Circulating 25-hydroxyvitamin D concentration can predict bowel resection risk among individuals with inflammatory bowel disease in a longitudinal cohort with 13 years of follow-up.

BACKGROUND: Although the beneficial properties of vitamin D in anti-inflammation and immunity-modulation are promising in the management of inflammatory bowel disease (IBD), data were limited for the critical IBD prognosis. The association between serum vitamin D levels and the risk of bowel resection in individuals with IBD remains largely unknown. MATERIALS AND METHODS: We performed a longitudinal cohort study among 5474 individuals with IBD in the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] was measured using direct competitive chemiluminescent immunoassay. Bowel resection events were ascertained via national inpatient data. Multivariable-adjusted Cox proportional hazard regression was used to examine the association between serum 25(OH)D and bowel resection risk, presented with hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) was used to evaluate dose-response associations. RESULTS: During a mean follow-up of 13.1 years, we documented 513 incident bowel resection cases. Compared to participants with vitamin D deficiency, non-deficient participants showed a significantly reduced bowel resection risk in IBD (HR 0.72, 95% CI 0.59-0.87, P=0.001), Crohn's disease (CD, HR 0.74, 95% CI 0.56-0.98, P=0.038), and ulcerative colitis (UC, HR 0.73, 95% CI 0.57-0.95, P=0.020). When comparing extreme quintiles of 25(OH)D level, participants with IBD showed a 34% reduced risk of bowel resection (95% CI 11%-51%, P=0.007) and participants with UC showed a 46% reduced risk (95% CI 19%-64%, P=0.003), while this association was not significant in CD (HR 0.93, 95% CI 0.59-1.45, P=0.740). Linear dose-response associations were observed using the RCS curve (all P-nonlinearity>0.05). CONCLUSION: Increased serum level of 25(OH)D is independently associated with reduced bowel resection risk in IBD. This association was significant in UC but may not be stable in CD. Vitamin D deficiency is a risk factor for bowel resection in individuals with IBD, and may be an effective metric in predicting and risk-screening surgical events.

Bacteroides vulgatus alleviates dextran sodium sulfate-induced colitis and depression-like behaviour by facilitating gut-brain axis balance.

Background: Patients with inflammatory bowel disease (IBD) have a higher prevalence of depression. Gut microbiota dysbiosis plays an important role in IBD and depression. However, few studies have explored the characteristic microbiota of patients with IBD and depression (IBDD), or their role in IBDD. Methods: We performed deep metagenomic sequencing and 16S rDNA quantitative PCR to characterise the gut microbial communities of patients with IBDD and patients with IBD without depression (IBDND). We then assessed the effect of the microbiota on colitis and depression in mouse models of dextran sulfate sodium salt (DSS)-induced colitis and lipopolysaccharide (LPS)-induced depression. Furthermore, liquid chromatography-tandem mass spectrometry was used to analyse the microbiota-derived metabolites involved in gut-brain communication. Evans Blue tracer dye was used to assess blood-brain barrier (BBB) permeability. Results: Our results showed that the faecal abundance of Bacteroides vulgatus (B. vulgatus) was lower in patients with IBDD than in those with IBDND. In the DSS-induced colitis mouse model, the B. vulgatus group showed a significantly lower disease activity index score, lesser weight loss, and longer colon length than the DSS group. Moreover, B. vulgatus relieved depression-like behaviour in the DSS-induced colitis mouse model and in the LPS-induced depression mouse model. Furthermore, the key metabolite of B. vulgatus was p-hydroxyphenylacetic acid (4-HPAA), which was found to relieve intestinal inflammation and alleviate depression-like behaviours in mouse models. By increasing the expression of the tight junction protein claudin-5 in the vascular endothelium of the BBB, B. vulgatus and 4-HPAA play critical roles in gut-brain communication. Conclusion: B. vulgatus and B. vulgatus-derived 4-HPAA ameliorated intestinal inflammation and relieved depressive symptoms through the gut-brain axis. Thus, administration of B. vulgatus or 4-HPAA supplementation is a promising therapeutic strategy for treating IBD, particularly IBDD.

