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Epidemiological and translational data increasingly implicate environmental pollutants in inflammatory bowel disease (IBD). Indeed, the global incidence of IBD has been rising, particularly in developing countries, in parallel with the increased use of chemicals and synthetic materials in daily life and escalating pollution levels. Recent nationwide and ecological studies have reported associations between agricultural pesticides and IBD, particularly Crohn's disease. Exposure to other chemical categories has also been linked with an increased risk of IBD. To synthesise available data and identify knowledge gaps, we conducted a systematic review of human studies that reported on the impact of environmental pollutants on IBD risk and outcomes. Furthermore, we summarised in vitro data and animal studies investigating mechanisms underlying these associations. The 32 included human studies corroborate that heavy and transition metals, except zinc, air pollutants, per- and polyfluorinated substances, and pesticides are associated with an increased risk of IBD, with exposure to air pollutants being associated with disease-related adverse outcomes as well. The narrative review of preclinical studies suggests several overlapping mechanisms underlying these associations, including increased intestinal permeability, systemic inflammation and dysbiosis. A consolidated understanding of the impact of environmental exposures on IBD risk and outcomes is key to the identification of potentially modifiable risk factors and to inform strategies towards prediction, prevention and mitigation of IBD., Competing Interests: Competing interests: MF reports receiving lecture/consultant fees from Abbvie, Ferring, Tillots, MSD, Biogen, Amgen, Fresenius, Hospira, Sandoz, Pfizer, Bristol Myers Squibb, Celgene, Gilead, Boehringer, Eli Lilly, Nordic-Pharma, Arena, Galapagos, Janssen and Takeda. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, TiGenix and hold stock options in Intestinal Biotech Development.MA reports consulting for Douglas Pharmaceutical., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In utero exposure to maternal inflammation may impact immune system development and subsequent risk of disease. We investigated whether a maternal diagnosis of IBD before childbirth is linked to a higher risk of IBD in offspring compared with a diagnosis after childbirth. Further, we analysed paternal IBD status for comparison., Design: Using Danish health registers, we identified all individuals born in Denmark between 1997 and 2022 and their legal parents, as well as their IBD status. Cox proportional hazards regression analyses adjusted for calendar period and mode of delivery were used to estimate offspring IBD risk by maternal and paternal IBD status before and after childbirth., Results: Of 1 290 358 children, 10 041 (0.8%) had mothers with IBD diagnosis before childbirth and 9985 (0.8%) had mothers with IBD diagnosis after childbirth. Over 18 370 420 person-years, 3537 individuals were diagnosed with IBD. Offspring of mothers with IBD before childbirth had an adjusted HR of IBD of 6.27 (95% CI 5.21, 7.54) compared with those without maternal IBD, while offspring of mothers with IBD after childbirth had an adjusted HR of 3.88 (95% CI 3.27, 4.60). Corresponding adjusted HRs were 5.26 (95% CI 4.22, 6.56) among offspring with paternal IBD before childbirth and 3.73 (95% CI 3.10, 4.50) for paternal IBD after childbirth., Conclusion: Offspring had a greater risk of IBD when either parent was diagnosed before childbirth rather than later, emphasising genetic predisposition and environmental risk factors rather than maternal inflammation in utero as risk factors for IBD., Competing Interests: Competing interests: The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. The authors disclose the following: MA is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK129762-03). MA reports consulting for Douglas Pharmaceutical. MJ has received research grants for other investigator-driven studies from Takeda, and the NOVO Nordisk Foundation (grant no. NNF23OC0081717), has been on the advisory board of Pharmacosmos, has received consultation fee from Ferring and Takeda, and has received speaker’s fees from Tillotts Pharma, MSD, Ferring and Takeda. JT has received grant support from Abbvie and Janssen, consulting fees from Janssen, Abbvie and Pfizer, and speaker fees from Janssen, Abbvie, Pfizer and Sandoz. TJ reports having consulted for Ferring and Pfizer. The other authors disclose no conflicts., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Patients with Crohn's disease (CD) exhibit great heterogeneity in disease presentation and treatment responses, where distinct gut bacteria and immune interactions may play part in the yet unresolved disease aetiology. Given the role of antibodies in the barrier defence against microbes, we hypothesised that gut bacterial antibody-coating patterns may influence underlying disease-mediated processes., Design: Absolute and relative single and multicoating of gut bacteria with IgA, IgG1, IgG2, IgG3 and IgG4 in patients with CD and healthy controls were characterised and compared with disease activity. IgG2-coated and non-coated taxa from patients with severe CD were identified, profiled for pathogenic characteristics and monitored for enrichment during active disease across cohorts., Results: Patients with severe CD exhibited higher gut bacterial