Serum urate is associated with an increased risk of inflammatory bowel disease: A bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). However, it remains unclear whether the observations are causal because of confounding factors. AIM: To investigate the causal associations between urate levels and IBD using bidirectional Mendelian randomization (MR). METHODS: Independent genetic variants for urate levels and IBD were selected as instrumental variables from published genome-wide association studies (GWASs). Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD (the UK Biobank, the FinnGen database and a large GWAS meta-analysis) and one for urate levels (a large GWAS meta-analysis). MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger and sensitivity analyses (MR-PRESSO). A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model. RESULTS: Genetically higher serum urate levels were strongly associated with an increased risk of UC [odds ratio (OR): 1.95, 95% confidence interval (CI): 1.86-2.05] after outlier correction, and the ORs (95%CIs) for IBD and CD were 0.94 (95%CI: 0.86-1.03) and 0.91 (95%CI: 0.80-1.04), respectively. Animal studies have confirmed the positive association between urate levels and UC. Moreover, genetically predicted IBD was inversely related to urate levels (OR: 0.97, 95%CI: 0.94-0.99). However, no association was observed between genetically influenced UC or CD and urate levels. CONCLUSION: Urate levels might be risk factors for UC, whereas genetically predicted IBD was inversely associated with urate levels. These findings provide essential new insight for treating and preventing IBD.

Macrophage-derived exosomes promote intestinal mucosal barrier dysfunction in inflammatory bowel disease by regulating TMIGD1 via mircroRNA-223.

BACKGROUND & AIM: Exosomes are effective mediators of cell-to-cell interactions and transport several regulatory molecules, including microRNAs (miRNAs), involved in diverse fundamental biological processes. The role of macrophage-derived exosomes in the development of inflammatory bowel disease (IBD) has not been previously reported. This study investigated specific miRNAs in macrophage-derived exosomes in IBD and their molecular mechanism. METHODS: A dextran sulfate sodium (DSS)-induced IBD mouse model was established. The culture supernatant of murine bone marrow-derived macrophages (BMDMs) cultured with or without lipopolysaccharide (LPS) was used for isolating exosomes, which were subjected to miRNA sequencing. Lentiviruses were used to alter miRNA expression and investigate the role of macrophage-derived exosomal miRNAs. Both mouse and human organoids were co-cultured with macrophages in a Transwell system to model cellular IBD in vitro. RESULTS: LPS-induced macrophages released exosomes containing various miRNAs and exacerbated IBD. Based on miRNA sequencing of macrophage-derived exosomes, miR-223 was selected for further analysis. Exosomes with upregulated miR-223 expression contributed to the exacerbation of intestinal barrier dysfunction in vivo, which was further verified using both mouse and human colon organoids. Furthermore, time-dependent analysis of the mRNAs in DSS-induced colitis mouse tissue and miR-223 target gene prediction were performed to select the candidate gene, resulting in the identification of the barrier-related factor Tmigd1. CONCLUSION: Macrophage-derived exosomal miR-223 has a novel role in the progression of DSS-induced colitis by inducing intestinal barrier dysfunction through the inhibition of TMIGD1.

PADs and NETs in digestive system: From physiology to pathology.

Peptidylarginine deiminases (PADs) are the only enzyme class known to deiminate arginine residues into citrulline in proteins, a process known as citrullination. This is an important post-translational modification that functions in several physiological and pathological processes. Neutrophil extracellular traps (NETs) are generated by NETosis, a novel cell death in neutrophils and a double-edged sword in inflammation. Excessive activation of PADs and NETs is critically implicated in their transformation from a physiological to a pathological state. Herein, we review the physiological and pathological functions of PADs and NETs, in particular, the involvement of PAD2 and PAD4 in the digestive system, from inflammatory to oncological diseases, along with related therapeutic prospects.

Corticotropin releasing hormone promotes inflammatory bowel disease via inducing intestinal macrophage autophagy.

