The exposome and personalised medicine in IBD

Behrooz Z. Alizadeh, EpiCom Member

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 [4], 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 [6].

The exposome and the aetiopathogenesis of IBD

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) [9]. 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.

The exposome and susceptibility to IBD

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 [21]. In addition to confirmation of the divergent effect of smoking [22], 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 [21]. 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 [21]. 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 [23]. By implementing GIEQ in the prospective 1000IBD cohort of 1000 patients at UMCG [24], embedded within the Dutch IBD Parelsnoer national biobank [25], and the multidisciplinary multigeneration population-based Lifelines Cohort Study consisting of 167,729 persons [26], 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 [27].

The exposome and the course of IBD

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 [23], concerning disease course in a multifactorial case-only study, nested within the 1000IBD cohort [24]. 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 [32].

Exposome initiatives

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 [33], 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) [23], 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 [36] and the application of appropriate computationally advanced data analysis and statistical modelling [26].

The exposome in the personalised management of IBD

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 [35]. 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. 


  1. van den Heuvel TRA, Jeuring SFG, Zeegers MP, et al. A 20-year temporal change analysis in incidence, presenting phenotype and mortality, in the Dutch IBDSL cohort – can diagnostic factors explain the increase in IBD incidence? J Crohns Colitis. 2017;11:1169–79.
  2. Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785–94.
  3. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390:2769–78.
  4. Mak WY, Zhao M, Ng SC, et al. The epidemiology of inflammatory bowel disease: East meets west. J Gastroenterol Hepatol. 2020;35:380–9.
  5. Kotze PG, Underwood FE, Damiao AOMC, et al. Progression of inflammatory bowel diseases throughout Latin America and the Caribbean: a systematic review. Clin Gastroenterol Hepatol. 2020;18:304–12.
  6. Ananthakrishnan AN, Kaplan GG, Ng SC. Changing global epidemiology of inflammatory bowel diseases: sustaining health care delivery into the 21st century. Clin Gastroenterol Hepatol. 2020;18:1252–60.
  7. Hu S, Vich Vila A, Gacesa R, et al. Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. Gut. 2020 Jul 10. doi: 10.1136/gutjnl-2019-319706. [Epub ahead of print].
  8. Imhann F, Vich Vila A, Bonder MJ, et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut. 2018;67:108–19.
  9. Lynch SV, Ng SC, Shanahan F, et al. Translating the gut microbiome: ready for the clinic?. Nat Rev Gastroenterol Hepatol. 2019;16:656–61.
  10. Vich Vila A, Collij V, Sanna S, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun. 2020;11:362.
  11. Imhann F, Vich Vila A, Bonder MJ, et al. The influence of proton pump inhibitors and other commonly used medication on the gut microbiota. Gut Microbes. 2017;8:351–8.
  12. Kosnicki KL, Penprase JC, Cintora P, et al. Effects of moderate, voluntary ethanol consumption on the rat and human gut microbiome. Addict Biol. 2019;24:617–30.
  13. Torres J, Hu J, Seki A, et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut. 2020;69:42–51.
  14. Bolyen E, Rideout JR, Dillon MR, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37:852–7.
  15. Jakobsson HE, Jernberg C, Andersson AF, et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One. 2010;5:e9836.
  16. Das B, Ghosh TS, Kedia S, et al. Analysis of the gut microbiome of rural and urban healthy Indians living in sea level and high altitude areas. Sci Rep. 2018;8:10104.
