Gastroenterology Report最新文献

Background: Intestinal barrier defect is an essential inflammatory bowel disease (IBD) pathogenesis. Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. β-arrestin1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors desensitization, endocytosis, and degradation. However, its role in maintaining the intestinal barrier remains unclear.

Methods: Dextran sulfate sodium-induced colitis was performed in ARRB1 knockout and wild-type mice. Intestinal permeability and tight junction proteins were measured to evaluate the intestinal barrier. Mitochondria function and mitophagic flux in mice and cell lines were detected. Finally, the interaction between ARRB1 and mitofusin 2 was investigated by co-immunoprecipitation and dual luciferase assay.

Results: We identified that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo. ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower adenosine triphosphate (ATP) production, and severe oxidative stress. In vitro, the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue-induced protein kinase1 (PINK1), and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 impaired ARRB1-mediated tight junction protection. The interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin 2.

Conclusions: Our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by promoting mitophagy. These results reveal a novel link between ARRB1 and the intestinal tight junction barrier, which provides theoretical support for colitis treatment.

Microorganisms play an important role in the pathogenesis of inflammatory bowel disease (IBD). The oral cavity, the second-largest microbial niche, is connected to the gastro-intestinal tract. Ectopic gut colonization by oral microbes is a signature of IBD. Current studies suggest that patients with IBD often report more oral manifestations and these oral issues are closely linked with disease activity. Murine studies have indicated that several oral microbes exacerbate intestinal inflammation. Moreover, intestinal inflammation can promote oral microbial dysbiosis and the migration of oral microbes to the gastro-intestinal tract. The reciprocal consequences of oral microbial dysbiosis and IBD, specifically through metabolic alterations, have not yet been elucidated. In this review, we summarize the relationship between oral bacteria and IBD from multiple perspectives, including clinical manifestations, microbial dysbiosis, and metabolic alterations, and find that oral pathogens increase anti-inflammatory metabolites and decrease inflammation-related metabolites.

Chronic liver disease (CLD) is a significant contributor to global mortality. For people who are living with CLD, however, there is a substantial and often overlooked burden of physical and psychological symptoms that significantly affect health-related quality of life. CLD frequently presents with a multitude of interrelated and intricate symptoms, including fatigue, pruritus, muscle cramps, sexual dysfunction, and falls. Increasingly, there is interest in studying and developing interventional strategies to provide a more global approach to managing these complex patients. Moreover, in addition to established guidelines for the management of conventional complications, such as ascites and hepatic encephalopathy, there have been efforts in developing evidence-based guidance for the treatment of the more subjective yet still problematic elements. This review will address the management of these less "classical" but nonetheless important symptoms.

Cirrhosis with complications of liver decompensation and hepatocellular carcinoma (HCC) constitute a leading cause of morbidity and mortality worldwide. Portal hypertension is central to the progression of liver disease and decompensation. The most recent Baveno VII guidance included revision of the nomenclature for chronic liver disease, termed compensated advanced chronic liver disease, and leveraged the use of liver stiffness measurement to categorize the degree of portal hypertension. Additionally, non-selective beta blockers, especially carvedilol, can improve portal hypertension and may even have a survival benefit. Procedural techniques with interventional radiology have become more advanced in the management of refractory ascites and variceal bleeding, leading to improved prognosis in patients with decompensated liver disease. While lactulose and rifaximin are the preferred treatments for hepatic encephalopathy, many alternative treatment options may be used in refractory cases and even procedural interventions such as shunt embolization may be of benefit. The approval of terlipressin for the treatment of hepatorenal syndrome (HRS) in the USA has improved the way in which HRS is managed and will be discussed in detail. Malnutrition, frailty, and sarcopenia lead to poorer outcomes in patients with decompensated liver disease and should be addressed in this patient population. Palliative care interventions can lead to improved quality of life and clinical outcomes. Lastly, the investigation of systemic therapies, in particular immunotherapy, has revolutionized the management of HCC. These topics will be discussed in detail in this review.

Interventional endoscopy can play a key role in the multidisciplinary management of complex inflammatory bowel disease (IBD) as an adjunct to medical and surgical therapy. The primary role of interventional IBD (IIBD) includes the treatment of Crohn's disease-related stricture, fistula, and abscess. Endoscopic balloon dilation (EBD), endoscopic stricturotomy, and placement of endoscopic stents are different forms of endoscopic stricture therapy. EBD is the most widely used therapy whereas endoscopic stricturotomy has higher long-term efficacy than EBD. Fully covered and partially covered self-expanding metal stents are useful in long and refractory strictures whereas lumen-apposing metal stents can be used in short, and anastomotic strictures. Endoscopic fistula/abscess therapy includes endoscopic fistulotomy, seton placement, endoscopic ultrasound-guided drainage of rectal/pelvic abscess, and endoscopic injection of filling agents (fistula plug/glue/stem cell). Endoscopic seton placement and fistulotomy are mainly feasible in short, superficial, single tract fistula and in those with prior surgical seton placement. Similarly, endoscopic fistulotomy is usually feasible in short, superficial, single-tract fistula. Endoscopic closure therapies like over-the-scope clips, suturing, and self-expanding metal stent should be avoided for de novo/bowel to hollow organ fistulas. Other indications include management of postoperative complications in IBD such as management of surgical leaks and complications of pouchitis in ulcerative colitis. Additional indications include endoscopic resection of ulcerative colitis-associated neoplasia (by endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection), retrieval of retained capsule endoscope, and control of bleeding. IIBD therapies can potentially act as a bridge between medical and surgical therapy for properly selected IBD patients.

Background: The efficacy of anti-TNF therapy in Crohn's disease (CD), such as infliximab, is often compromised by the development of anti-drug antibodies (ADAs). The genetic variation HLA-DQA1*05 has been linked to the immunogenicity of biologics, influencing ADA formation. This study investigates the correlation between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab in a Chinese Han population and assesses clinical outcomes.

Methods: In this retrospective cohort study, 345 infliximab-exposed CD patients were genotyped for HLADQ A1*05A $>$ G (rs2097432). We evaluated the risk of ADA development, loss of infliximab response, adverse events, and treatment discontinuation among variant and wild-type allele individuals.

Results: A higher percentage of patients with ADAs formation was observed in HLA-DQA1*05 G variant carriers compared with HLA-DQA1*05 wild-type carriers (58.5% vs 42.9%, P = 0.004). HLA-DQA1*05 carriage significantly increased the risk of ADAs development (adjusted hazard ratio = 1.65, 95% CI 1.18-2.30, P = 0.003) and was associated with a greater likelihood of infliximab response loss (adjusted HR = 2.55, 95% CI 1.78-3.68, P < 0.0001) and treatment discontinuation (adjusted HR = 2.21, 95% CI 1.59-3.06, P < 0.0001). Interestingly, combined therapy with immunomodulators increased the risk of response loss in HLA-DQA1*05 variant carriers.

Conclusions: HLA-DQA1*05 significantly predicts ADAs formation and impacts treatment outcomes in infliximab-treated CD patients. Pre-treatment screening for this genetic factor could therefore be instrumental in personalizing anti-TNF therapy strategies for these patients.