クローン病

BACKGROUND AND AIMS: Increased intake of ultra-processed food (UPF) may elevate the risk of Crohn's disease (CD), yet the biological mechanisms remain unexplored. We aimed to profile UPF-related metabolomic features linked to incident CD and localize key mediators. METHODS: This study involved two parts: construction of a UPF metabolic signature in the discovery cohort (n=10,229, UK Biobank), with internal (n=91,306) and external validation (n=7,893, Whitehall-II Study), and validation of key metabolic drivers in two Western and one Eastern cohort (n=752, ONE-IBD). High-throughput metabolomics platforms measured circulating metabolites. Elastic net regression was applied to derive UPF metabolic signature, and key metabolites were prioritized by integrating multivariable regression, network-based clustering, prospective association analyses, and mediation analyses. We further explored genetic mechanisms by Mendelian randomization, colocalization, and gene-environment analyses. RESULTS: A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HRper SD=2.65, 95% CI 1.57-4.48). Within the identified metabolite cluster, docosahexaenoic acid (DHA) was among the most consistently prioritized metabolites, mediating 17.1% of the UPF-CD association. Validation in ONE-IBD supported DHA linking UPF to CD incidence. Mendelian randomization revealed a protective effect of DHA on CD (OR=0.70, 95% CI 0.60-0.81), and colocalization implicated rs174546 in FADS1 as key genetic locus. CONCLUSION: Our findings suggest lower circulating DHA may represent one metabolic pathway linking UPF intake to increased CD risk, apart from additive harm to metabolic depletion. This highlights potential targets for precision nutrition in CD prevention in future trials.

Crohn's disease (CD)-associated mucosal injury involves immune-cell infiltration, epithelial cell death, and junctional disruption, but how specific myeloid states contribute to epithelial lipid peroxidation remains unclear. We integrated longitudinal single-cell transcriptomics, spatial transcriptomics, macrophage-epithelial co-culture, epithelial RNA-seq, exploratory candidate-gene prioritization, GPX4 functional validation, and a TNBS-induced chronic colitis model to investigate IL1B-high macrophage-associated epithelial injury. In paired pretreatment and post-treatment biopsies, persistent active disease (POST-ACT) showed a higher relative representation of myeloid cells, increased epithelial programmed-cell-death-related transcriptional activity, and stronger predicted myeloid-epithelial communication than remission samples. Myeloid subclustering identified a pro-inflammatory IL1B-high macrophage state relatively enriched in pooled POST-ACT cells, while RCTD-based spatial mapping supported non-random local co-occurrence of inferred IL1B-high macrophage and injury-associated epithelial signals. In vitro, IL1B-high macrophage co-culture increased epithelial cell death, reduced GSH, and increased MDA and lipid ROS in FHC and NCM460 cells; these changes were partially attenuated by Ferrostatin-1. Integration of ferroptosis-related genes, differential expression, LASSO, and random forest prioritized GPX4, PGD, and LPCAT3. GPX4 was consistently downregulated and was selected for functional validation; GPX4 overexpression partially restored ZO-1, E-cadherin, and Occludin expression. Blocking IL-1β/IL1R1 signaling with an anti-IL-1β neutralizing antibody or the IL1R1 antagonist AF12198 attenuated lipid peroxidation, GPX4 downregulation, and loss of junction-associated molecules in the shared co-culture system. In TNBS colitis, Ferrostatin-1 or anti-IL-1β treatment alleviated selected mucosal injury phenotypes, and adding IL-1β blockade to anti-TNF produced incremental improvement over anti-TNF alone. Collectively, these findings support an IL1B-high macrophage-associated epithelial injury axis involving IL-1β-IL1R1 signaling, reduced GPX4-related lipid-peroxide defense, ferroptosis-like lipid peroxidation injury, and junction-associated molecular alterations in CD.

