Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis.

BACKGROUND: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

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.

Birth weight, childhood obesity, adulthood obesity and body composition, and gastrointestinal diseases: a Mendelian randomization study.

OBJECTIVE: This Mendelian randomization study aimed to investigate the associations of birth weight, childhood BMI, and adulthood BMI, waist-hip ratio, and body composition with the risk of 24 gastrointestinal diseases. METHODS: Independent genetic instruments associated with the exposures at the genome-wide significance level (p < 5 × 10-8 ) were selected from corresponding large-scale genome-wide association studies. Summary-level data for gastrointestinal diseases were obtained from the UK Biobank, the FinnGen study, and large consortia of European ancestry. RESULTS: Genetically predicted higher levels of birth weight were associated with a lower risk of gastroesophageal reflux. Genetically predicted higher childhood BMI was associated with an increased risk of duodenal ulcer, nonalcoholic fatty liver disease, and cholelithiasis. However, the associations did not persist after adjusting for genetically predicted adulthood BMI. Genetically predicted higher adulthood BMI and waist-hip ratio were associated with 19 and 17 gastrointestinal diseases, respectively. Genetically predicted greater visceral adiposity was associated with an increased risk of 17 gastrointestinal diseases. There were no strong associations among genetically predicted whole-body fat and fat-free mass indices with gastrointestinal diseases. CONCLUSIONS: This study suggests that greater adulthood adiposity, measured as either BMI, waist-hip ratio, or visceral adipose tissue, is causally associated with an increased risk of a broad range of gastrointestinal diseases in the European population.

Adiposity as a risk factor for inflammatory bowel disease and the mediating effect of metabolic and inflammatory status: A population-based cohort study.

BACKGROUND: To examine whether general and abdominal adiposity was a risk factor for the new-onset of inflammatory bowel disease (IBD) and the potential mediating effect of metabolic and inflammation status. METHODS: A total of 492,998 individuals free of IBD recruited from 2006 to 2010 in the UK Biobank were included in our study, with ongoing follow-up linking to the health-related outcome. Multivariable Cox regression models were used to evaluate the associations between general adiposity (body mass index) and abdominal adiposity (waist circumference) and the subsequent risk of IBD and its subtype. We also investigated the potential mediating effects of metabolic and inflammation status by carrying out exploratory mediation analyses. RESULTS: During a median follow-up of 12.5 years, we documented 2954 incident IBD cases (915 Crohn's disease [CD] and 2039 ulcerative colitis). After adjustment for important confounders, body mass index (hazard ratio [HR] highest quintile [Q5] vs. lowest quintile [Q1] = 1.18, 95% confidence interval [CI] 1.04-1.32; P-trend = 0.006) and waist circumference (HR Q5 vs. Q1  = 1.30, 95% CI 1.14-1.49; P-trend <0.001) showed a positive association with the risk of IBD. The associations were partially mediated by metabolic status (24%; 15%), C-reactive protein (36%; 19%) and inflammation score (82%; 46%). CONCLUSIONS: Adiposity bore a risk factor for incident IBD, whereas unhealthy metabolism, especially inflammation, seemed to be an important intermediate condition between the association. Our findings provide evidence for possible mechanisms relating adiposity to IBD from an epidemiological perspective, and experimental studies are needed for further demonstration.

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.

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.

Azelaic Acid Regulates the Renin-Angiotensin System and Improves Colitis Based on Network Pharmacology and Experimentation.

Inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, has a complicated etiology that might be brought on by metabolic dysbiosis. Previous metabonomic studies have found a correlation between decreased azelaic acid (AzA) and IBD. Herein, data from the Metabolomics Workbench showed that the content of AzA decreased in IBD patients (PR000639) and dextran sulfate sodium (DSS)-induced mice (PR000837). The effects of AzA on IBD were then examined using a DSS-induced mouse model, and the results demonstrated that AzA alleviated clinical activity, decreased pro-inflammatory cytokine production, and reduced CD4+CD25+Foxp3+Treg percentages in mesenteric lymph nodes. Through network pharmacology analysis, we discovered 99 candidate IBD-associated genes that are potentially regulated by AzA. After the enrichment analysis of the candidate genes, the renin-angiotensin system (RAS) pathway was one of the most substantially enriched pathways. Additionally, AzA reversed the increased expression of important RAS components (ACE, ACE2, and MAS1L) following DSS induction, suggesting that AzA exerts therapeutic effects possibly via the RAS pathway. This study suggests that AzA may be a promising drug for treating IBD.