Psychosocial stress is a vital factor contributing to the pathogenesis and progression of inflammatory bowel disease (IBD). The contribution of intestinal macrophage autophagy to the onset and development of IBD has been widely studied. Herein, we investigated the underlying mechanism of psychosocial stress in an IBD mouse model pertaining to macrophage autophagy. Corticotropin releasing hormone (CRH) was peripherally administrated to induce psychosocial stress. For in vivo studies, dextran sulfate sodium (DSS) was used for the creation of our IBD mouse model. For in vitro studies, lipopolysaccharide (LPS) was applied on murine bone marrow-derived macrophages (BMDMs) as a cellular IBD-related challenge. Chloroquine was applied to inhibit autophagy. We found that CRH aggravated the severity of DSS-induced IBD, increasing overall and local inflammatory reactions and infiltration. The levels of autophagy in intestinal macrophages and murine BMDMs were increased under these IBD-related inflammatory challenges and CRH further enhanced these effects. Subsequent administration of chloroquine markedly attenuated the detrimental effects of CRH on IBD severity and inflammatory reactions via inhibition of autophagy. These findings illustrate the effects of peripheral administration of CRH on DSS-induced IBD via the enhancement of intestinal macrophage autophagy, thus providing a novel understanding as well as therapeutic target for the treatment of IBD.

Establishment and validation of a computer-assisted colonic polyp localization system based on deep learning.

BACKGROUND: Artificial intelligence in colonoscopy is an emerging field, and its application may help colonoscopists improve inspection quality and reduce the rate of missed polyps and adenomas. Several deep learning-based computer-assisted detection (CADe) techniques were established from small single-center datasets, and unrepresentative learning materials might confine their application and generalization in wide practice. Although CADes have been reported to identify polyps in colonoscopic images and videos in real time, their diagnostic performance deserves to be further validated in clinical practice. AIM: To train and test a CADe based on multicenter high-quality images of polyps and preliminarily validate it in clinical colonoscopies. METHODS: With high-quality screening and labeling from 55 qualified colonoscopists, a dataset consisting of over 71000 images from 20 centers was used to train and test a deep learning-based CADe. In addition, the real-time diagnostic performance of CADe was tested frame by frame in 47 unaltered full-ranged videos that contained 86 histologically confirmed polyps. Finally, we conducted a self-controlled observational study to validate the diagnostic performance of CADe in real-world colonoscopy with the main outcome measure of polyps per colonoscopy in Changhai Hospital. RESULTS: The CADe was able to identify polyps in the test dataset with 95.0% sensitivity and 99.1% specificity. For colonoscopy videos, all 86 polyps were detected with 92.2% sensitivity and 93.6% specificity in frame-by-frame analysis. In the prospective validation, the sensitivity of CAD in identifying polyps was 98.4% (185/188). Folds, reflections of light and fecal fluid were the main causes of false positives in both the test dataset and clinical colonoscopies. Colonoscopists can detect more polyps (0.90 vs 0.82, P < 0.001) and adenomas (0.32 vs 0.30, P = 0.045) with the aid of CADe, particularly polyps < 5 mm and flat polyps (0.65 vs 0.57, P < 0.001; 0.74 vs 0.67, P = 0.001, respectively). However, high efficacy is not realized in colonoscopies with inadequate bowel preparation and withdrawal time (P = 0.32; P = 0.16, respectively). CONCLUSION: CADe is feasible in the clinical setting and might help endoscopists detect more polyps and adenomas, and further confirmation is warranted.

Prognostic and Predictive Value of BGN in Colon Cancer Outcomes and Response to Immunotherapy.

BACKGROUND: Colon cancer is one of the most frequent malignancies and causes high mortality worldwide. Exploring the tumor-immune interactions in the tumor microenvironment and identifying new prognostic and therapeutic biomarkers will assist in decoding the novel mechanism of tumor immunotherapy. BGN is a typical extracellular matrix protein that was previously validated as a signaling molecule regulating multiple processes of tumorigenesis. However, its role in tumor immunity requires further investigation. METHODS: The differentially expressed genes in three GEO datasets were analyzed, and BGN was identified as the target gene by intersection analysis of PPIs. The relevance between clinical outcomes and BGN expression levels was evaluated using data from the GEO database, TCGA and tissue microarray of colon cancer samples. Univariable and multivariable Cox regression models were conducted for identifying the risk factors correlated with clinical prognosis of colon cancer patients. Next, the association between BGN expression levels and the infiltration of immune cells as well as the process of the immune response was analyzed. Finally, we predicted the immunotherapeutic response rates in the subgroups of low and high BGN expression by TIS score, ImmuCellAI and TIDE algorithms. RESULTS: BGN expression demonstrated a statistically significant upregulation in colon cancer tissues than in normal tissues. Elevated BGN was associated with shorter overall survival as well as unfavorable clinicopathological features, including tumor size, serosa invasion and length of hospitalization. Mechanistically, pathway enrichment and functional analysis demonstrated that BGN was positively correlated with immune and stromal scores in the TME and primarily involved in the regulation of immune response. Further investigation revealed that BGN was strongly expressed in the immunosuppressive phenotype and tightly associated with the infiltration of multiple immune cells in colon cancer, especially M2 macrophages and induced Tregs. Finally, we demonstrated that high BGN expression presented a better immunotherapeutic response in colon cancer patients. CONCLUSION: BGN is an encouraging predictor of diagnosis, prognosis and immunotherapeutic response in patients with colon cancer. Assessment of BGN expression represents a novel approach with great promise for identifying patients who may potentially benefit from immunotherapy.