Fatty acids and lipid mediators in inflammatory bowel disease: from mechanism to treatment.

Inflammatory Bowel Disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Though the pathogenesis of IBD remains unclear, diet is increasingly recognized as a pivotal factor influencing its onset and progression. Fatty acids, essential components of dietary lipids, play diverse roles in IBD, ranging from anti-inflammatory and immune-regulatory functions to gut-microbiota modulation and barrier maintenance. Short-chain fatty acids (SCFAs), products of indigestible dietary fiber fermentation by gut microbiota, have strong anti-inflammatory properties and are seen as key protective factors against IBD. Among long-chain fatty acids, saturated fatty acids, trans fatty acids, and ω-6 polyunsaturated fatty acids exhibit pro-inflammatory effects, while oleic acid and ω-3 polyunsaturated fatty acids display anti-inflammatory actions. Lipid mediators derived from polyunsaturated fatty acids serve as bioactive molecules, influencing immune cell functions and offering both pro-inflammatory and anti-inflammatory benefits. Recent research has also highlighted the potential of medium- and very long-chain fatty acids in modulating inflammation, mucosal barriers, and gut microbiota in IBD. Given these insights, dietary intervention and supplementation with short-chain fatty acids are emerging as potential therapeutic strategies for IBD. This review elucidates the impact of various fatty acids and lipid mediators on IBD and delves into potential therapeutic avenues stemming from these compounds.

Pancreatic cancer challenge in 52 Asian countries: age-centric insights and the role of modifiable risk factors (1990-2019).

Background: Pancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population. Methods: Data from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age-Period-Cohort model, and decomposition analysis to evaluate incidence trends and effects. Results: From 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY. Conclusion: With the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.

Regulatory mechanism of miR-722 on C5aR1 and its functions against bacterial inflammation in half-smooth tongue sole (Cynoglossus semilaevis).

MicroRNAs (miRNAs) are small non-coding RNAs involved in various biological processes, including immunity. Previously, we investigated the miRNAs of half-smooth tongue sole (Cynoglossus semilaevis) and found that miR-722 (designated Cse-miR-722) was significantly differentially expressed after infection with Vibrio anguillarum, reflecting its importance in immune response. Our preliminary bioinformatic analysis suggested that Cse-miR-722 could target C5aR1 (designated CsC5aR1), which was known to play crucial roles in complement activation and inflammatory response, as a receptor of C5a. However, the underlying mechanisms of their interactions and specific functions in inflammatory and immune response are still enigmas. In this study, we successfully cloned the precursor sequence of Cse-miR-722 (94 bp) and the full length of CsC5aR1 (1541 bp, protein molecular weight 39 kDa). The target gene of Cse-miR-722 was verified as CsC5aR1 by a dual luciferase reporter assay, and Cse-miR-722 was confirmed to regulate CsC5aR1 at the protein level using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The expression of CsC5aR1 and Cse-miR-722 in liver cells and four immune tissues of half-smooth tongue sole changed significantly after LPS stimulation and infection with V. anguillarum. To explore the functional role of Cse-miR-722 in half-smooth tongue sole, we performed both in vitro and in vivo experiments. Cse-miR-722 was observed to affect phagocytosis and respiratory burst activity of macrophages by regulating CsC5aR1 in half-smooth tongue sole. Furthermore, we found that Cse-miR-722 regulated the expression of CsC5aR1, CsC5a, and the inflammatory factors CsIL1-ß, CsIL6, CsIL8, and CsTNF-α both in vitro and in vivo. In addition, Cse-miR-722 reduced mortality and pathological damage. This study clarified the regulatory mechanism of Cse-miR-722 on CsC5aR1 and provided insight into the regulatory roles of Cse-miR-722 in immune responses, laying a theoretical foundation for the feasibility of using miR-722 to prevent and control bacterial diseases in teleost.

Evolving Trends and Burden of Inflammatory Bowel Disease in Asia, 1990-2019: A Comprehensive Analysis Based on the Global Burden of Disease Study.

