Interaction between diet and genetics in patients with inflammatory bowel disease.

In this editorial, we comment on the article by Marangoni et al, published in the recent issue of the World Journal of Gastroenterology 2023; 29: 5618-5629, about "Diet as an epigenetic factor in inflammatory bowel disease". The authors emphasized the role of diet, especially the interaction with genetics, in promoting the inflammatory process in inflammatory bowel disease (IBD) patients, focusing on DNA methylation, histone modifications, and the influence of microRNAs. In this editorial, we explore the interaction between genetics, gut microbiota, and diet, in an only way. Furthermore, we provided dietary recommendations for patients with IBD. The Western diet, characterized by a low fiber content and deficiency the micronutrients, impacts short-chain fatty acids production and may be related to the pathogenesis of IBD. On the other hand, the consumption of the Mediterranean diet and dietary fibers are associated with reduced risk of IBD flares, particularly in Crohn's disease (CD) patients. According to the dietary guidance from the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD), the regular consumption of fruits and vegetables while reducing the consumption of saturated, trans, dairy fat, additives, processed foods rich in maltodextrins, and artificial sweeteners containing sucralose or saccharine is recommended to CD patients. For patients with ulcerative colitis, the IOIBD recommends the increased intake of natural sources of omega-3 fatty acids and follows the same restrictive recommendations aimed at CD patients, with the possible inclusion of red meats. In conclusion, IBD is a complex and heterogeneous disease, and future studies are needed to elucidate the influence of epigenetics on diet and microbiota in IBD patients.

Novel XIAP mutation with early-onset Crohn's disease complicated with acute heart failure: a case report.

BACKGROUND: The X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses and plays a role in preventing cell death. XIAP mutations are associated with several diseases, primarily including hemophagocytic lymphohistiocytosis and inflammatory bowel disease (IBD). We report the clinical features and results associated with hemizygous mutation of the XIAP gene in a young male with Crohn's disease complicated with acute heart failure.This 16-year-old patient ultimately died of heart failure. CASE PRESENTATION: A young male of 16 years of age was initially diagnosed with Crohn's disease based on evidences from endoscopic and histological findings. Although supportive care, anti-infective drugs and biologics were administered consecutively for 11 months, his clinical manifestations and laboratory indices (patient's condition) did not improved. Additionally, the patient exhibited a poor nutritional status and sustained weight loss. Subsequently, acute heart failure led to the exacerbation of the patient's condition. He was diagnosed with wet beriberi according to thiamine deficiency, but the standard medical therapy for heart failure and thiamine supplementation did not reverse the adverse outcomes. Comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother. CONCLUSION: A novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be one of the potential pathogenic factors in Crohn's disease and plays an important role in the progression of heart failure. Additionally, thiamine deficiency triggers a vicious cycle.

The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization.

Background: Many existing studies indicated that patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), tend to have the risk of low total body bone mineral density (BMD), and are more likely to have osteoporosis (OS). To determine the causal relationship between IBD and bone metabolic disorders, we herein performed a two-sample Mendelian randomization analysis (TSMR) using publicly available summary statistics. Methods: Summary statistics of total body BMD, OS and IBD were downloaded from the Open Genome-Wide Association Study (GWAS), FinnGen consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The European and East Asian populations have consisted in this Mendelian Randomization (MR) work. A range of quality control procedures were taken to select eligible instrument SNPs closely associated with total body BMD, OS and IBD. To make the conclusions more reliable, we applied five robust analytical methods, among which the inverse variance weighting (IVW) method acted as the major method. Besides, heterogeneity, pleiotropy and sensitivity were evaluated. Results: In the European population, the genetic association of UC on total body BMD (OR=0.97, 95%CI=0.96,0.99, P<0.001) and overall IBD on total body BMD (OR=0.98, 95%CI=0.97,1.00, P=0.013) were significant, while the effect of CD on total body BMD was not significant enough (OR=0.99, 95%CI=0.98,1.00, P=0.085). All of UC, CD and overall IBD can be the genetic risk factor of having OS with pathological fracture (UC: OR=1.13, 95%CI=1.02,1.26, P=0.024, CD: OR=1.14, 95%CI=1.05,1.25, P=0.003, overall IBD: OR=1.13, 95%CI=1.02,1.24, P=0.015). In East Asian groups, only CD had a causal relationship with OS (OR=1.04, 95% CI=1.01,1.07, P=0.019). Conclusion: Our study revealed genetically predicted associations between IBD on total body BMD and OS in European and East Asian populations. This work supplemented the results of previous retrospective studies and demonstrated the necessity of BMD monitoring in patients with IBD.