Incidence and risk factors for post-ERCP pancreatitis in pancreas divisum patients without chronic pancreatitis.

Aims: The studies on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in pancreas divisum (PD) patients without chronic pancreatitis (CP) are rare. In this study, we aimed to evaluate the incidence of PEP in PD patients without CP and the risk and protective factors for PEP.Methods: Consecutive patients with symptomatic PD that underwent ERCP from January 2005 to December 2017 were retrospectively analyzed. The patients were divided into PD without CP group and CP group. The basic information and medical records of patients were collected. The risk and protective factors for PEP in PD patients without CP were analyzed by univariate logistic analysis.Results: A total of 89 ERCP procedures were performed in 51 PD patients without CP, and 249 procedures in 136 patients with CP. The incidence of PEP was significantly higher in PD patients without CP than those with CP (15.7% vs. 5.6%, p = .005). Female gender were independent risk factors for PEP, while dorsal duct stent placement was a protective factor.Conclusion: CP may be a protective factor against PEP in PD patients. Female was a risk factor for PEP in PD patients and dorsal duct stent placement was a preventive factor that reduced the incidence of PEP in PD patients without CP.

Extracellular Vesicles with Possible Roles in Gut Intestinal Tract Homeostasis and IBD.

The intestinal tract consists of various types of cells, such as epithelial cells, Paneth cells, macrophages, and lymphocytes, which constitute the intestinal immune system and play a significant role in maintaining intestinal homeostasis by producing antimicrobial materials and controlling the host-commensal balance. Various studies have found that the dysfunction of intestinal homeostasis contributes to the pathogenesis of inflammatory bowel disease (IBD). As a novel mediator, extracellular vesicles (EVs) have been recognized as effective communicators, not only between cells but also between cells and the organism. In recent years, EVs have been regarded as vital characters for dysregulated homeostasis and IBD in either the etiology or the pathology of intestinal inflammation. Here, we review recent studies on EVs associated with intestinal homeostasis and IBD and discuss their source, cargo, and origin, as well as their therapeutic effects on IBD, which mainly include artificial nanoparticles and EVs derived from microorganisms.

Intestinal autophagy links psychosocial stress with gut microbiota to promote inflammatory bowel disease.

Psychosocial stress is a critical inducing factor of inflammatory bowel diseases (IBD), while autophagy is a novel central issue of IBD development. The present study investigated the potential role of autophagy in stress-related IBD in patients and animal model. The correlation between psychosocial stress and intestinal autophagy was determined in 23 patients with IBD. Corticotropin-releasing hormone (CRH), a well-established inducer of psychosocial stress, was administrated in dextran sulfate sodium (DSS)-induced IBD mice and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDM). In IBD patients, the autophagy markers beclin-1, LC3-II/I ratio, Atg16L1, and Atg4B were significantly enhanced. The psychosocial stress score was positively associated with the levels of beclin-1 and the LC3II/I ratio in intestinal biopsy specimens. In IBD mouse model, CRH significantly aggravated intestinal inflammation, increased Paneth cell metaplasia, and enhanced intestinal autophagy (beclin-1, Atg16L1, PIK3R4, and Atg4B upregulation; GAA, CTSD, and PPKAA1 downregulation). Additionally, the CRH-induced gut microbial dysbiosis was evidenced by a marked increase in the number of detrimental bacteria. In LPS-stimulated BMDM, CRH substantially increased M1/M2 polarization and thus promoted inflammation. In both IBD mice and LPS-treated BMDM, blockade of autophagy by chloroquine abrogated the unbeneficial effects of CRH, whereas autophagy inducer rapamycin resulted in a pronounced protective effect against IBD lesion. Our data demonstrate that psychosocial stress may link the enhanced intestinal autophagy by modulating gut microbiota and inflammation to aggravate IBD. These data indicate autophagy as a promising therapeutic target for psychosocial stress-related IBD.