BACKGROUND: Asia's inflammatory bowel disease (IBD) burden has rapidly increased recently, but the epidemiological trends in Asia remain unclear. We report IBD's incidence, prevalence, mortality, and Disability-Adjusted Life Years (DALY) in 52 Asian countries from 1990 to 2019. METHODS: Data from the Global Burden of Disease 2019 were analyzed for IBD burden across 52 countries, using metrics like incidence, prevalence, mortality rates, and DALY. The epidemiological trend of IBD from 1990 to 2019 was assessed with the Joinpoint and APC methods. Decomposition and frontier analyses examined factors behind IBD case and death changes. The NORPRED forecasted Asia's morbidity and mortality trends from 2019 to 2044. RESULTS: From 1990 to 2019, The incidence and prevalence of IBD increased in Asia, while mortality and DALY decreased. East Asia had the highest increase in disease burden. IBD incidence was highest among the 30-34 age group, with prevalence peaking in the 45-49 age group. In high-income regions, IBD peak age shifted to younger groups. Decompose analysis showed population growth as the primary factor for the increasing IBD cases in Asia. NORDPRED model predicted a continued IBD burden increase in Asia over the next 25 years. CONCLUSIONS: Between 1990 and 2019, ASIR and ASPR of IBD in Asia increased, while ASMR and ASDR decreased. Due to population growth and aging, the IBD burden is expected to rise over the next 25 years, particularly in East Asia.

Molecular basis of inherited protein C deficiency results from genetic variations in the signal peptide and propeptide regions.

BACKGROUND: Inherited protein C deficiency (PCD) caused by mutations in protein C (PC) gene (PROC) increases the risk of thrombosis. Missense mutations in PC's signal peptide and propeptide have been reported in patients with PCD, but their pathogenic mechanisms, except mutations in R42 residue, remain unclear. OBJECTIVES: To investigate the pathogenic mechanisms of inherited PCD caused by 11 naturally occurring missense mutations in PC's signal peptide and propeptide. METHODS: Using cell-based assays, we evaluated the impact of these mutations on various aspects such as activities and antigens of secreted PC, intracellular PC expression, subcellular localization of a reporter protein, and propeptide cleavage. Additionally, we investigated their effect on pre-messenger RNA (pre-mRNA) splicing using a minigene splicing assay. RESULTS: Our data revealed that certain missense mutations (L9P, R32C, R40C, R38W, and R42C) disrupted PC secretion by impeding cotranslational translocation to the endoplasmic reticulum or causing endoplasmic reticulum retention. Additionally, some mutations (R38W and R42L/H/S) resulted in abnormal propeptide cleavage. However, a few missense mutations (Q3P, W14G, and V26M) did not account for PCD. Using a minigene splicing assay, we observed that several variations (c.8A>C, c.76G>A, c.94C>T, and c.112C>T) increased the incidence of aberrant pre-mRNA splicing. CONCLUSION: Our findings suggest that variations in PC's signal peptide and propeptide have varying effects on the biological process of PC, including posttranscriptional pre-mRNA splicing, translation, and posttranslational processing. Additionally, a variation could affect the biological process of PC at multiple levels. Except for W14G, our results provide a clear understanding of the relationship between PROC genotype and inherited PCD.

Higher dietary fibre intake is associated with lower risk of inflammatory bowel disease: prospective cohort study.

BACKGROUND: Limited prospective studies that have examined the association of dietary fibre with IBD have provided inconsistent evidence. AIM: To examine any associations between dietary fibre intake and subsequent incidence of IBD, Crohn's disease (CD) and ulcerative colitis (UC) METHODS: We conducted a prospective cohort study of 470,669 participants from the UK Biobank and estimated dietary fibre intake from a valid food frequency questionnaire at baseline. Incident IBD was ascertained from primary care data and inpatient data. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between dietary fibre intake and the risk of IBD, CD and UC. RESULTS: During an average follow-up of 12.1 years, we ascertained 1473 incident IBD cases, including 543 cases of CD and 939 cases of UC. Comparing the lowest quintiles, an inverse association was observed between dietary fibre intake and risk of IBD (HR 0.74, 95% CI 0.58-0.93, p = 0.011) and CD (HR 0.48, 95% CI 0.32-0.72, p < 0.001), but not UC (HR 0.92, 95% CI 0.69-1.24, p = 0.595). For specified sources, dietary fibre intake from fruit and bread decreased the risk of CD, while dietary fibre intake from cereal decreased the risk of UC. CONCLUSIONS: Higher consumption of dietary fibre was associated with a lower risk of IBD and CD, but not UC. Our findings support current recommendations to increase the intake of dietary fibre.

