Risk Of Ulcerative Colitis Research Articles

Causal relationship between hypothyroidism and ulcerative colitis: a bidirectional Mendelian randomization study.

Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism. We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level. Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways. Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells.

Association of Childhood Abuse with Incident Inflammatory Bowel Disease.

A link between inflammatory bowel disease (IBD), stressful life events and psychological factors has previously been reported. Our objective was to examine the relationship between childhood emotional, physical, and sexual abuse and risk of IBD using a large cohort of female health professionals. We included participants in the Nurses' Health Study II who completed the Physical and Emotional Abuse Subscale of the Childhood Trauma Questionnaire and the Sexual Maltreatment Scale of the Parent-Child Conflict Tactics Scale in 2001. Diagnosis of IBD was determined by self-report and confirmed independently by two physicians through review of medical records. We used Cox proportional hazard modeling to estimate the risk of Crohn's disease (CD) and ulcerative colitis (UC) while adjusting for covariates. Among 68,167 women followed from 1989 until 2017, there were 146 incident cases of CD and 215 incident cases of UC. Compared to women with no history of abuse, the adjusted hazard ratios of CD were 1.16 (95% CI 0.67 - 2.02) for mild, 1.58 (95% CI 0.92 - 2.69) for moderate, and 1.95 (95% CI 1.22 - 3.10) for severe abuse (Ptrend = 0.002). We did not observe an association between childhood abuse and risk of UC. Women who reported early life severe abuse had an increased risk of CD. These data add to the growing body of evidence on the critical role of early life stressors in development of CD.

Helicobacter pylori infection and inflammatory bowel disease: a 2-sample Mendelian randomization study.

Observational studies have discovered a contradictory phenomenon between Helicobacter pylori (H. pylori) infection and inflammatory bowel disease (IBD). The study aimed to confirm the causal association between H. pylori and IBD, including ulcerative colitis (UC) and Crohn's disease (CD). We conducted a Mendelian randomization (MR) study with two sample Genome-Wide Association Studies (GWAS) to determine whether there is a causal relationship between H. pylori infection and IBD, as well as the possible pathogenic factors that may be involved. The reliability of the main MR assumptions was examined through a series of sensitivity analyses. Two genetic variants (SNPs) previously identified were employed as instrumental variables (IVs) for H. pylori infection. GWAS data for IBD, UC, and CD were obtained from the recent DF10 release10 of the FinnGen study. Our findings indicated a significant association between H. pylori seropositivity and an increased risk of IBD and UC (IBD: OR: 1.16, 95% CI, 1.03-1.31, P < 0.05; UC: OR: 1.22, 95% CI, 1.08-1.37, P < 0.001) while no causal relationship with CD (P > 0.05). Analysis of the main virulence pathogenic factors revealed a causal relationship between cytotoxin-associated protein A (CagA) and IBD and UC (IBD: OR: 1. 06, 95% CI, 1.001-1.11, P < 0.05; UC: OR: 1.07, 95% CI, 1.004-1.14, P < 0.05), while no correlation was found for vacuolar cytotoxin A (VacA) (P > 0.05). After applying the False Discovery Rate (FDR) correction, the causal relationship between CagA and the risk of IBD or UC was no longer statistically significant. This study suggests a potential causal relationship between H. pylori infection and IBD, particularly UC. The effect may be more pronounced in individuals with previous H. pylori infections.

Identification of novel proteins in inflammatory bowel disease based on the gut-brain axis: a multi-omics integrated analysis

