|Berhooz Z. Alizadeh
In the past few decades, the incidence of Inflammatory Bowel Diseases (IBD) started rising especially in industrialised Western countries, affecting more than two million Americans and Europeans [1–3]. At the turn of the twenty-first century, however, IBD became a global disease, rapidly affecting the Eastern and Southern developing nations [3–5]. So, the global prevalence of IBD is currently estimated at 0.7% and is expected to increase to 1% by 2030 [1, 3, 6].The rise in IBD has coincided with an increase in urbanisation, sanitisation, and adoption of a Western lifestyle , as well as advances in infrastructure, better access to healthcare, and increased awareness of community following socioeconomic development. It is therefore assumed that the primary suspect underlying the globalisation of IBD is the alteration of the human environment, called the exposome (meaning exposures to environmental and lifestyle factors throughout life, starting at conception), and the associated embracing of Western lifestyles by other nations .
The aetiopathogenesis of IBD involves both fixed inherited (genetic, and some elements of epigenetic) susceptibility and modifiable exposome factors. In between, the microbiome and epigenome act as the transfer (connection) hub [7, 8]. As an example, much of the attention of the scientific community has recently focussed on the role of the microbiota in IBD, as evidence has shown the gut microbiota to be implicated in the aetiology of IBD and to be of potential use as an effective therapy (i.e. probiotics) . Yet, it has turned out that the biodiversity of the gut microbiota is highly influenced by and dependent on the exposome, specifically on factors such as early life exposures to the intrafamilial environment, life-long dietary habits, lifestyle, environmental events, and the community reservoir of pathogens [10–17]. The gut microbiota is not an independent player; rather it acts as a messenger that mediates interactions between external exposome factors and the internal immune system. Even the development and maturation of the immune system are influenced by exposome factors, including birth environment, diet, viral infection, lifestyle, and environmental factors. Moreover, returning to the earlier statement about genetics, it is to be noted that three key mechanisms of evolution of genetic susceptibility to diseases, namely natural selection, genetic drift, and gene flow, are all affected by major environmental forces and the behaviour of nature [18–20]. Collectively, the role of the exposome in the aetiopathogenesis of IBD (and, in general, human disease and health) is multifaceted and non-negotiable, yet it has been neglected and not fully outlined over the past few decades.
To unearth the environmental factors implicated in IBD, van der Sloot and colleagues (our team at UMCG in the Netherlands) have conducted a multiphase research programme over the past five years. In 2017, van der Sloot et al. reported a comprehensive systematic review on the role of exposome factors in IBD . In addition to confirmation of the divergent effect of smoking , breastfeeding (as a childhood exposure), Helicobacter pylori infection, and vitamin D were found to be associated with a lower risk of IBD, while increased hygiene, bacterial gastroenteritis, urban living surroundings, air pollution, and the use of antibiotics, non-steroidal anti-inflammatory drugs, and oral contraceptives were related to an increased risk of IBD . When closely scrutinising the various studies and IBD cohorts, a major challenge was the lack of an accurate tool to measure the exposome factors in IBD patients . To meet this challenge, van der Sloot and colleagues (2018–9) developed and validated the comprehensive GIEQ questionnaire consisting of 844 items, of which 454 are applicable for the study of 93 exposome factors . By implementing GIEQ in the prospective 1000IBD cohort of 1000 patients at UMCG , embedded within the Dutch IBD Parelsnoer national biobank , and the multidisciplinary multigeneration population-based Lifelines Cohort Study consisting of 167,729 persons , van der Sloot and colleagues (2019) found that, in addition to the above-mentioned factors, stressful life events, high perceived stress, alcohol use and bronchial hyperreactivity were associated with an increased risk of IBD; they also found that prenatal smoke exposure, having a bed partner, allergies and cowmilk hypersensitivity were related to susceptibility to Crohn’s Disease, while carpet flooring and neuroticism were related to the risk of Ulcerative Colitis .