Ambient Air Pollution and Risk of Enterotomy, Gastrointestinal Cancer, and All-Cause Mortality among 4,708 Individuals with Inflammatory Bowel Disease: A Prospective Cohort Study.

BACKGROUND: Previous studies indicated that air pollution plausibly increases the risk of adverse outcomes in inflammatory bowel disease (IBD) via proinflammatory mechanisms. However, there is scant epidemiological data and insufficient prospective evidence assessing associations between ambient air pollution and clinical outcomes of IBD. OBJECTIVES: We aimed to investigate the associations between ambient air pollution and clinical outcomes among individuals with IBD. METHODS: Leveraging data from the UK Biobank, we included 4,708 individuals with IBD recruited in the period 2006-2010 in this study. A land use regression model was used to assess annual mean concentrations of ambient air pollutants nitrogen including oxides (NOx), nitrogen dioxide (NO2), and particulate matter (PM) with aerodynamic diameter ≤10µm (PM10) and PM with aerodynamic diameter ≤2.5µm (PM2.5). Individuals with IBD were followed up for incident clinical outcomes of enterotomy, gastrointestinal cancer, and all-cause mortality, ascertained via death registry, inpatient, primary care, and cancer registry data. Cox proportional hazard model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the magnitude of the associations. RESULTS: During a mean follow-up of 12.0 y, 265 enterotomy events, 124 incident gastrointestinal cancer, and 420 death events were documented among individuals with IBD. We found that each interquartile range (IQR) increase in exposure to PM2.5 was associated with increased risk of enterotomy (HR=1.16; 95% CI: 1.00, 1.34, p=0.043), whereas an IQR increase in exposure to NOx (HR=1.10; 95% CI: 1.01, 1.20, p=0.016), NO2 (HR=1.16; 95% CI: 1.03, 1.29, p=0.010), PM10 (HR=1.15; 95% CI: 1.03, 1.30, p=0.015), and PM2.5 (HR=1.14; 95% CI: 1.02, 1.28, p=0.019) was associated with increased risk of all-cause mortality among individuals with IBD. We did not observe any significant associations between air pollutants and gastrointestinal cancer in the primary analyses. Consistent results were observed in subgroup and sensitivity analyses. CONCLUSIONS: Ambient pollution exposure was associated with an increased risk of enterotomy and all-cause mortality among individuals with IBD, highlighting the important role of environmental health in improving the prognosis of IBD. https://doi.org/10.1289/EHP12215.

Higher Fiber Intake is Associated with Reduced Risk of Related Surgery among Individuals with Inflammatory Bowel Disease in a Prospective Cohort Study.

BACKGROUND: Evidence for the effects of dietary fiber on adverse outcomes in individuals with inflammatory bowel disease (IBD) is insufficient and controversial. OBJECTIVES: We aimed to prospectively explore the association between dietary fiber intake and the risk of IBD-related surgery. METHODS: We identified 5580 individuals with diagnosed IBD [Crohn disease (CD, n = 1908) and ulcerative colitis (UC, n = 3672)] at baseline in the UK Biobank via electronic medical records and self-reported information. Dietary fiber intake was estimated by a partial fiber score derived from a valid food frequency questionnaire. IBD-related surgery (enterotomy, perianal surgery, and others) was ascertained via inpatient data. Cox proportional model was applied to estimate hazard ratios with 95% confidence intervals (CIs) of dietary fiber in quartiles for the risk of IBD-related surgery. RESULTS: During a mean follow-up period of 11.2 y, we documented 624 IBD-related surgery among 5580 individuals with IBD (mean age, 57.3; 52.8% females). Compared with individuals in the lowest quartiles, those with second to fourth quartiles of fiber intake were associated with 23% (95% CI: 5%, 38%, P = 0.015), 29% (95% CI: 11%, 43%, P = 0.003), and 28% (95% CI: 10%, 43%, P = 0.005) reduced risk (P-trend = 0.002) of IBD-related surgery. Similar associations were observed in CD (P-trend = 0.005) but not UC (P-trend = 0.131). We observed inverse associations of fiber in vegetables and fruits (P-trend = 0.017 and 0.007) but positive associations of fiber in bread (P-trend = 0.046) with the risk of IBD-related surgery. CONCLUSIONS: Higher intake of fiber is associated with reduced IBD-related surgery risk in patients with IBD with CD but not UC.