Differential expression and bioinformatics analysis of exosome circRNAs in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor with an unfavorable prognosis. Increasing evidence indicated circRNAs were associated with the pathogenesis and progression of tumors, but data on the expression of serum exosomal circRNAs in PDAC are scarce. This study attempted to explore the prognostic value and function of serum exosomes in PDAC patients. METHODS: Microarray-based circRNA expression was determined in PDAC and paired with normal serum samples, and the intersection of differentially expressed circRNAs (DECs) in serum exosomal samples and GSE79634 tissue samples was conducted. A specific CircRNA database was applied to investigate DECs binding miRNAs. Target genes were predicted using the R package multiMiR. Cox regression analyses were applied for constructing a prognostic model. The immunological characteristics analysis was carried out through the TIMER, QUANTISEQ, XCELL, EPIC, and ssGSEA algorithms. RESULTS: 15 DECs were finally identified, and a circRNA-miRNA-mRNA network was established. A prognostic risk model was developed to categorize patients according to the risk scores. Furthermore, the association between risk score and immune checkpoint genes including CD80, TNFSF9, CD276, CD274, LGALS9, and CD44 were significantly elevated in the high-risk group, while ICOSLG and ADORA2A were upregulated in the low-risk group. CONCLUSIONS: Our results may provide new clues for the prognosis and treatment of PDAC.

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.

Antioxidants, minerals and vitamins in relation to Crohn's disease and ulcerative colitis: A Mendelian randomization study.

BACKGROUND: Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC. METHODS: Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed. RESULTS: Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91-0.97), vitamins D (OR = 0.65, 95% CI: 0.54-0.79) and K1 (OR = 0.93, 95% CI: 0.90-0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23-1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88-0.95), phosphorus (OR = 0.69, 95% CI: 0.58-0.82), selenium (OR = 0.91, 95% CI: 0.85-0.97), zinc (OR = 0.91, 95% CI: 0.89-0.94), folate (OR = 0.71, 95% CI: 0.56-0.92) and vitamin E (OR = 0.78, 95% CI: 0.69-0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22-1.76) and magnesium (OR = 1.24, 95% CI: 1.03-1.49) were associated with increased risk of UC. CONCLUSIONS: Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD.

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.

Intake of Ultra-processed Foods Is Associated with an Increased Risk of Crohn's Disease: A Cross-sectional and Prospective Analysis of 187 154 Participants in the UK Biobank.

BACKGROUND AND AIMS: Ultra-processed food [UPF] consumption has been linked to globally increasing incidence and prevalence of chronic diseases, including inflammatory bowel diseases [IBD]. We aimed to investigate the association between UPF consumption and IBD incidence, prevalence, and IBD-relevant outcomes. METHODS: We performed a cross-sectional and prospective cohort study in 187 854 individuals included in the national UK Biobank, using 24-h dietary recall questionnaires. Multivariable logistic regression and Cox proportional hazard regression were used to examine the association between UPFs and the prevalence and incidence risk of IBD, respectively. RESULTS: A total of 185 849 participants with a mean age of 56.2 were included, with a mean follow-up of 9.84 years. During follow-up, 841 developed IBD (251 Crohn's disease [CD], and 590 ulcerative colitis [UC]). UPF intake in IBD patients was significantly higher: CD: odds ratio [OR] 1.94 (95% confidence interval [CI]: 1.52, 2.49, p <0.001); UC: OR 1.39 [95% CI: 1.17, 1.65, p <0.001]. Compared with low consumption, higher UPF consumption was significantly associated with incident CD: hazard ration [HR] 2.00 [95% CI: 1.32, 3.03, p = 0.001], but not UC. We also found a significant association between UPF intake and need of IBD-related surgery: HR 4.06 [95% CI: 1.52, 10.86, p = 0.005]. CONCLUSION: Higher intake of UPFs was associated with higher incidence of CD, but not UC. In individuals with a pre-existing diagnosis of IBD, consumption of UPFs was significantly higher compared with controls, and was associated with an increased need for IBD-related surgery. Further studies are needed to address the impact of UPF intake on disease pathogenesis and outcomes.

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.

