Environment, Not Just Genes: Exposome Framework Targets Inflammatory Bowel Disease Prevention

Inflammatory bowel disease, encompassing Crohn’s disease and ulcerative colitis, is rising at an alarming pace worldwide, and its roots lie as much in the environment as in our DNA. A new Perspective published in Nature Reviews Gastroenterology & Hepatology argues that the field can no longer afford to study environmental risk factors one exposure at a time. Instead, a team led by Manasi Agrawal of the Icahn School of Medicine at Mount Sinai, together with Vishal Midya, Alvise Vianello, Damaskini Valvi, Gilaad G. Kaplan and Jean-Frederic Colombel, proposes a comprehensive exposome framework designed to move the science from association to prevention. The exposome, first proposed by cancer epidemiologist Christopher Wild in 2005, captures the totality of physical, chemical, biological and psychosocial exposures that shape human health across the entire lifespan, serving as the environmental complement to the genome.

The urgency of this shift is grounded in hard epidemiological data. Twin studies and large meta-analyses indicate that genetic factors explain only a modest fraction of chronic disease burden, with heritability estimates for most human traits far below what would be needed to account for the rapid global rise of immune-mediated disorders. Genes simply do not change fast enough to explain why inflammatory bowel disease has surged in industrialized nations and is now emerging in regions that historically had very low incidence. Population-based studies of immigrants tell a striking story: people who move from low-incidence to high-incidence countries acquire elevated disease risk within a single generation, and their children, born in the new environment, often reach incidence rates approaching those of the host population. That pattern points squarely at modifiable environmental exposures acting on genetically susceptible individuals.

Decades of research have already identified a substantial catalog of risk factors. Smoking increases the risk of Crohn’s disease while paradoxically appearing protective in ulcerative colitis, yet molecular work shows that smoking alters DNA methylation at inflammatory loci in ways that plausibly mediate gut inflammation. Air pollution has been linked to ulcerative colitis through epigenetic changes in the CXCR2 gene and the MHC class III region. Antibiotic use, particularly early in life and during pregnancy, disturbs the developing gut microbiome and raises offspring risk. Appendectomy, oral contraceptives, gastrointestinal infections with pathogens such as Salmonella, Campylobacter and Helicobacter species, and Epstein-Barr virus timing all leave measurable fingerprints on disease risk. Conversely, protective exposures have emerged too: early-life contact with agriculture, biodiversity and green space, a diverse diet rich in plant-based foods, and physical activity are consistently associated with lower incidence.

The Perspective distinguishes carefully between early-life and later-life exposures, a distinction the authors argue is essential for prevention science. The developmental origins of health and disease paradigm, rooted in David Barker’s work on fetal programming, holds that exposures during critical windows of immune and microbiome development can set long-term trajectories of disease susceptibility. In inflammatory bowel disease, the preclinical phase can last years, with altered gut microbiome composition, elevated fecal calprotectin and subtle immune changes detectable in at-risk first-degree relatives long before symptoms appear. Studies analyzing deciduous teeth have even reconstructed prenatal and postnatal metal exposure histories, linking them to later Crohn’s disease risk. Early exposures such as mode of delivery, breastfeeding, infant diet diversity and childhood antibiotic courses therefore represent unusually potent intervention targets, because they act before the disease process has gained momentum.

At the same time, the authors highlight exposures that traditional epidemiology has largely overlooked, and this is where the exposome concept becomes technically transformative. Food contact contaminants are a case in point. Plastic teabags release billions of microparticles and nanoparticles into hot tea, microwavable plastic containers shed both microplastics and intentionally and non-intentionally added chemical substances, and nonstick cookware can contaminate food with microplastics and PTFE. Perfluoroalkyl and polyfluoroalkyl substances, the so-called forever chemicals, migrate from food packaging into the diet, and elevated serum levels of these compounds have been associated with later occurrence of inflammatory bowel disease and with intestinal barrier defects in experimental systems. Pesticide residues on produce, antibiotic residues in animal products, and synthetic chemicals in processed food collectively form a chronic, low-dose chemical mixture that no single-exposure study can adequately capture.

Among emerging pollutants, microplastics and nanoplastics occupy a special place of concern. These particles have now been detected in human stool, blood, lung tissue, placenta, atherosclerotic plaques and even human brain tissue, with some evidence of bioaccumulation over time. In animal models, chronic exposure to polystyrene nanoplastics induces mechanical and immune barrier dysfunction in the intestine. In humans, one analysis of fecal samples found that microplastic concentrations correlated with inflammatory bowel disease status, although the authors of the new Perspective are careful to note that causality remains unproven and that more rigorous science, standardized definitions and better detection methods are urgently needed. Novel analytical tools, including stimulated Raman scattering microscopy capable of single-particle nanoplastic imaging and surface-enhanced Raman spectroscopy with nanogap arrays, are now making it possible to detect and quantify these particles at environmentally relevant concentrations.