  17. Ghosh TS, Rampelli S, Jeffery IB, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut. 2020;69:1218–28.
  18. Bourrat P. Natural selection and drift as individual-level causes of evolution. Acta Biotheor. 2018;66:159–176.
  19. Johnson MTJ, Prashad CM, Lavoignat M, et al. Contrasting the effects of natural selection, genetic drift and gene flow on urban evolution in white clover (Trifolium repens). Proc Biol Sci. 2018;285:20181019.
  20. Sutton JT, Nakagawa S, Robertson BC, et al. Disentangling the roles of natural selection and genetic drift in shaping variation at MHC immunity genes. Mol Ecol. 2011;20:4408–20.
  21. van der Sloot KWJ, Amini M, Peters V, et al. Inflammatory bowel diseases: review of known environmental protective and risk factors involved. Inflamm Bowel Dis. 2017;23:1499–509.
  22. Mahid SS, Minor KS, Soto RE, et al. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. 2006;81:1462–71.
  23. van der Sloot KWJ, Weersma RK, Dijkstra G, et al. Development and validation of a web-based questionnaire to identify environmental risk factors for inflammatory bowel disease: the Groningen IBD Environmental Questionnaire (GIEQ). J Gastroenterol. 2019;54:238–48.
  24. Imhann F, Van der Velde KJ, Barbieri R, et al. The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1. BMC Gastroenterol. 2019;19:5.
  25. Spekhorst LM, Imhann F, Festen EAM, et al. Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease. BMJ Open. 2017;7: e016695.
  26. Scholtens S, Smidt N, Swertz MA, et al. Cohort profile: LifeLines, a three-generation cohort study and biobank. Int J Epidemiol. 2015;44:1172–80.
  27. van der Sloot KWJ, Weersma RK, Alizadeh BZ, et al. Identification of environmental risk factors associated with the development of Inflammatory Bowel Disease. J Crohns Colitis. 2020 Jun 23; doi: 10.1093/ecco-jcc/jjaa114. [Epub ahead of print].
  28. Cravo ML, Velho S, Torres J, et al. Lower skeletal muscle attenuation and high visceral fat index are associated with complicated disease in patients with Crohn's disease: an exploratory study. Clin Nutr ESPEN. 2017;21:79–85.
  29. Torres J, Mehandru S, Colombel JF, et al. Crohn's disease. Lancet. 2017;389:1741–55.
  30. Van Der Sloot KW, Joshi AD, Bellavance DR, et al. Visceral adiposity, genetic susceptibility, and risk of complications among individuals with Crohn's disease. Inflamm Bowel Dis. 2017;23:82–8.
  31. Auzolle C, Nancey S, Tran-Minh ML, et al. Male gender, active smoking and previous intestinal resection are risk factors for post-operative endoscopic recurrence in Crohn's disease: results from a prospective cohort study. Aliment Pharmacol Ther. 2018;48:924–32.
  32. van der Sloot KWJ, Geertsema P, Rijkmans HC, et al. Environmental factors associated with biological use and surgery in inflammatory bowel disease. J Gastroenterol Hepatol. 2020 Aug 24; doi: 10.1111/jgh.15223. [Epub ahead of print].
  33. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47:979–86.
  34. de Jong M, van der Meulen-de Jong A, Romberg-Camps M, et al. Development and feasibility study of a telemedicine tool for all patients with IBD: MyIBDcoach. Inflamm Bowel Dis. 2017;23:485–93.
  35. de Jong MJ, van der Meulen-de Jong AE, Romberg-Camps MJ, et al. Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial. Lancet. 2017;390:959–68.
  36. Beamish LA, Osornio-Vargas AR, Wine E. Air pollution: an environmental factor contributing to intestinal disease. J Crohns Colitis. 2011;5:279–86.
  37. Torres J, Caprioli F, Katsanos KH, et al. Predicting outcomes to optimize disease management in Inflammatory Bowel Diseases. J Crohns Colitis. 2016;10:1385–94.
  38. Colombel JF, Narula N, Peyrin-Biroulet L. Management strategies to improve outcomes of patients with inflammatory bowel diseases. Gastroenterology. 2017;152:351–361.e5.
  39. Martins R, Carmona C, George B, et al. Management of Crohn's disease: summary of updated NICE guidance. BMJ. 2019;367:l5940.

Posted in ECCO News, Committee News, EpiCom, Volume 15, Issue 4