Insight into the In-Situ Encapsulation-Reassembly Strategy To Fabricate PW12@NiCo-LDH Acid-Base Bifunctional Catalysts.

Acid-base bifunctional catalysts have attracted increasing attention due to the improved overall efficiency of synthetic reactions. Herein, we reported the successful fabrication of a PW12@NiCo-LDH acid-base bifunctional catalyst by using the in-situ encapsulation-reassembly strategy. The evolution process of morphology and structure was monitored carefully by various time-dependent characterizations. X-ray absorption fine structure (XAFS) and density functional theory (DFT) calculations demonstrated that the terminal oxygen of PW12 in PW12@NiCo-LDH preferred to assemble with the oxygen vacancies on NiCo-LDH. When applied for deacetalization-Knoevenagel condensation, the PW12@NiCo-LDH displayed >99% conversion of benzaldehyde dimethyl acetal (BDMA) and >99% yield of ethyl α-cyanocinnamate (ECC). Moreover, PW12@NiCo-LDH can be recycled at least 10 cycles without obvious structural change, which can be attributed to the confinement of PW12 into the NiCo-LDH nanocage. Such excellent catalytic activity of PW12@NiCo-LDH was benefited from the short mass transfer pathway between acid sites and base sites, which was caused by the stable assembly between PW12 and NiCo-LDH.

Adverse health effects of emerging contaminants on inflammatory bowel disease.

Inflammatory bowel disease (IBD) is becoming increasingly prevalent with the improvement of people's living standards in recent years, especially in urban areas. The emerging environmental contaminant is a newly-proposed concept in the progress of industrialization and modernization, referring to synthetic chemicals that were not noticed or researched before, which may lead to many chronic diseases, including IBD. The emerging contaminants mainly include microplastics, endocrine-disrupting chemicals, chemical herbicides, heavy metals, and persisting organic pollutants. In this review, we summarize the adverse health effect of these emerging contaminants on humans and their relationships with IBD. Therefore, we can better understand the impact of these new emerging contaminants on IBD, minimize their exposures, and lower the future incidence of IBD.

Willingness to Undergo Gastroscopy for Early Gastric Cancer Screening and Its Associated Factors During the COVID-19 Pandemic - A Nationwide Cross-Sectional Study in China.

Purpose: This study aimed to investigate the willingness of Chinese adults aged 40 years and older to undergo gastroscopy for gastric cancer (GC) screening during the COVID-19 pandemic in 2020. The secondary purpose was to identify factors influencing willingness to undergo gastroscopy. Methods: A cross-sectional questionnaire survey was conducted in selected cities and counties from nine provinces in China using a multi-stage sampling approach. A multivariate logistic regression model was used to determine the independent predictors of willingness to undergo gastroscopy. Results: This study included 1900 participants, and 1462 (76.95%) responded that they would undergo gastroscopy for GC screening. Participants of younger age, from the eastern region, living in an urban area, with higher educational levels, with Helicobacter pylori (H. pylori) infection, or with precancerous stomach lesions, were more willing to undergo gastroscopy. The top four reasons to reject gastroscopy were fear of pain or discomfort, worry about a possible devastating test result, no symptoms in self-feeling, and concern about the high expense. Of all those who would reject gastroscopy for GC screening, 36.76% (161/438) would be willing to accept painless gastroscopy, while 24.89% (109/438) would be willing to undergo gastroscopy screening if higher medical reimbursement rates were available. Participants considered that gastroscopy was a relatively fearful and unknown procedure, accompanied by high risks and benefits compared to all other life events. Conclusion: In general, 76.95% of participants over 40 years old were willing to undergo gastroscopy for GC screening in China during the COVID-19 pandemic. Participants' willingness to undergo GC screening increased due to medical resource constraints and increased interest in their health. Individuals with H. pylori infection are more likely to undergo gastroscopy, whereas old age individuals, those with lower educational levels, and those living in rural areas are more likely to reject gastroscopy.