Video education can improve awareness of risks for patients undergoing endoscopic retrograde cholangiopancreatography: A randomized trial.

OBJECTIVE: We conducted a randomized trial aiming at improving patients' informed consent for undergoing endoscopic retrograde cholangiopancreatography (ERCP) in clinical care by comparing the efficacy of an additional educational video to written informed consent with that of written informed consent alone. METHODS: This was a single-center, randomized controlled trial. Consecutive patients undergoing ERCP were randomized to a video education or a control group. An educational video detailing ERCP procedure plus standard written informed consent was administered to the video education group, while the control group reviewed standard written informed consent only. The primary outcome was the patients' perception of the risk or possibility of ERCP complications. Their perception of the benefits of ERCP, alternative treatments and overall satisfaction with the process of informed consent were also compared. RESULTS: In total 205 patients were included in the study (104 in the control group and 101 in the video education group). Patients' comprehension of ERCP-related complications in the video education group was significantly increased (P < 0.001), and these patients were more likely to correctly identify the incidence of such complications. Significantly more patients in the video education group were very satisfied with informed consent process (87.1% vs 76.0%, P = 0.040) and fewer patients needed additional explanations (31.7% vs 47.1%, P = 0.024). CONCLUSIONS: A supplementary educational video could greatly improve patient's understanding of ERCP procedure, in particular, its potential risks and complications, as well as their overall satisfaction with the process of informed consent (ClinicalTrials.gov no. NCT02810379).

Effect of supplemental simethicone for bowel preparation on adenoma detection during colonoscopy: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Although several randomized controlled trials (RCTs) have reported that supplemental simethicone (SIM) can improve bowel preparation based on polyethylene glycol, there is no consensus as to whether SIM can ultimately increase the adenoma detection rate (ADR) during colonoscopy. A meta-analysis was performed to assess the effect of SIM on ADR during colonoscopy. METHODS: Databases including PubMed, EMBASE, and the Cochrane Library were searched to find relevant RCTs. RCTs evaluating the effect of pre-procedure SIM on the ADR during colonoscopy were finally included, and fixed effect models were applied. RESULTS: Six trials involving 1855 patients were finally included. The present meta-analysis suggested that the ADR during colonoscopy was significantly increased by supplemental SIM (27.9% vs 23.3%, P = 0.02), with a relative risk of 1.20 (95% confidence interval 1.03-1.39). Subgroup analysis suggested that supplemental SIM may be more useful to improve ADR during colonoscopy in endoscopic centers with low baseline ADR. CONCLUSIONS: Supplemental SIM for bowel preparation based on polyethylene glycol is useful to improve the ADR during colonoscopy.

Effect of WeChat and short message service on bowel preparation: an endoscopist-blinded, randomized controlled trial.

OBJECTIVE: Adequate bowel preparation is essential for a successful colonoscopy; clinical studies suggest reinforced education can improve the preparation process. However, there have been no trials to compare WeChat directions (the most widely used social media app in China) with those of the short message service (SMS). This study was aimed to assess the effect of WeChat and SMS on the bowel preparation quality. PARTICIPANTS AND METHODS: This was a single-center, prospective, endoscopically blinded, randomized, controlled study. Patients in reinforced education groups received additional reminder messages by WeChat and SMS 2 days before colonoscopy. The primary outcome was bowel preparation quality evaluated by the Boston bowel preparation scale (BBPS) score and the rate of adequacy (BBPS score ≥6). Secondary outcomes included polyp detection rate, adenoma detection rate, and mean total adenomas detected. Patient tolerance level and subjective feelings were also evaluated. RESULTS: The total BBPS score and the percentage of adequacy were significantly higher in the reinforced education groups compared with the control (WeChat vs. control, P<0.001; SMS vs. control, P<0.001). Moreover, statistically significant differences between the two interventions were found in the total BBPS score but not in the rate of adequacy (P=0.007 and 0.561, respectively). The detection of adenomas, using multiplicity detection rate, advanced adenoma detection rate, and mean total adenomas detected, was much higher in the intervention groups (P=0.039, 0.037, and 0.019, respectively). CONCLUSION: WeChat was superior to SMS for bowel preparation, although both of them may help improving the detection of adenomas.