BackgroundThe gut-brain axis has garnered increasing attention, with observational studies suggesting its involvement in the disease activity and progression of inflammatory bowel disease (IBD), but the precise mechanisms remain unclear.Materials and methodsIn this study, we aimed to investigate “novel proteins” underlying IBD in the brain using a comprehensive multi-omics analysis approach. We performed integrated analyses of proteomics and transcriptomics in the human prefrontal cortex (PFC) tissue, coupled with genome-wide association studies (GWAS) of IBD, crohn’s disease (CD), and ulcerative colitis (UC). This included performing protein-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR), and colocalization analysis to identify brain proteins associated with IBD and its subtypes.ResultsPWAS analyses identified and confirmation 9, 9, and 6 brain proteins strongly associated with IBD, CD, and UC, respectively. Subsequent MR analyses revealed that increased abundance of GPSM1, AUH, TYK2, SULT1A1, and FDPS, along with corresponding gene expression, led to decreased risk of IBD. For CD, increased abundance of FDPS, SULT1A1, and PDLIM4, along with corresponding gene expression, also decreased CD risk. Regarding UC, only increased abundance of AUH, along with corresponding gene expression, was significantly associated with decreased UC risk. Further TWAS and colocalization analyses at the transcriptome level supported strong associations of SULT1A1 and FDPS proteins with reduced risk of IBD and CD.ConclusionThe two “novel proteins,” SULT1A1 and FDPS, are strongly associated with IBD and CD, elucidating their causal relationship in reducing the risk of IBD and CD. This provides new clues for identifying the pathogenesis and potential therapeutic targets for IBD and CD.

Therapeutic targets for gastrointestinal diseases: proteome-wide Mendelian randomization and colocalization analyses.

This study was aimed to identify serum proteins linked with gastrointestinal diseases by proteome-wide Mendelian randomization analysis. We determined the casual relationship between 732 kinds of circulating proteins and the 24 kinds of gastrointestinal diseases via Mendelian randomization analysis. Four circulating proteins (FCGR3B, IL-12B, MAPKAPK2, and IL-23R) were associated with the occurrence of ulcerative colitis (UC), and IL23R was also correlated with risk of Crohn's disease (CD). Genetically predicted levels of IL23R were strongly correlated with the risk of UC and CD based on the high supporting evidence of colocalization analysis. Five circulating proteins (NOV, EFEMP1, ADGRE2, LCT, and SEMA3G) were associated with the risk of diverticulosis disease. With high supporting evidence of colocalization, genetically predicted levels of NOV and SEMA3G were inversely correlated with the risk of diverticulosis disease. Five circulating proteins (FUT3, FUT5, CRHBP, SULT2A1, and QPCTL) were associated with the occurrence of cholelithiasis. With high supporting evidence of colocalization, genetically predicted levels of FUT3 and CRHBP were inversely correlated with the risk of cholelithiasis. The proteome-wide Mendelian randomization investigation identified several circulating proteins associated with the risk of UC, CD, diverticular disease and cholelithiasis, which reinforced the understanding of molecular pathogenesis and design of therapeutic targets.

Maternal diet in pregnancy and the risk of inflammatory bowel disease in the offspring: a prospective cohort study

BackgroundDiet has been hypothesized as a risk factor for development of inflammatory bowel disease (IBD). ObjectiveTo explore associations between maternal diet diversity and quality in pregnancy and the offspring’s risk of IBD. MethodsWe used data from a nationwide cohort study on 85,129 Norwegian children followed from birth (1999–2009) with information on maternal diet in pregnancy from validated food frequency questionnaires. Hazard ratios (aHRs) for IBD, Crohn’s disease (CD), and ulcerative colitis (UC) by maternal diet diversity, quality and intake amounts of individual food groups were adjusted for maternal body mass index, parental IBD, and socio-demographic factors. Sensitivity analyses adjusted for the child's early-life diet quality and antibiotic treatment. Dietary exposures were classified into tertiles, comparing low (reference) to medium, and high levels. ResultsDuring a mean follow-up time of 16.1 years (1,367,837 person-years of follow-up), 268 children developed IBD (CD, n=119; UC, n=76; IBD-unclassified, n=73). High compared with low diet diversity in pregnancy was associated with a lower risk of UC in the offspring (aHR 0.46, 95% confidence interval 0.25-0.87), with consistent findings after further adjustment for the child's early-life diet quality and antibiotic treatment. High compared with low diet diversity in pregnancy yielded aHRs of 0.81 for CD (0.51-1.28) and 0.75 for any IBD (0.55-1.02) in the offspring. A high compared with low diet quality in pregnancy or intakes of specific food groups were not associated with the offspring’s risk of IBD or its subtypes. ConclusionsOur findings suggest that a higher maternal diet diversity in pregnancy may be associated with a lower risk of UC in the offspring.