A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase.

Vitamin K is a vital micronutrient implicated in a variety of human diseases. Warfarin, a vitamin K antagonist, is the most commonly prescribed oral anticoagulant. Patients overdosed on warfarin can be rescued by administering high doses of vitamin K because of the existence of a warfarin-resistant vitamin K reductase. Despite the functional discovery of vitamin K reductase over eight decades ago, its identity remained elusive. Here, we report the identification of warfarin-resistant vitamin K reductase using a genome-wide CRISPR-Cas9 knockout screen with a vitamin K-dependent apoptotic reporter cell line. We find that ferroptosis suppressor protein 1 (FSP1), a ubiquinone oxidoreductase, is the enzyme responsible for vitamin K reduction in a warfarin-resistant manner, consistent with a recent discovery by Mishima et al. FSP1 inhibitor that inhibited ubiquinone reduction and thus triggered cancer cell ferroptosis, displays strong inhibition of vitamin K-dependent carboxylation. Intriguingly, dihydroorotate dehydrogenase, another ubiquinone-associated ferroptosis suppressor protein parallel to the function of FSP1, does not support vitamin K-dependent carboxylation. These findings provide new insights into selectively controlling the physiological and pathological processes involving electron transfers mediated by vitamin K and ubiquinone.

The Contribution of Genetic Risk and Lifestyle Factors in the Development of Adult-Onset Inflammatory Bowel Disease: A Prospective Cohort Study.

INTRODUCTION: The joint associations across genetic risk, modifiable lifestyle factors, and inflammatory bowel disease (IBD) remains unclear. METHODS: Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into high, intermediate, and low genetic risk categories. Weighted healthy lifestyle scores were constructed based on 5 common lifestyle factors and categorized into favorable (4 or 5 healthy lifestyle factors), intermediate (3 healthy lifestyle factors), and unfavorable (0-2 healthy lifestyle factors) groups. Cox proportional hazards regression model was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for their associations. RESULTS: During the 12-year follow-up, 707 cases with CD and 1576 cases with UC were diagnosed in the UK Biobank cohort. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk with no multiplicative interaction between them. The HR of CD and UC were 2.24 (95% CI 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with a high genetic risk, respectively. The HR of CD and UC for individuals with an unfavorable lifestyle were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively. The HR of individuals with a high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI 1.58-2.66 for UC) were reduced nearly by half, compared with those with a high genetic risk but an unfavorable lifestyle (4.40, 95% CI 2.91-6.66 for CD and 4.44, 95% CI 3.34-5.91 for UC). DISCUSSION: Genetic and lifestyle factors were independently associated with susceptibility to incident CD and UC. Adherence to a favorable lifestyle was associated with a nearly 50% lower risk of CD and UC among participants at a high genetic risk.

The efficacy and safety of endoscopic ultrasound-guided fine-needle biopsy in gallbladder masses.