Comparison of efficacy of colonoscopy between the morning and afternoon: A systematic review and meta-analysis.

OBJECTIVE: Colonoscopy performed in the afternoon, rather than morning, has been reported to be associated with lower rates of adenoma and polyp detection (ADR and PDR) and cecal intubation (CIR). This meta-analysis evaluated the efficacy of afternoon colonoscopy relative to morning colonoscopy. METHODS: The databases MEDLINE, Web of Science, EMBASE, and the Cochrane Library were searched to identify potential relevant studies. The primary outcome was ADR and the secondary outcomes were CIR and PDR. The outcomes were estimated by relative risk (RR) and 95% confidence interval (CI) with a random effects model. RESULTS: Sixteen studies with 38,063 participants met the inclusion criteria. The pooled analyses indicated that ADR (RR: 1.08, 95% CI: 1.00-1.17) and CIR (RR: 1.01, 95% CI: 1.00-1.02) were stable during the whole day. In subgroup analyses, the effect of full-day block or inferior bowel preparation were more prominent, reflected by a significant reduction of ADR (RR: 1.18, 95% CI: 1.09-1.28; RR: 1.12, 95% CI: 1.01-1.24) and CIR (RR: 1.08, 95% CI: 1.02-1.13; RR: 1.02, 95% CI: 1.01-1.03) in the afternoon, respectively. CONCLUSIONS: Colonoscopy quality, as indicated by the ADR and CIR, is not affected by the time of day for procedures performed in block shifts. However, endoscopists' working full-day blocks and inferior bowel preparation are associated with a significant decrease in ADR and CIR in the afternoon.

Impact of Paneth Cell Autophagy on Inflammatory Bowel Disease.

Intestinal mucosal barrier, mainly consisting of the mucus layer and epithelium, functions in absorbing nutrition as well as prevention of the invasion of pathogenic microorganisms. Paneth cell, an important component of mucosal barrier, plays a vital role in maintaining the intestinal homeostasis by producing antimicrobial materials and controlling the host-commensal balance. Current evidence shows that the dysfunction of intestinal mucosal barrier, especially Paneth cell, participates in the onset and progression of inflammatory bowel disease (IBD). Autophagy, a cellular stress response, involves various physiological processes, such as secretion of proteins, production of antimicrobial peptides, and degradation of aberrant organelles or proteins. In the recent years, the roles of autophagy in the pathogenesis of IBD have been increasingly studied. Here in this review, we mainly focus on describing the roles of Paneth cell autophagy in IBD as well as several popular autophagy-related genetic variants in Penath cell and the related therapeutic strategies against IBD.

Impact of intraduodenal acetic acid infusion on pancreatic duct cannulation during endoscopic retrograde cholangiopancreatography: A double-blind, randomized controlled trial.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with risk of complications. Methods to facilitate ductal cannulation may reduce complications. Intraduodenal acid infusion is a physiological approach to stimulate secretin release in human body and may facilitate cannulation. The objective of this study was to investigate the effect of intraduodenal acid infusion on pancreatic duct cannulation during ERCP. METHODS: It was a single center, double-blind, randomized controlled trial. Consecutive patients undergoing first ERCP for pancreatic diseases were randomized toreceive 50 mL acetic acid intraduodenal infusion at ERCP (acetic acid group) or 50 mL saline (control group). The primary outcome, difficult cannulation rate (cannulation time >5 min), in the two groups was compared. RESULTS: Two hundred ten patients were included in the final analysis (105 in each group). The difficult cannulation rate were 39.1% in the control group and 20.9% in the acetic acid group, and the difference was statistically significant (P = 0.004). The overall successful deep cannulation rate was 89.5% and 85.7%, respectively (P = 0.402). The cannulation time was remarkably shortened (182 vs 286 s, P = 0.018), and the cannulation attempts were significantly decreased (3.4 vs 4.4, P = 0.008). The fluoroscopy time was also significantly reduced (60 vs 86 s, P = 0.028). The incidence of post-ERCP pancreatitis and hyperamylasemia was comparable (7.6% vs 10.5% and 10.5% vs 19.1%, P > 0.05). CONCLUSION: Intraduodenal acetic acid infusion can significantly decrease difficult pancreatic cannulation rate, facilitate pancreatic duct cannulation, and reduce radiation exposure (ClinicalTrials.gov number, NCT02800772).