APEX1 in intestinal epithelium triggers neutrophil infiltration and intestinal barrier damage in ulcerative colitis

Ulcerative colitis (UC) can lead to the generation of large amounts of reactive oxygen species and DNA damage. DNA repair caused by base excision repair (BER) enzymes is an important mechanism for maintaining genomic integrity. However, the specific relationship between the function of BER enzymes and UC remains unclear. To address this, we conducted a study on non-cancerous colon tissue from patients with UC, focusing on the role of apurinic/apyrimidinic endonuclease 1 (APEX1) in BER to explore its significance in the progression of UC. Our research found that the expression of APEX1 in epithelium cells was significantly correlated to the severity of inflammatory bowel disease (IBD) and the infiltration and function of neutrophils in human UC and mouse models, particularly in relation to neutrophil extracellular traps (NETs) and the degranulation processes. APEX1 deficiency resulted in decreased production of the chemokines CXCL1 by the NF-κB pathway in epithelium cells, leading to reduced accumulation and activation of neutrophils associated with colitis in colon tissue, as well as decreased levels of IL-1β. Furthermore, APEX1 deficiency reduced symptoms of colitis by decreasing epithelial cell apoptosis and altering the gut microbiome. Studies related to the redox activity of APEX1 have shown that the combination of the redox inhibitor E3330 with 5-aminosalicylic acid (5-ASA) can effectively alleviate colitis, indicating that APEX1 has promising prospects for clinical treatment of IBD. APEX1 is required for interactions between neutrophil and intestinal epithelial cells. This study provided a mechanism demonstrating that APEX1 protein triggered the risk of UC by promoting neutrophil infiltration and compromising intestinal epithelial barrier function.

Dietary Anthocyanin Intake, Genetic Risk, and Incident Ulcerative Colitis: A Prospective Cohort Study.

evidence from animal experiments indicates that anthocyanin supplements can contribute to intestinal health. Nevertheless, no evidence has linked dietary anthocyanins to the prevention potential against inflammatory bowel disease (IBD) in humans. We leveraged data from 188,044 IBD-free individuals (mean age 59 years; 55.2% females) from the prospective cohort UK Biobank. The anthocyanin intake was estimated using dietary information from validated 24 h dietary recalls. Incident IBD was ascertained via national health-related records. Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into low- and high-risk groups by median value. The Cox proportional regression model was applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). During the mean follow-up of 9.7 years, we documented 255 CD and 606 UC. We found that compared with participants with the lowest quartiles of anthocyanin intake, those in the highest quartiles were associated with 24% (95% CI 6%-38%, p = 0.012; p-trend = 0.003) and 35% (95% CI 16%-49%, p = 0.001; p-trend < 0.001) reduced risk of IBD and UC, respectively. The inverse associations were stronger (p-interaction = 0.022) among individuals with a high genetic risk of UC. We did not observe a significant association between anthocyanin intake and CD (p-trend = 0.536). Higher dietary anthocyanin intake was associated with reduced risk of IBD and UC, but not CD. Genetic factors may modify the influence of dietary anthocyanin on UC susceptibility, and possible mechanisms need to be further elucidated in the future.

The Impact of Gastrectomy on Inflammatory Bowel Disease Risk in Gastric Cancer Patients: A Critical Analysis.

Gastrectomy, a prevalent surgical procedure for gastric cancer, results in substantial alterations to the gastrointestinal tract, including reduced gastric acid production and significant modifications to the gut microbiota. These changes can impair postoperative recovery, influence metabolic functions, and predispose patients to inflammatory bowel disease (IBD). Studies have shown an increased risk of IBD, particularly Crohn's disease (CD) and ulcerative colitis (UC), in patients following gastrectomy and bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). For instance, patients undergoing RYGB have a higher hazard ratio for developing CD, while SG patients show an increased risk for UC. The surgical alteration of the gastrointestinal tract promotes dysbiosis, with a significant increase in pathogenic bacteria and a decrease in beneficial microbial populations. This dysbiosis can impair the intestinal mucosal barrier and promote systemic inflammation. Understanding the mechanisms behind these changes and their clinical implications is essential for developing effective postoperative management strategies. Probiotics and enhanced recovery after surgery (ERAS) protocols have shown promise in mitigating these adverse effects, improving gut microbiota balance, and enhancing patient outcomes. Further research is necessary to fully elucidate the long-term impacts of gastrectomy on gastrointestinal health and to refine therapeutic approaches for postoperative care.