BACKGROUND: Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) is a widely used modality for acquiring various target samples, but its efficacy in gallbladder masses is unknown. The aim of this retrospective study was to evaluate the efficacy and safety of EUS-FNB in patients with gallbladder masses. METHODS: The study samples were composed of patients from March 2015 to July 2019 who needed to identify the nature of gallbladder masses through EUS-FNB. The outcomes of this study were the adequacy of specimens, diagnostic yields, technical feasibility, and adverse events of the EUS-FNB in gallbladder masses. RESULTS: A total of 27 consecutive patients with a median age of 58 years were included in this study. The 22-gauge FNB needle was feasible in all lesions. The median follow-up period of the patients was 294 days. The specimens sufficient for diagnosis account for 89% (24/27) and 93% (25/27) in cytology and histology, respectively. The overall diagnostic yields for malignancy showed the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95.45% [95% confidence interval (CI): 75.12%-99.76%], 100% (95% CI: 46.29%-100%), 100% (95% CI: 80.76%-100%), 83.33% (95% CI: 36.48%-99.12%), and 96.30% (95% CI: 80.20%-99.99%), respectively. The subgroup analysis revealed that FNB could obtain sufficient specimens and high diagnostic yields in both gallbladder mass < 20.5 mm group and ≥ 20.5 mm group. One patient experienced mild abdominal pain after the procedure and recovered within one day. CONCLUSIONS: EUS-FNB is a reasonable diagnostic tool for the pretreatment diagnosis of patients with gallbladder masses, especially for patients who may miss the opportunity of surgery and need sufficient specimens to identify the pathological type so as to determine chemotherapy regimens. Further large-scale studies are needed to confirm our conclusion.

Metabolic dysfunction-associated fatty liver disease and liver function markers are associated with Crohn's disease but not Ulcerative Colitis: a prospective cohort study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is recently recognized as a condition featured with metabolic dysfunctions in liver. It has been supposed that MAFLD might contribute to the development of IBD, but evidence from prospective cohort studies is lacking and inconclusive. METHODS: A total of 221,546 females and 183,867 males from the UK Biobank cohort enrolled in 2006-2010 were included to examine whether MAFLD and liver function markers were related to incident IBD. MAFLD was identified based on hepatic steatosis defined by fatty liver index plus the prevalence of overweight, type 2 diabetes mellitus, or at least two metabolic abnormalities. Biomarker related to liver function (albumin [ALB], alkaline phosphatase [ALP], alanine transaminase [ALT], aspartate transaminase [AST]; gamma-glutamyl transferase [GGT], total bilirubin [TB], total protein [TP]) was measured using colorimetric or enzymatic assays. The incidence of IBD was ascertained based on primary care and inpatient records. Cox proportional hazard model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for the magnitude of their associations. RESULTS: With a mean follow-up of 12.1 years, 2228 incident IBD cases were documented. We identified 150,385 individuals with MAFLD at baseline and 86% participants' circulating liver function markers were within the normal range. Participants with MAFLD were associated with a 12% (HR 1.12, 95% CI 1.03, 1.23, p = 0.012) increased risk of IBD compared with those without MAFLD at baseline; the association was stronger (p-Heterogeneity = 0.006) with Crohn's disease (HR 1.35, 95% CI 1.15, 1.59, p < 0.001) than ulcerative colitis (HR 1.03, 95% CI 0.93, 1.15, p = 0.57). As for the serum liver function markers, the HRs of IBD for per 1-SD increment in ALB, ALP, AST, and TB concentration were 0.86 (95% CI 0.83, 0.90, p < 0.001), 1.18 (95% CI 1.13, 1.24, p < 0.001), 0.95 (95% CI 0.91, 0.99, p = 0.027), 0.92 (95% CI 0.87, 0.96, p < 0.001), respectively. We did not observe significant associations of GGT and TP with IBD. CONCLUSIONS: Individuals with MAFLD were at increased risk of developing IBD, especially CD, but not UC. Circulating levels of liver function biomarkers as the surrogate indicators of MAFLD were also associated with IBD risk.

Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis.

BACKGROUND AND AIMS: Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. METHODS: We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. RESULTS: Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 × 10-10]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 × 10-19] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. CONCLUSION: Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

Sleep duration and daytime napping in relation to incident inflammatory bowel disease: a prospective cohort study.