When IBD is diagnosed, patients tend to modify their behaviour to avoid the obstacles posed by the disease and to reduce its impact on daily life. These actions typically include: (1) acquiring medical knowledge and joining patient social organisations, (2) modification of lifestyle, such as doing more physical activities, (3) avoidance of exposure to environmental risk factors such as alcohol, smoking, infection, cold weather, air pollution and cannabis use and (4) making unguided dietary modifications, such as avoiding meat and using more fiber. The fact that these mostly unsubstantiated patient-oriented measures afford some level of relief and self-satisfaction supports the claims that, firstly, exposome factors contribute to the severity of the disease course, the disease behavior, the incidence of disease complications and the long-term outcome of IBD [28–31] and, secondly, alteration of modifiable risk factors is effective in reducing the disease burden and improving the quality of life in IBD patients. To date, the question of which exposome factors influence disease progression remains unresolved. van der Sloot et al. recently examined a wide spectrum of exposome factors, as measured by the GIEQ , concerning disease course in a multifactorial case-only study, nested within the 1000IBD cohort . This study identified 16 risk factors for complicated disease outcomes, of which 11 were novel; among these, poor quality sleep, lack of physical activities, smoking, household size, working shifts, type of preferred beverage and flooring showed the most pronounced association .
Despite all the efforts, the quality of evidence remains insufficient to allow transfer of knowledge of the exposome to clinical application. As we have learned from past experiences of exposome studies and from the successful large-scale genetic studies , it is essential to build well-powered and carefully designed multi-ethnic studies in order to fully and precisely appreciate the role of exposome factors with modest effects in complex diseases such as IBD. Exposome-focussed initiatives therefore require expansion into multidisciplinary longitudinal studies based upon standardised methodology, the application of a comprehensive data collection tool for exposome factors (like GIEQ) , the formation of large-scale consortia (as in the IIBCGC: https://www.ibdgenetics.org/), persistent collection of patient-reported outcomes on exposure to environmental factors (as is planned in MyIBDcoach) [34, 35], compilation of ecological information  and the application of appropriate computationally advanced data analysis and statistical modelling .
Understanding of the IBD-associated exposome has the potential to contribute to the implementation of precision medicine. Once the exposome factors for IBD have been truly identified, integration of the measurement of these factors into the daily monitoring of patients will assist multidisciplinary teams in implementing patient-tailored therapies [37–39]. Particularly the recent advances in telemedicine and the introduction of tools such as MyIBDcoach have assisted in ensuring that continual regular care and long-term monitoring of patients have become a reality [34, 35]. Telemedicine is of value in the monitoring of disease activity, clinical symptoms, treatment compliance, treatment side effects, quality of life, and also exposome factors such as lifestyle, nutritional status, participation in (paid) labour, smoking, and major life events . Identifying the IBD-associated modifiable exposome risk factors enhances the implementation of personalised (patient-tailored) care for IBD on two levels: firstly, the identification and stratification of patients based on their risk for disease complications, and secondly, the opportunity to modify exposome risk factors in patients’ favour.
The exposome is implicated in the aetiopathogenesis of IBD, the disease course, and the disease-associated complications. Nevertheless, the current data are inconsistent, and the quality of evidence is insufficient. The prevalence of IBD is rising rapidly, and multidisciplinary, large-scale exposome-focussed initiatives are needed to comprehend the true impact of exposome factors in IBD. The identification of exposome factors leads to better stratification of patients at high risk for disease complications and to more effective monitoring of patients and contributes to the implementation of personalised management and prevention strategies.
This statement can not be concluded without major contributions of the IBD exposome initiative at UMCG. To whom I am sincerely grateful. My special thanks go to our enthusiastic Ph.D. Fellow, K. van der Sloot, for her wonderful work. I also wish to express my gratitude to my wonderfully knowledgeable colleague, G. Dijkstra, whom I co-supervised the ongoing exposure projects, for his mindful comments, and highly valued suggestions.