Roseburia intestinalis stimulates TLR5-dependent intestinal immunity against Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder characterized by intestinal immune dysfunction. Multiple factors, including gut dysbiosis, are involved in the pathogenesis of CD. However, the effect of commensal bacteria on controlling the inflammatory response in individuals with CD remains unclear. METHODS: We detected Toll-like receptor 2 (TLR2), TLR4, and TLR5 expression in Roseburia intestinalis (R. intestinalis)-treated mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Then, we quantified the signs of colonic inflammation, the proportion of regulatory T cells (Tregs) and the expression of thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)-ß in TLR-5-deficient (Tlr5-/-) mice, bone marrow chimera mice (generated using wild-type (WT) and Tlr5-/- mice), and anti-TSLP/anti-TGFß-treated C57BL/6 mice with colitis induced by TNBS. In vitro, we used the lipopolysaccharide (LPS)-stimulated human intestinal epithelial cell line Caco-2 as an inflammatory colon cell model treated with or without the TLR5-siRNA intervention in the presence of R. intestinalis and incubated human monocyte-derived dendritic cells (DCs) with the supernatant of Caco-2 cells. Then, we cocultured human CD4+ T cells with the aforementioned DCs to determine the differentiation of Tregs. Additionally, samples from patients with CD were collected to analyse the correlation between TLR5/TSLP/TGFß expression and the percentage of R. intestinalis. FINDINGS: Here, we show that R. intestinalis inhibits the development of CD by increasing the differentiation of anti-inflammatory Tregs. Mechanistically, R. intestinalis stimulates TSLP production in intestinal epithelial cells (IECs) through TLR5 but not TLR2 or TLR4. TSLP produced by IECs specifically induces the secretion of interleukin-10 (IL-10) and TGFß from DCs, which is necessary for subsequent Treg differentiation. Consequently, the depletion of TLR5 (using Tlr5-/- mice) or inhibition of TSLP (using anti-TSLP neutralizing antibodies) attenuates the protective effect of R. intestinalis on experimental colitis in mice. Importantly, the expression of TSLP in patients with CD is positively correlated with the level of R. intestinalis. INTERPRETATION: These findings reveal the previously unknown mechanism of R. intestinalis-mediated intestinal immune regulation, which may provide the basis for new therapeutic strategies for CD. FUNDING: This work was funded by the National Natural Science Foundation of China (81670504 and 81970494), the Key Project of Research and Development Plan of Hunan Province (2019SK2041) and the Changsha Municipal Natural Science Foundation (kq2014258).

Assessment of the safety and probiotic properties of Roseburia intestinalis: A potential "Next Generation Probiotic".

Roseburia intestinalis is an anaerobic bacterium that produces butyric acid and belongs to the phylum Firmicutes. There is increasing evidence that this bacterium has positive effects on several diseases, including inflammatory bowel disease, atherosclerosis, alcoholic fatty liver, colorectal cancer, and metabolic syndrome, making it a potential "Next Generation Probiotic." We investigated the genomic characteristics, probiotic properties, cytotoxicity, oral toxicity, colonization characteristics of the bacterium, and its effect on the gut microbiota. The genome contains few genes encoding virulence factors, three clustered regularly interspaced short palindromic repeat (CRISPR) sequences, two Cas genes, no toxic biogenic amine synthesis genes, and several essential amino acid and vitamin synthesis genes. Seven prophages and 41 genomic islands were predicted. In addition to a bacteriocin (Zoocin A), the bacterium encodes four metabolic gene clusters that synthesize short-chain fatty acids and 222 carbohydrate-active enzyme modules. This bacterium is sensitive to antibiotics specified by the European Food Safety Authority, does not exhibit hemolytic or gelatinase activity, and exhibits some acid resistance. R. intestinalis adheres to intestinal epithelial cells and inhibits the invasion of certain pathogens. In vitro experiments showed that the bacterium was not cytotoxic. R. intestinalis did not affect the diversity or abundance of the gut flora. Using the fluorescent labelling method, we discovered that R. intestinalis colonizes the cecum and mucus of the colon. An oral toxicity study did not reveal any obvious adverse effects. The lethal dose (LD)50 of R. intestinalis exceeded 1.9 × 109 colony forming units (CFU)/kg, whereas the no observed adverse effect level (NOAEL) derived from this study was 1.32 × 109 CFU/kg/day for 28 days. The current research shows that, R. intestinalis is a suitable next-generation probiotic considering its probiotic properties and safety.