BACKGROUND: Sleep dysregulation has been linked to gastrointestinal dysfunction and inflammation. AIMS: To explore the associations between sleep duration, daytime napping and inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Exposure information was obtained from the baseline questionnaire. Sleep duration was coded as continuous and categorical (≤5, 6, 7, 8, ≥9 h/day) variables. Daytime napping was defined as yes (sometimes/usually) and no (never/rarely). Incident IBD cases were defined from primary care and hospital inpatient records. Polygenic risk scores (PRS) for the outcomes were constructed and categorised into low, intermediate and high risk. Hazard ratio (HR) and confidence interval (CI) were estimated using Cox proportional hazard regression. RESULTS: The analysis included 2604 incident IBD cases (806 CD and 1798 UC) with a median follow-up of 12.0 years. Comparing sleep duration ≤5 with 7 h/day, the HR of IBD, CD and UC was 1.36 (95% CI, 1.17-1.59), 1.53 (95% CI, 1.17-2.00) and 1.29 (95% CI, 1.07-1.56), respectively. Comparing participants with and without daytime napping, the HR of IBD, CD and UC was 1.13 (95% CI, 1.05-1.23), 1.25 (95% CI, 1.08-1.44) and 1.09 (95% CI, 0.90-1.20), respectively. No interaction of sleep duration and daytime napping with PRS was detected.  However, the associations appeared stronger in individuals with high rather than low PRS. CONCLUSIONS: This study reveals positive associations between short sleep duration and daytime napping and IBD risk.

Associations between inflammatory bowel disease, social isolation, and mortality: evidence from a longitudinal cohort study.

Background: Social well-being of patients with inflammatory bowel disease (IBD) is garnering increased attention; however, the impact of social isolation remained poorly understood. Objectives: We investigated the joint association of social isolation and IBD with premature deaths to articulate the profound impact of social isolation in IBD prognosis. Design: Longitudinal cohort study. Methods: We leveraged data of 486,014 participants from UK Biobank (including 5791 with IBD), the mean follow-up was 11.84 years. Diagnoses of IBD and its subtypes of Crohn's disease (CD) and ulcerative colitis were confirmed with the combination of self-reporting, primary care, and hospital admission data. Social isolation was measured by the frequency of meeting family/friends, leisure and social activity, and communal/solitary living. Mortality was ascertained through data linkage with national death registries. Multivariable Cox regression models were conducted to estimate hazard ratio (HR) and 95% confidence interval (CI). Results: Comparing non-isolated non-IBD population, the HRs of mortality in patients with IBD who were socially isolated or not were 2.06 (95% CI: 1.69, 2.51) and 1.33 (95% CI: 1.21, 1.45), respectively. The excess risk of death was observed in socially isolated patients with IBD (HR = 1.69, 95% CI: 1.36, 2.11), particularly among patients with CD (HR = 2.06, 95% CI: 1.48, 2.87) than their non-isolated counterparts. Data from subgroup and sensitivity analyses were consistent with those from the primary analysis. Conclusion: Socially isolated patients with IBD especially CD increases the risk of premature death. Preventing social isolation might be a promising approach to improve IBD prognosis. Plain language summary: Social isolation as a risk factor to excess mortality in patients with IBD: findings from a longitudinal cohort study Social isolation is prevalent in individuals with inflammatory bowel disease (IBD); however, its potential health impact on IBD prognosis has not been quantitatively well examined. In this study, we explored the association between social isolation and subsequent death, with the focus on patients with IBD.We leveraged data of 486,014 participants (including 5791 with IBD) from UK Biobank. We measured social isolation by the frequency of meeting family/friends, leisure and social activity, and communal/solitary living. We ascertained patients with IBD and mortality by self-report data and data linkage with primary care, hospital, and national death registry. Participants were followed up for a mean of 11.84 years.Comparing non-isolated non-IBD population, we found that patients with IBD who were deemed as socially isolated or not were associated with a 2.06-fold (1.69-2.51) and 1.33-fold (1.21-1.45) risk of death, respectively. Furthermore, we revealed that socially isolated patients with IBD and subtype Crohn's disease (CD) had 69% (36-111%) and 106% (48-187%) increased risk of premature death compared with their non-isolated counterparts, respectively.Social isolation merits attention in IBD care and management. Patients with IBD, especially CD, are more likely to be affected when socially isolated. Targeted social support strategies ought to be devised to improve IBD prognosis.