IgG2-coating. Supervised clustering identified 25 bacteria to be enriched in CD patients with high IgG2-coating. Sorting, sequencing and in silico -based assessments of the virulent potential of IgG2-coated and bulk stool bacteria were performed to evaluate the nature and pathogenicity of IgG2-coated and non-coated bacteria. The analyses demonstrated IgG2-coating of both known pathogenic and non-pathogenic bacteria that co-occurred with two non-coated pathobionts, Campylobacter and Mannheimia . The two non-coated pathobionts exhibited low prevalence, rarely coincided and were strongly enriched during disease flares in patients with CD across independent and geographically distant cohorts., Conclusion: Distinct gut bacterial IgG2-coating was demonstrated in patients with severe CD and during disease flares. Co-occurrence of non-coated pathobionts with IgG2-coated bacteria points to an uncontrolled inflammatory condition in severe CD mediated via escape from antibody coating by two gut pathobionts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is an increasing incidence of inflammatory bowel disease (IBD) for which environmental factors are suspected. Antibiotics have been associated with development of IBD in earlier generations, but their influence on IBD risk in adults is uncertain., Objective: To assess the impact of antibiotic exposure, including dose-response, timing and antibiotic class, on the risk of IBD in all individuals aged ≥10 years., Design: Using Denmark nationwide registries, a population-based cohort of residents aged ≥10 years was established between 2000 and 2018. Incidence rate ratios (IRRs) for IBD following antibiotic exposure were calculated using Poisson regression., Results: There were a total of 6 104 245 individuals, resulting in 87 112 328 person-years of follow-up, and 52 898 new cases of IBD. Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, although was greatest among individuals aged 40-60 years and ≥60 years (age 10-40 years, IRR 1.28, 95% CI 1.25 to 1.32; age 40-60 years, IRR 1.48, 95% CI 1.43 to 1.54; age ≥60 years, IRR 1.47, 95% CI 1.42 to 1.53). For all age groups a positive dose-response was observed, with similar results seen for both ulcerative colitis and Crohn's disease. The highest risk of developing IBD was seen 1-2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens., Conclusion: Antibiotic exposure is associated with an increased risk of IBD, and was highest among individuals aged 40 years and older. This risk increased with cumulative antibiotic exposure, with antibiotics targeting gastrointestinal pathogens and within 1-2 years after antibiotic exposure., Competing Interests: Competing interests: ASF: Research support from Crohn’s and Colitis Foundation; consultant for GLG, M3, Janssen, Guidepoint. JF: consultant Vedanta Biosciences and Innovation Pharmaceuticals; Scientific Advisory Board Vedanta Biosciences. JC: research grants from AbbVie, Janssen Pharmaceuticals and Takeda; payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, Vifor; holds stock options in Intestinal Biotech Development., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The benefit of continuing 5-aminosalicylate (5-ASA) in patients with ulcerative colitis (UC) who initiate anti-tumour necrosis factor-alpha (anti-TNF) biologics is unknown. We aimed to compare clinical outcomes in patients with UC already on 5-ASA who started anti-TNF and then either stopped or continued 5-ASA., Design: Our primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, UC-related hospitalisation or surgery. We used two national databases: the United States (US) Truven MarketScan health claims database and the Danish health registers. Patients with UC who started anti-TNF after having been on oral 5-ASA for at least 90 days were included. Patients were classified as stopping 5-ASA if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors and healthcare utilisation. Adjusted HRs (aHR) with 95% CI are reported comparing stopping 5-ASA with continuing 5-ASA., Results: A total of 3589 patients with UC were included (2890 US and 699 Denmark). Stopping 5-ASA after initiating anti-TNF was not associated with an increased risk of adverse clinical events in the U.S. cohort (aHR 1.04; 95% CI 0.90 to 1.21, p=0.57) nor in the Danish cohort (aHR 1.09; 95% CI 0.80 to 1.49, p=0.60). Results were similar in sensitivity analyses investigating concomitant immunomodulator use and duration of 5-ASA treatment before initiating anti-TNF., Conclusion: In two national databases, stopping 5-ASA in patients with UC starting anti-TNF therapy did not increase the risk of adverse clinical events. These results should be validated in a prospective clinical trial., Competing Interests: Competing interests: RCU has served as an advisory board member or consultant for Janssen, Pfizer and Takeda; research grant from AbbVie. JFC has served as an advisory board member or consultant for AbbVie, Amgen, Boehringer-Ingelheim, Arena Pharmaceuticals, Celgene, Celltrion, Enterome, Eli Lilly, Ferring Pharmaceuticals, Genentech, Janssen and Janssen, Medimmune, Merck & Co, Nextbiotix, Novartis Pharmaceuticals, Otsuka Pharmaceutical Development & Commercialization, Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, Theradiag; speaker for AbbVie, Ferring, Takeda, Celgene; stock options: Intestinal Biotech Development, Genefit; research grants: AbbVie, Takeda, Janssen and Janssen., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)