Measurement technology is the second pillar of the exposome revolution. High-resolution mass spectrometry platforms can now screen thousands of chemicals in biological samples without needing to know in advance which ones to look for, an approach known as non-targeted analysis. Coupled with ion mobility separation and computational metabolomics, these platforms are expanding the observable chemical space of human exposure from a few hundred targeted biomarkers to tens of thousands of features. On the statistical side, new methods designed for real-world exposure complexity, including weighted quantile sum regression, quantile-based g-computation and Bayesian kernel machine regression, allow researchers to model the health effects of correlated chemical mixtures rather than isolated agents. Machine learning approaches have begun to identify synergistic interactions among pesticides, phthalates, phenols and trace metals, and longitudinal personal monitoring with wearable sensors has revealed how dynamically an individual’s chemical exposure profile shifts from day to day.

The framework’s most consequential contribution, however, may be its prevention architecture, which differentiates between primary and primordial prevention. Primary prevention, borrowed from cardiovascular medicine, means identifying individuals at elevated risk, such as first-degree relatives of patients with inflammatory bowel disease, stratifying them by genetic, microbiome and exposome risk scores, and intervening before disease onset. Recent trials in adjacent fields show this is feasible: teplizumab has delayed type 1 diabetes in at-risk relatives and abatacept has shown promise in preventing rheumatoid arthritis in high-risk individuals, providing templates for immunoprophylaxis in inflammatory bowel disease. Primordial prevention operates one level deeper, aiming to lower the population-wide baseline of risk before susceptibility even arises, through community and policy interventions. Crucially, the authors emphasize the actionable exposome: those exposures that individuals, clinicians or policymakers can realistically modify today, as opposed to the vast conceptual exposome that remains beyond immediate control.

Individual-level mitigation strategies already have an evidentiary basis. Lifestyle studies suggest that a substantial fraction of inflammatory bowel disease cases could be prevented through modifiable behaviors, including a prudent plant-rich diet, regular physical activity, smoking cessation and avoidance of e-cigarettes. Randomized trials have shown that a low-plastic diet reduces urinary levels of plastic-associated phthalates and bisphenols, while simple dietary choices, such as avoiding heating food in plastic containers, reduce microplastic intake. For persistent pollutants like PFAS, interventions including plasma donation and anion exchange resin treatment have demonstrated measurable reductions in body burden. Dietary components rich in anthocyanins and other antioxidants may counteract some pollutant effects. At the community level, the levers are broader: air quality regulation, pesticide policy, green urban planning, washing machine filtration to reduce microfiber emissions, point-of-use drinking water filters, and international treaties to end plastic pollution all shape the exposures that entire populations experience from conception onward.

The authors also confront the global inequities embedded in this agenda. Inflammatory bowel disease is progressing through four epidemiological stages worldwide, from nascent emergence to high prevalence, and the environmental drivers differ profoundly between a newly industrializing city in Asia and a saturated North American market. Industrialized nations that created the modern exposome bear responsibility for generating evidence and technology that low- and middle-income regions can adapt as they urbanize, ideally avoiding the worst exposures from the start. Whether the exposome framework can also illuminate other overlapping immune-mediated diseases, from multiple sclerosis to rheumatoid arthritis, remains an open and tantalizing question. What is clear from this Perspective is that the era of treating environmental risk as an afterthought to genetics is ending, and that a coordinated science of exposure measurement, risk prediction and two-tiered prevention offers the first realistic pathway toward a future in which inflammatory bowel disease is not merely treated but prevented.

Subject of Research: The role of lifespan environmental exposures, the exposome, in inflammatory bowel disease risk and prevention

Article Title: The exposome and inflammatory bowel disease: a framework for primary and primordial prevention

Article References: Agrawal, M., Midya, V., Vianello, A., Valvi, D., Kaplan, G. G., & Colombel, J.-F. (2026). The exposome and inflammatory bowel disease: a framework for primary and primordial prevention. Nature Reviews Gastroenterology & Hepatology. https://doi.org/10.1038/s41575-026-01260-2

Image Credits: AI Generated

DOI: 10.1038/s41575-026-01260-2

Keywords: exposome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, microplastics, PFAS, prevention, environmental risk factors, gut microbiome, air pollution, early-life exposures, epigenetics