[Herbal cake-partitioned moxibustion regulates M1 and M2 macrophage polarization of colonic mucosa in rats with Crohn's disease].

OBJECTIVE: To observe the effect of herbal cake-partitioned moxibustion (Moxi) on the expressions of inflammatory factors and M1/M2 polarization in colonic mucosal macrophages in Crohn's disease (CD) rats, so as to explore its underlying mechanisms in the treatment of CD. METHODS: Forty male SD rats were randomly divided into normal, model, Moxi and medication groups (n=10). The CD model was established by enema of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) solution (5%TNBS∶50% alcohol=2∶1, 3 mL/kg), once every 7 days, 4 times altogether. For rats of the Moxi group, cake-partitioned moxibustion was given to "Tianshu" (ST25) and "Qihai" (CV6), two moxa-cones for each acupoint every time, once daily for 10 days. For rats of the medication group, intragastric perfusion of mesalazine solution was given twice daily for 10 days. After the treatment, the colonic mucosa tissue was sampled, and the macrophages were isolated, purified and cultured. The pathological changes of colon tissues were observed by H.E. staining. The ultrastructure of colon tissue was observed by transmission electron microscopy. The expression levels of α7nAChR, NF-κB p65 and TNF-α in colon mucosal macrophages were detected by Western blot. The number of M1 and M2 macrophages in colon mucosa was detected by flow cytometry and immunofluorescence assay. RESULTS: Compared with the normal group, the colon tissue of rats presented huge ulceration and inflammatory manifestations, the junction of colon epithelial cells was loose, the structure of organelles was damaged; the expression level of α7nAChR in macrophages of colon mucosa was significantly decreased (P<0.01), while the expression levels of NF-κB p65 and TNF-α, and the number of M1 and M2 macrophages were increased (P<0.01, P<0.05) in the model group. In comparison with the model group, the morphology and structure of colon mucosa tissues of rats in Moxi and medication groups were improved; the expression level of α7nAChR, the number of M2 macrophage in colon mucosa were significantly increased (P<0.01, P<0.05), while the expression levels of NF-κB p65 and TNF-α, and the number of M1 macrophage were significantly decreased (P<0.01, P<0.05) in both the Moxi and medication groups. CONCLUSION: Herbal cake-partitioned moxibustion may inhibit NF-κB activation by up-regulating the expression level of α7nAChR to promote the polarization of macrophages from M1 to M2 type, and reduce the proportion of M1 macrophages, inhibit the expression of TNF-α in colonic mucosa of CD rats, so as to relieve the intestinal inflammation.

Correlation Between IL-8 Gene Polymorphisms and Pathogenesis of Crohn's Disease.

Context: The risk of inflammatory bowel disease (IBD) is substantially heightened if patients' first-degree relatives have it. The genetic and immune factors related to the disease have attracted great attention, including patients innate genetic polymorphisms. Interleukin-8 (IL-8) plays a vital role in digestive-system diseases, especially in gastrointestinal diseases. Objective: The study intended to explore the expression of interleukin-8 (IL-8) in the colon tissues of patients with Crohn's disease and the correlation between its polymorphisms and the disease's occurrence. Design: The research team performed a prospective study. Setting: The study took place in the Department of Gastroenterology at Zhuji People's Hospital of Zhejiang Province in Zhuji, China. Participants: Participants were 100 patients with Crohn's disease at the hospital between November 2016 and June 2018 and 100 healthy individuals. The research team assigned participants with Crohn's disease to the Crohn's disease group and the healthy participants to the control group. Outcome Measures: The research team: (1) determined differences in the protein expression of the IL-8 between the groups; (2) examined the conformity of the data to that of the Hardy-Weinberg equilibrium; (3) analyzed the differences in the genotypes and alleles for the IL-8 single nucleotide polymorphisms (SNPs) rs102039, rs103284 and rs105432 between the groups; and (4) for the Crohn's disease group, examined the differences in the disease's location and behavior for the participants with different genotypes. Results: The protein expression level of IL-8 in the colon tissues in Crohn's disease group was significantly higher than that in control group (P < .05). The genetic association analysis showed significant correlations between the polymorphisms rs103284 and rs105432 and alleles of the IL-8 gene and the occurrence of Crohn's disease (P < .05), but no associations existed between the gene polymorphism rs102039 and alleles and Crohn's disease (P > .05). Significant correlations existed between the IL-8 gene polymorphisms rs103284 and rs105432 and the disease's location and behavior (P < .05). Conclusions: IL-8 had a significantly increased expression in the colon tissues of the participants with Crohn's disease, and some genotypes and alleles for the gene polymorphisms rs103284 and rs105432 were significantly higher in the Crohn's disease group than in the control group. In addition, the disease's location and behavior were significantly different for participants in the Crohn's disease group with different genotypes.