Case-control study of IL23R rs76418789 polymorphism, smoking, and ulcerative colitis in Japan

BackgroundInterleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. MethodsThe study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. ResultsThe frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44–0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. ConclusionIL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

The contribution of dietary advanced glycation end-products and genetic risk in the development of inflammatory bowel disease: a prospective cohort study.

Dietary advanced glycation end products (AGEs) may promote oxidative stress and inflammation in the gastrointestinal tract. The aim of this study is to investigate the association between dietary AGE intake and the risk of inflammatory bowel disease (IBD). We included 121,978 participants without IBD at baseline from the UK Biobank. We estimated consumption of three common AGEs (Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)) by matching 24-h dietary questionnaires to a validated dietary AGE database. We used Cox proportional hazards regression models to calculate the hazard ratio (HR) and 95% CI of the association between dietary AGEs and IBD risk. During a median follow-up of 13.72 years, 671 participants developed IBD (192 with Crohn's disease (CD) and 478 with ulcerative colitis (UC)). Among the assessed dietary AGEs, only CEL was associated with an increased risk of IBD (HR = 1.09, 95% CI: 1.01-1.18, p = 0.020) and CD (HR = 1.18, 95% CI: 1.03-1.36, p = 0.014), particularly for participants who were overweight, physically inactive, and non-smokers. Among participants at a high genetic risk of CD, HRs (95% CI) of CD were 1.26 (1.00-1.57) for CML, 1.41 (1.12-1.77) for CEL, and 1.28 (1.01-1.62) for MG-H1 (p < 0.05 for each). However, none of the dietary AGEs was significantly associated with UC risk, irrespective of genetic predisposition. Dietary CEL was associated with an increased risk of IBD and CD, but not UC. Further interventional studies are required to support the potential benefit of AGE restriction, especially for individuals at a high genetic risk of CD.

Causal association between inflammatory bowel disease and acute pancreatitis: a two-sample bidirectional mendelian randomization study.

Acute pancreatitis (AP) is an extraintestinal manifestation of inflammatory bowel disease (IBD). Numerous observational studies have reported an increased risk of AP in patients diagnosed with IBD. However, the causal association and directionality between IBD or its subtypes and the development of AP remains unclear due to the limitations of observational research. This study aims to explore the relationship between IBD or its subtypes and AP risk using Mendelian Randomization (MR) method. A two-sample bidirectional MR study was conducted, selecting genetic variants associated with IBD and AP as instrumental variables from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and FinnGen databases, respectively. The inverse-variance weighted (IVW) method used as the primary approach for causal inference. The Cochran Q test was employed for heterogeneity assessment. Sensitivity analyses were performed using the MR Egger intercept test, MR-Presso, and Leave-one-out method. The results revealed that IBD (OR = 1.049, 95% CI = 1.010-1.090, p = 0.013) and ulcerative colitis (UC) (OR = 1.057, 95% CI = 1.013-1.102, p = 0.011) were significantly associated with an increased risk of AP. However, Crohn's disease (CD) (OR = 1.023, 95% CI = 0.993-1.055, p = 0.134) did not show a causal association with the risk of AP. Interestingly, AP was suggestively associated with a decreased risk of CD (OR = 0.797, 95% CI = 0.637-0.997, p = 0.047). Furthermore, there was no causal association between AP and the risk of IBD (OR = 0.886, 95% CI = 0.753-1.042, p = 0.144) or UC (OR = 0.947, 95% CI = 0.773-1.159, p = 0.595). In conclusion, this study provides genetic evidence supporting the causal influence of IBD (specifically UC) on AP, while CD does not appear to have a causal impact on AP.

Antibiotics, passive smoking, high socioeconomic status and sweetened foods contribute to the risk of paediatric inflammatory bowel disease: A systematic review with meta-analysis.

