating capsule, show promise in improving symptoms and quality of life.

Summary: Constipation significantly impacts patients' quality of life and well being and the majority of patients are refractory to conservative measures and OTC treatments. Both pharmacologic and nonpharmacologic treatments hold promise for improving constipation and quality of life.

Purpose of review: Gut microbiota-mucosa-epithelial cells co-exist in an intricate three-way relationship that underpins gut homeostasis, and ultimately influences health and disease conditions. The O-glycans of mucin glycoproteins have been uncovered as a centrepiece of this system, although understanding the phenomena at play at the molecular level has been challenging and subject to significant traction over the last years. The purpose of this review is to discuss the recent advances in the phenomena that mediate microbiota and mucus multidirectional interactions in the human gut.

Recent findings: The mucus biosynthesis and degradation by both commensal and pathogenic bacteria is under tight regulation and involves hundreds of carbohydrate-active enzymes (CAZy) and transporters. The fucosylation of O-glycans from mucin-2 seems to dictate binding by pathogenic species and to influence their virulence. Less clear is the influence of O-glycans in quorum sensing and biofilm formation. We have reviewed the advances in the in vitro models available to recreate the phenomena that capture the physiological context of the intestinal environment, emphasising models that include mucus and other aspects relevant to the physiological context.

Summary: The recent findings highlight the importance of merging advances in analytical (glycans analysis) and omics techniques along with original robust in vitro models that enable to deconstruct part of the high complexity of the living gut and expand our understanding of the microbes-mucosa relationships and their significance in health and disease.

Purpose of review: Proteases constitute a group of enzymes that hydrolyze peptide bonds. Intestinal proteases are an integral part of gut homeostasis and digestion. This review discusses the broader classification of proteases, regulation of proteolytic activity (PA) in the intestinal tract, and how dysregulation of intestinal proteases contributes to the pathophysiology of conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease. We also discuss recent advancements in therapeutic modulation that directly or indirectly target intestinal proteases and can be utilized to treat these illnesses.

Recent findings: Host and microbiota derived proteases have been associated with symptoms in subsets of patients with IBS, IBD and celiac disease. Elevated PA mediates barrier dysfunction, visceral hypersensitivity as well as immune activation and inflammation. Recent mechanistic studies have revealed the nature of disease-associated proteases and mechanisms regulating their activity, particularly those driven by the microbiota. Advancements in activity-based probes have allowed novel ways of in vivo imaging of PA. Newer strategies targeting proteases include monoclonal antibodies, engineered microbiota as well as specific protease inhibitors.

Summary: Significant progresses made in the detection as well as regulation of PA is likely to provide therapeutic advancements for gastrointestinal diseases.