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.

Computer-Aided Imaging Analysis of Probe-Based Confocal Laser Endomicroscopy With Molecular Labeling and Gene Expression Identifies Markers of Response to Biological Therapy in IBD Patients: The Endo-Omics Study.

BACKGROUND: We aimed to predict response to biologics in inflammatory bowel disease (IBD) using computerized image analysis of probe confocal laser endomicroscopy (pCLE) in vivo and assess the binding of fluorescent-labeled biologics ex vivo. Additionally, we investigated genes predictive of anti-tumor necrosis factor (TNF) response. METHODS: Twenty-nine patients (15 with Crohn's disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4ß7 therapy. Biopsies were taken for fluorescein isothiocyanate-labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort. RESULTS: In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn's disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7). CONCLUSIONS: Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF-responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders.

Gene/environment interaction in the susceptibility of Crohn's disease patients to aluminum.

BACKGROUND & AIM: The key role of environmental factors in the pathogenesis of Inflammatory Bowel Diseases (IBD) is recognized. Aluminum is suspected to be a risk factor for IBD. However, mechanisms linking aluminum exposure to disease development are unknown. We examined the role of aluminum transport and subcellular localisation on human colon susceptibility to aluminum-induced inflammation. METHODS: Human colon biopsies isolated from Crohn's disease (CD) or control patients and Caco-2 cells were incubated with aluminum. The effects of aluminum were evaluated on cytokine secretion and transporter expression. The role of aluminum kinetics parameters was studied in Caco-2 using transport inhibitors and in human colon biopsies by assessing genetic polymorphisms of transporters. RESULTS: Aluminum exposure was shown to induce cytokine secretion in colon of CD but not healthy patients. In Caco-2 cells, aluminum internalisation was correlated with inflammatory status. In human colon, analysis of genetic polymorphisms and expression of ABCB1 and SLC26A3 transporters showed that their decreased activity was involved in aluminum-induced inflammation. CONCLUSIONS: We hypothesize that alteration in detoxifying response would lead to a deregulation of intestinal homeostasis and to the expression of IBD. Our study emphasizes the complexity of gene/environment interaction for aluminum adverse health effect, highlighting at risk populations or subtypes of patients. A better understanding of correlations between gene expression or SNP and xenobiotic kinetics parameters would shift the medical paradigm to more personalized disease management and treatment.

The Effects of Fatty Acids on Inflammatory Bowel Disease: A Two-Sample Mendelian Randomization Study.

Inflammatory Bowel Disease (IBD) is a severe relapsing inflammation of the gastrointestinal tract. The association between fatty acids (FAs) and IBD is controversial and it remains unclear whether there is a causal relationship between them. Mendelian randomization (MR) analysis was province/state for affiliations from the same country performed to clarify the causality. Eligible single nucleotide polymorphisms were selected as instrumental variables from six Genome-wide association studies, involving 114,999 individuals in UK Biobank. The summary-level data on IBD, including Crohn's disease (CD) and ulcerative colitis (UC), were obtained from the International Inflammatory Bowel Disease Genetics Consortium with 20,883 and 27,432 individuals involved. The primary inverse variance weighted (IVW) method as well as other supplementary analysis ones were adopted to evaluate the causal relationship between diverse FAs and IBD. The tests for heterogeneity and pleiotropy, and Leave-one-out analysis were adopted to verify the stability of the results. Omega-3 FA was found to have a causal effect on UC instead of CD. For each Standard Deviation increase in Omega-3 FA genetic levels, the risk of ulcerative colitis was found to be reduced by 39.9% by the IVW method (p = 1.766 × 10-4), by 57.8% by the MR Egger (p = 1.11 × 10-2), by 51.5% by the Weighted median estimator (p = 7.706 × 10-4), by 39% by the Maximum likelihood estimation (p = 3.262 × 10-4), and by 54.5% by the penalized weighted median estimator (p = 1.628 × 10-4). No causal relationship was found between other FAs (including total FA, saturated FA, polyunsaturated FA, monounsaturated FA and omega-6 FA) and IBD. The pleiotropic test and Leave-one-out analysis both proved the validity and reliability of these MR analyses. Omega-3 FA was observed to have a protective effect against UC, providing a new perspective on the investigation of the associations between FAs and IBD.