Genetic and environmental factors influence pathogenesis and rising incidence of paediatric inflammatory bowel disease (PIBD). The aim was to meta-analyse evidence of diet and environmental factors in PIBD. A systematic search was conducted to identify diet and environmental factors with comparable risk outcome measures and had been reported in two or more PIBD studies for inclusion in meta-analyses. Those with ≥2 PIBD risk estimates were combined to provide pooled risk estimates. Of 4763 studies identified, 36 studies were included. PIBD was associated with higher risk with exposure to ≥/=4 antibiotic courses (includes prescriptions/purchases/courses), passive smoking, not being breastfed, sugary drink intake, being a non-Caucasian child living in a high-income country and infection history (odds ratio [OR] range: 2-3.8). Paediatric Crohn's disease (CD) was associated with higher risk with exposure to antibiotics during early childhood, ≥/=4 antibiotic courses, high socioeconomic status (SES), maternal smoking, history of atopic conditions and infection history (OR range: 1.6-4.4). A history of infection was also associated with higher risk of paediatric ulcerative colitis (UC) (OR: 3.73). Having a higher number of siblings (≥2) was associated with lower risk of paediatric CD (OR: 0.6) and paediatric UC (OR: 0.7). Pet exposure was associated with lower risk of paediatric UC (OR: 0.5). Several factors associated with PIBD risk were identified that could potentially be used to develop a disease screening tool. Future research is needed to address risk reduction in PIBD.

Anorexia and bulimia in relation to ulcerative colitis: a Mendelian randomization study.

Evidence for anorexia and bulimia in relation to the risk of ulcerative colitis (UC) is limited and inconsistent. The objective of this research was to utilize bi-directional, two-sample Mendelian randomization (MR) analysis to predict the causal association between anorexia nervosa and bulimia nervosa with UC. The genome-wide association studies (GWAS) provided data for anorexia and bulimia from the UK Biobank, utilizing single-nucleotide polymorphisms (SNP) as instrumental variables. Additionally, genetic associations with UC were collected from various sources including the FinnGen Biobank, the UK Biobank and the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The main analytical approach utilized in this study was the inverse-variance-weighted (IVW) method. To evaluate horizontal pleiotropy, the researchers conducted MR-Egger regression and MR-PRESSO global test analyses. Additionally, heterogeneity was assessed using the Cochran's Q test. This study found a negative association between genetically predicted bulimia (OR = 0.943, 95% CI: 0.893-0.996; p = 0.034) and the risk of UC in the IIBDGC dataset, indicating that individuals with bulimia have approximately a 5.7% lower risk of developing UC. No association was observed in the other two datasets. Conversely, genetically predicted anorexia was not found to be causally associated with UC. In bi-directional Mendelian randomization, UC from the IIBDGC dataset was negatively associated with the risk of anorexia (OR = 0.877, 95% CI: 0.797-0.965; p = 0.007), suggesting that UC patients have approximately a 12.3% lower risk of developing anorexia, but not causally associated with bulimia. Genetically predicted bulimia may have a negative association with the onset of UC, while genetically predicted anorexia does not show a causal relationship with the development of UC. Conversely, genetically predicted UC may have a negative association with the development of anorexia.

Life’s essential 8, genetic susceptibility, and risk of inflammatory bowel diseases: a population-based cohort study

BackgroundEvidence has shown that the individual metrics in Life’s Essential 8 (LE8), an updated cardiovascular health (CVH) concept proposed by the American Heart Association, play a role in the development of inflammatory bowel disease (IBD). However, epidemiological evidence on the overall LE8 on IBD risk remains limited. We aimed to assess the longitudinal associations of LE8-defined CVH and the risks of IBD and its subtypes, ulcerative colitis (UC) and Crohn’s disease (CD). We also tested whether genetic susceptibility could modify these associations.MethodsA total of 260,836 participants from the UK Biobank were included. LE8 scores were determined by 8 metrics (physical activity, diet, nicotine exposure, sleep, body mass index, blood pressure, blood glucose, and blood lipids), and were divided into three levels: low CVH (0–49), moderate CVH (50–79), and high CVH (80–100). Cox proportional hazards models were used to calculate the hazard ratios (HRs) and confidence intervals (CIs) of the risk of IBD in relation to CVH status.ResultsOver a median follow-up 12.3 years, we documented 1,500 IBD cases (including 1,070 UC and 502 CD). Compared to participants with low CVH, the HRs (95% CIs) of those with high CVH for IBD, UC, and CD were 0.67 (0.52, 0.83), 0.70 (0.52, 0.93), and 0.55 (0.38, 0.80), respectively. These associations were not modified by genetic susceptibility (all P for interactions > 0.05). The lowest HR (UC: 0.30, 95% CI: 0.20–0.45; CD: 0.33, 95% CI: 0.20–0.57) was observed in participants with both high CVH and low genetic risk.ConclusionsBetter CVH, defined by LE8, was associated with significantly lower risks of IBD, UC, and CD, irrespective of genetic predisposition. Our results underscore the importance of adherence to LE8 guidelines for maintaining CVH as a potential strategy in the prevention of IBD.

Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis

Abstract Background It is crucial to pinpoint the metabolites that cause Crohn’s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC. Methods As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance–weighted method, while stability of the findings was evaluated through sensitivity analyses. Results After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10−3; and OR, 0.64; P = 1.90 × 10−2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10−4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10−2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10−2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10−2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites. Conclusions In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.

Role of Environmental Risk Factors in the Etiology of Inflammatory Bowel Diseases: A Multicenter Study.

The increasing global incidence and prevalence of inflammatory bowel disease (IBD) necessitates an investigation into the potential influence of environmental risk factors on its origin. This multicenter case-control study aimed to investigate potential environmental risk factors contributing to IBD development in Turkey. The study included 156 Crohn's disease (CD), 277 ulcerative colitis (UC) patients, and 468 controls (matched for age and gender) from six hospitals' gastroenterology departments. Data collection relied on the International Organization of IBD's questionnaire on environmental factors. Each environmental factor was initially analyzed using univariate and subsequently multivariate logistic regression models. In the multivariate model, regular coffee consumption was associated with decreased odds for both CD (OR 0.28; 95% CI 0.14-0.55) and UC (OR 0.25; 95% CI 0.15-0.42). Stress was associated with UC (OR 3.27; 95% CI 1.76-6.10) and CD (OR 4.40; 95% CI 2.12-9.10) development. A history of childhood infectious diseases (gastroenteritis, upper respiratory tract infections, etc.) raised the odds for both CD (OR 9.45; 95% CI 2.51-35.6) and UC (OR 7.56; 95% CI 1.57-36.4). Conversely, consuming well/spring water (OR 0.22; 95% CI 0.10-0.50) and childhood antibiotic use (OR 0.41; 95% CI 0.18-0.93) showed a positive association against UC. Increased consumption of refined sugar and industrial food products emerged as risk factors for IBD. Smoking increased the risk for CD (OR 2.38; 95% CI 1.16-4.91), while ex-smoking increased the risk for UC (OR 3.16; 95% CI 1.19-8.37). This study represents the first multicenter case-control study in Turkey examining the effects of environmental factors on IBD. It revealed that coffee consumption is positively associated, while stress and childhood infection-related diseases are risk factors. These findings, which are not supported by other studies, provide insight into the relationships between these factors and IBD.

Bidirectional associations between periodontitis and inflammatory bowel disease: A systematic review of longitudinal studies with meta-analysis and trial sequential analysis.