AIM: This systematic review synthesises Mendelian randomization (MR) studies to evaluate genetic evidence for the role of alcohol consumption across multiple health domains. METHODS: We systematically searched PubMed, Embase, CINAHL, and PsycINFO for MR studies on alcohol phenotypes and health outcomes. Eligible studies used genetic variants as instruments for alcohol phenotypes such as alcohol consumption, alcohol use disorder, or Alcohol Use Disorder Identification Test scores. MR investigations were classified as single-variant or multiple-variant studies. We assessed the robustness of evidence as robust, probable, suggestive, insufficient, or non-evaluable. Due to mainly outcome sample overlap we conducted a qualitative synthesis of the evidence. RESULTS: We identified 88 MR studies covering 630 alcohol-disease investigations and up to 2433,011 participants. Most studies (84.4%) focused on European ancestry populations. Across 14 disease categories, 109 unique outcomes were assessed. We identified 30 robust, 98 probable, and 15 suggestive associations. Robust evidence linked alcohol consumption to increased risks of cardiovascular diseases (e.g., coronary artery disease, stroke, hypertension), several cancers (e.g., breast, colorectal, oropharyngeal, hepatocellular), alcohol-associated liver disease, chronic pancreatitis, Crohn's disease, Parkinson's disease, major depression, and all-cause mortality. An additional 113 probable and suggestive associations extended to other cancers, gastrointestinal, neurological, endocrine, eye, oral, and skin conditions. However, 487 (77%) investigations yielded insufficient or non-evaluable evidence. CONCLUSION: The reviewed MR evidence suggests associations between genetic liability to alcohol-related phenotypes and a range of disease and mortality outcomes. However, findings should be interpreted cautiously and supported by complementary causal inference approaches to strengthen causal interpretation.

BACKGROUND AND OBJECTIVES: To examine associations between high-level blast (HLB) exposure and occupational risk for low-level blast (LLB) exposure during military service and subsequent chronic medical diagnoses among US Veterans receiving Veterans Health Administration (VHA) care. METHODS: The Millennium Cohort Study is a population-based cohort study of US service members and Veterans enrolled beginning in 2001 and followed with surveys every 3-5 years. Analyses included participants enrolled between 2001 and 2013 who completed the 2011-2013 survey, had separated from military service, had complete blast and covariate data, and used VHA care for at least 2 calendar years during follow-up. HLB was assessed by self-report of injury resulting from blast or explosion. LLB risk was classified using military occupational specialty codes. Incident VHA-documented diagnoses from 2013 to 2021 were analyzed using modified Poisson regression to estimate adjusted prevalence ratios (APRs) and 95% CIs. RESULTS: Among N = 36,641 Veterans, HLB exposure was associated with increased likelihood of several VHA-documented incident diagnoses, including hepatitis B (APR [1.46]; 95% CI [1.13-1.89]), hepatitis C (1.89; [1.30-2.75]), diabetes (1.28; [1.07-1.52]), hypercholesterolemia (1.31; [1.18-1.46]), hyperlipidemia (1.12, [1.06-1.18]), obesity (1.07, [1.01-1.15]), seizures (1.79; [1.47-2.18]), angina (1.43; [1.18-1.73]), hypertension(1.08; [1.02-1.15]), other heart condition (1.15; [1.05-1.28]), stroke (1.35; [1.05-1.74]), chronic bronchitis (1.28; [1.07-1.52]), emphysema (1.26; [1.05-1.52]), sinusitis (1.13, [1.04-1.23]), neuropathy (1.38; [1.24-1.54]), and bladder infection (1.54; [1.14-2.08]). Occupational risk for LLB exposure was associated with lower likelihood of hepatitis C (0.67; [0.45-0.97]), diabetes (0.84; [0.72-0.99]), hyperlipidemia (0.94; [0.90-0.99]), sinusitis (0.91; [0.85-0.99]), and Crohn disease (0.62; [0.41-0.94]). A significant multiplicative interaction was observed for hepatitis B (1.92; [1.13-3.25]). Additive interaction estimates were generally subadditive, suggesting that high occupational risk for LLB attenuated rather than amplified the associations between HLB and most outcomes. DISCUSSION: Among Veterans receiving VHA care, HLB exposure during military service was associated with a higher prevalence of several clinical conditions years after separation from service. These findings suggest that blast exposure represents a long-term occupational health risk with implications for neurologic disease burden and systemic health.