Smad7 Antisense Oligonucleotide-Based Therapy in Crohn's Disease: Is it Time to Re-Evaluate?

Abundant preclinical work showed that in Crohn's disease (CD), the defective activity of the immunosuppressive cytokine tumor necrosis factor (TGF)-ß1 due to high levels of the intracellular inhibitor Smad7 contributes to amplify the tissue-damaging inflammatory response. Consistently, phase I and II studies documented clinical and endoscopic benefit in active CD patients treated with mongersen, an oral antisense oligonucleotide targeting Smad7. However, a multicenter, randomized, double-blind, placebo-controlled, phase III study was prematurely discontinued as a futility analysis showed that mongersen was not effective in CD patients. The reasons why the phase III study failed despite the fact that previous clinical trials documented the efficacy of the drug remain unknown. The primary objective of this Viewpoint was to provide clues about the factors explaining discrepancies among the clinical trials. We illustrate the recent data indicating that the various batches of mongersen, used during the phase III program, are chemically different, with some of them being unable to downregulate Smad7 expression. Overall, these findings suggest the necessity of new clinical studies to further evaluate the efficacy of chemically homogenous batches of mongersen in patients with inflammatory bowel diseases (IBDs), and, at the same time, they can help understand the failure of other clinical trials with antisense oligonucleotides in IBD (i.e. alicaforsen).

Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease.

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from complex host and environmental interactions. Investigating drug efficacy for IBD can improve our understanding of why treatment response can vary between patients. We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to integrate multi-modal data and predict inter-patient variation in drug response. Using explanation of our models, we interpret the ML models' predictions to infer unique combinations of important features associated with pharmacological responses obtained during preclinical testing of drug candidates in ex vivo patient-derived fresh tissues. Our inferred multi-modal features that are predictive of drug efficacy include multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data. Our aim is to understand variation in patient responses before a drug candidate moves forward to clinical trials. As a pharmacological measure of drug efficacy, we measured the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence/absence of test drugs. We initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor; however, we later showed our approach can be applied to other targets, test drugs or mechanisms of interest. Our best model predicted TNFα levels from demographic, medicinal and genomic features with an error of only 4.98% on unseen patients. We incorporated transcriptomic data to validate insights from genomic features. Our results showed variations in drug effectiveness (measured by ex vivo assays) between patients that differed in gender, age or condition and linked new genetic polymorphisms to patient response variation to the anti-inflammatory treatment BIRB796 (Doramapimod). Our approach models IBD drug response while also identifying its most predictive features as part of a transparent ML precision medicine strategy.

Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets.

BACKGROUND & AIMS: Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. METHODS: We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. RESULTS: We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.

Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn's Disease and Rheumatoid Arthritis.

Crohn's Disease (CD) and Rheumatoid Arthritis (RA) share some single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor types 2 and 22 (PTPN2/22). Recently, we reported that clinical samples from CD and RA patients associated with PTPN2:rs478582 or PTPN22:rs2476601 genotypes were linked to overactive immune response and exacerbation of inflammation. Here, we investigated in vitro the effects of these SNPs in Jurkat T-cells using CRISPR-Cas9. All cells were evaluated for PTPN22/22 loss of function and effects on cell response. We measured gene expression via RT-qPCR and cytokines by ELISA. We also measured cell proliferation using a BrdU labeling proliferation ELISA, and T-cell activation using CD-25 fluorescent immunostaining. In PTPN2 SNP-edited cells, PTPN2 expression decreased by 3.2-fold, and proliferation increased by 10.2-fold compared to control. Likewise, expression of PTPN22 decreased by 2.4-fold and proliferation increased by 8.4-fold in PTPN22 SNP-edited cells. IFN-γ and TNF-α secretions increased in both edited cell lines. CD25 expression (cell activation) was 80.32% in PTPN2 SNP-edited cells and 85.82% in PTPN22 SNP-edited cells compared to 70.48% in unedited Jurkat T-cells. Treatment of PTPN2 and PTPN22-edited cells with a maximum 20 µM spermidine restored PTPN2/22 expression and cell response including cell proliferation, activation, and cytokines secretion. Most importantly, the effect of spermidine on edited cells restored normal expression and secretion of IFN-γ and TNF-α. The data clearly demonstrated that edited SNPs in PTPN2 or PTPN22 were associated with reduced gene expression, which resulted in an increase in cell proliferation and activation and overactive immune response. The data validated our earlier observations in CD and RA clinical samples. Surprisingly, spermidine restored PTPN2/22 expression in edited Jurkat T-cells and the consequent beneficial effect on cell response and inflammation. The study supports the use of polyamines dietary supplements for management of CD and in RA patients.

Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn's Disease and Ulcerative Colitis: A Mendelian Randomization Study.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC. METHODS: We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances-nicotine, alcohol, and caffeine-to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy. RESULTS: We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P > 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found. CONCLUSIONS: We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.

Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study.

Several studies have examined environmental factors and inflammatory bowel diseases (IBD) using traditional approaches; however, provided results are still conflicting. Our aim was to determine whether lifestyle and nutrient exposures, related to IBD in observational meta-analyses, influence IBD risk using a Mendelian randomization (MR) approach. A two-sample MR approach was applied on summary-level genome-wide association results. Genetic variants strongly associated with measures of tobacco smoking, obesity and fat distribution, physical activity, and blood levels of vitamins and fatty acids were evaluated on genetic data from international IBD consortia including a total of 25,042 IBD cases (12,194 cases of Crohn's disease (CD) and 12,366 cases of ulcerative colitis (UC)) and 34,915 controls. Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02), but it was not associated with UC risk (OR 0.99, P = 0.88). Body-mass index (BMI) and body fat percentage were positively associated with CD (OR 1.11, P = 0.02, per standard deviation (SD) of 4.6 kg/m2; and OR 1.50, P = 3 × 10-10, per SD of 6.6%; respectively); while for UC, BMI was inversely associated (OR 0.85, P = 5 × 10-5; per SD) and body fat percentage showed a OR of 1.11 (P = 0.11; per SD). Additionally, among nutrient exposures, omega-3 fatty acids levels were inversely associated with CD (OR 0.67, P = 2 × 10-6). Our MR results did not support a protective effect for being a smoker on UC risk; however, they are compatible with a risk effect for higher body fat proportion and a protective role for higher levels of omega-3 fatty acids on CD etiology.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Methyl-donor supplementation prevents intestinal colonization by Adherent-Invasive E. coli in a mouse model of Crohn's disease.

Deficiencies in methyl-donor molecules (folate, B12 vitamin), DNA methylation alteration and high prevalence of Adherent-Invasive Escherichia coli (AIEC) are frequently observed in Crohn's disease (CD) patients. AIEC bacteria adhere to the enterocytes through abnormally expressed carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) glycoprotein on host cells. This work aims at studying the relationship between methyl-donor molecules and AIEC-induced intestinal inflammatory response. CEABAC10 mice, a mouse model of CD, were fed a control or Methyl-donor Supplemented diet (MS diet). CEACAM6 promoter was hypermethylated in intestinal epithelial cells from mice fed an MS diet, which was associated with a significant decrease in CEACAM6 expression. Transcriptomic analysis revealed increased expression of anti-microbial peptides, increase in HSP70 gene family expression and a decreased expression of inflammatory marker Calprotectin upon MS diet, associated to a lower ability of AIEC bacteria to colonize gut mucosa. We observed in a cohort of CD patients that serum folate concentration was inversely correlated to Crohn's disease endoscopic index of severity and to fecal inflammatory markers. This study demonstrates that methyl-donor supplementation through the diet induces a specific intestinal micro-environment limiting pathobiont colonization of the gut. Clinicians may wish to consider methyl-donor supplementation for methyl-donor deficient CD patients.

Vitamin C Deficiency and the Risk of Osteoporosis in Patients with an Inflammatory Bowel Disease.

Recent research studies have shown that vitamin C (ascorbic acid) may affect bone mineral density and that a deficiency of ascorbic acid leads to the development of osteoporosis. Patients suffering from an inflammatory bowel disease are at a risk of low bone mineral density. It is vital to notice that patients with Crohn's disease and ulcerative colitis also are at risk of vitamin C deficiency which is due to factors such as reduced consumption of fresh vegetables and fruits, i.e., the main sources of ascorbic acid. Additionally, some patients follow diets which may provide an insufficient amount of vitamin C. Moreover, serum vitamin C level also is dependent on genetic factors, such as SLC23A1 and SLC23A2 genes, encoding sodium-dependent vitamin C transporters and GSTM1, GSTP1 and GSTT1 genes which encode glutathione S-transferases. Furthermore, ascorbic acid may modify the composition of gut microbiota which plays a role in the pathogenesis of an inflammatory bowel disease.