The bidirectional associations between periodontitis and inflammatory bowel disease (IBD) with temporal directionality remain inconclusive. This study aims to evaluate the bidirectional associations between periodontitis and IBD through a systematic review and meta-analysis. Five databases (PubMed, Embase, Web of Science, Scopus and Cochrane Library) were systematically searched from inception to 27 February 2024. Two independent reviewers performed a review of the retrieved studies. Longitudinal studies, including cohort and nested case-control studies, were considered eligible for the study design. The pooled risk ratio (RR) and hazard ratio (HR) derived from the meta-analysis were used to assess whether periodontitis (or IBD) was a risk factor for IBD (or periodontitis). Trial sequential analysis (TSA) was performed to evaluate the reliability of the results. Four studies (n = 10 270 912) on the risk of IBD in patients with periodontitis and two (n = 33 420) on the risk of periodontitis in patients with IBD were included. The result suggested that periodontitis did not increase the risk of IBD (pooled RR = 1.04, 95% confidence interval [CI]: 0.99-1.09; p = .164; I-squared statistic [I2] = 27%). For subtypes of IBD, periodontitis was associated with the occurrence of ulcerative colitis (UC) (pooled RR = 1.12, 95% CI: 1.04-1.21; p = .003; I2 = 38%), but not with Crohn's disease (CD) (pooled RR = 0.98, 95% CI: 0.92-1.04; p = .475; I2 = 0%). Specifically, the risk of UC was higher among men (pooled HR = 1.11, 95% CI: 1.01-1.22; p = .025; I2 = 0%) and smokers (pooled HR = 1.23, 95% CI: 1.07-1.42; p = .004; I2 = 0%) with periodontitis than their counterparts without periodontitis. Patients with IBD may have a higher risk of developing periodontitis (pooled HR = 1.37, 95% CI: 1.26-1.49; p < .001; I2 = 18%); however, whether IBD subtypes increased the occurrence of periodontitis remained uncertain. The TSA results confirmed the reliability of the primary findings. Based on limited longitudinal evidence, patients with periodontitis do not exhibit an increased risk of developing IBD overall, but they are at increased risk of UC (not CD). On the contrary, patients with IBD have a higher risk of developing periodontitis over time. More high-quality longitudinal studies are needed to determine the effect of specific subtypes of IBD on periodontitis.

Dried fruit intake can lower the risk of ulcerative colitis: evidence from a Mendelian randomization study.

This study aims to examine the causal relationship between dietary factors and ulcerative colitis (UC). The analysis utilized data from genome-wide association studies (GWAS). Dried fruit, vegetables, processed meat, fresh fruit, and cereal intake were examined as exposure factors. UC was considered the outcome. Two-sample Mendelian randomization (TSMR) analysis was performed using methods. Heterogeneity and horizontal pleiotropy assessments were conducted to ensure the robustness of our findings. Additionally, we applied False Discovery Rate (FDR) corrections for multiple tests. The analysis revealed a significant inverse causal relationship between dried fruit intake and UC risk (odds ratio [OR]: 0.488, 95% confidence interval [CI]: 0.261 to 0.915, p = 0.025). No significant association was observed between vegetable intake (OR: 1.742, 95% CI: 0.561 to 5.415, p = 0.337), processed meat intake (OR: 1.136, 95% CI: 0.552 to 2.339, p = 0.729), fresh fruit intake (OR: 0.977, 95% CI: 0.465 to 2.054, p = 0.952), cereal intake (OR: 1.195, 95% CI: 0.669 to 2.134, p = 0.547). The low heterogeneity observed across analyses and the confirmation of stability through leave-one-out analysis reinforce the reliability of these results. Moreover, after adjusting for multiple tests, none of the dietary factors reached a p-value below the conventional significance threshold of 0.05. This study provides evidence of a potential association between dried fruit intake and a reduced risk of UC. Further MR studies incorporating larger GWAS datasets are needed to confirm these findings.

A Polygenic Risk Analysis for Identifying Ulcerative Colitis Patients with European Ancestry.

The incidence of ulcerative colitis (UC) has increased globally. As a complex disease, the genetic predisposition for UC could be estimated by the polygenic risk score (PRS), which aggregates the effects of a large number of genetic variants in a single quantity and shows promise in identifying individuals at higher lifetime risk of UC. Here, based on a cohort of 2869 UC cases and 2900 controls with genotype array datasets, we used PRSice-2 to calculate PRS, and systematically analyzed factors that could affect the power of PRS, including GWAS summary statistics, population stratification, and impact of variants. After leveraging a stepwise condition analysis, we eventually established the best PRS model, achieving an AUC of 0.713. Meanwhile, samples in the top 20% of the PRS distribution had a risk of UC more than ten times higher than samples in the lowest 20% (OR = 10.435, 95% CI 8.571-12.703). Our analyses demonstrated that including population-enriched, more disease-associated SNPs and using GWAS summary statistics from similar ethnic background can improve the power of PRS. Strictly following the principle of focusing on one population in all aspects of generating PRS can be a cost-effective way to apply genotype-array-derived PRS to practical risk estimation.