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Within You, Without You: Is Gastroenterology Ready to Embrace the “Exposome”?

2012; Elsevier BV; Volume: 142; Issue: 7 Linguagem: Inglês

10.1053/j.gastro.2012.04.029

1528-0012

Bruce E. Sands,

Microscopic Colitis

It was the twins who compelled me to consider the limitations of genetics. My 29-year-old patient had experienced 3 years of intermittent diarrhea that did not much trouble him, but the eventual onset of right lower quadrant abdominal pain and weight loss prompted an imaging study suggesting ileal Crohn's disease (CD), confirmed by colonoscopy and biopsy. The family history elicited no inflammatory bowel disease (IBD), but raised a single probing question from the patient: What was the likelihood that his twin brother, now residing 2500 miles away in Boise, Idaho, would also develop CD? We have long understood that IBD runs in families. Burrill Crohn himself noted a familial predisposition for regional ileitis, as it was then called. Many others since have confirmed his observation. The innovations of the Human Genome Project, the International HapMap Project, and genome-wide association studies (GWAS) based on linkage disequilibrium have facilitated the discovery of 99 risk loci associated with IBD,1Anderson C.A. Boucher G. Lees C.W. et al.Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet. 2011; 43: 246-252Crossref PubMed Scopus (1061) Google Scholar opening doors to remarkable new insights into the biology of these complex diseases, as well as new questions. The identification of NOD2, the first CD-associated gene described in 2001,2Hampe J. Cuthbert A. Croucher P.J. et al.Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.Lancet. 2001; 357 (16): 1925-1928Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 3Hugot J.P. Chamaillard M. Zouali H. et al.Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4756) Google Scholar, 4Ogura Y. Bonen D.K. Inohara N. et al.A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (4239) Google Scholar confirmed predictions that aberrant responses to the gut microbiome were central to the causation of CD, and expanded to include the previously unrecognized role of defective autophagy, with which NOD2 was also subsequently linked, in this aberrant response.5Fritz T. Niederreiter L. Adolph T. et al.Crohn's disease: NOD2, autophagy and ER stress converge.Gut. 2011; 60: 1580-1588Crossref PubMed Scopus (177) Google Scholar Other pathways highlighted by GWAS in IBD include loci involved in adaptive immunity and other loci thought to contribute to altered mucosal barrier function.1Anderson C.A. Boucher G. Lees C.W. et al.Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet. 2011; 43: 246-252Crossref PubMed Scopus (1061) Google Scholar Given the observation that both CD and ulcerative colitis may be observed in the same kindred, it is not surprising that, although most of the identified risk loci are distinct for a single disease, the 2 forms of IBD share a number of loci.1Anderson C.A. Boucher G. Lees C.W. et al.Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet. 2011; 43: 246-252Crossref PubMed Scopus (1061) Google Scholar Understanding the genetic underpinnings of IBD may well lead to new therapeutic approaches by identifying so-called druggable targets, but intensive work in experimental and translational biology is needed to fully explicate how the identified risk loci contribute to disease, and how best to intervene. Despite the dazzling progress in IBD genetics—considered among the most advanced of any disease of complex inheritance—my patient's question about his twin's risk of disease provided a moment of clarity about its limitations. In response, I was able to cite data that long predate GWAS studies. His twin's lifetime risk of CD approximates 50%—far greater than the 6% concordance observed in ulcerative colitis among monozygotic twins,6Tysk C. Lindberg E. Jarnerot G. et al.Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins A study of heritability and the influence of smoking.Gut. 1988; 29: 990-996Crossref PubMed Scopus (725) Google Scholar and higher than one expects for many other complex genetic diseases. The epiphany is that even if one could describe every risk locus contributing to CD susceptibility, genetics would never predict the twin's likelihood of developing the disease any better than the toss of a fair coin. In short, genetics alone has yet to result in accurate personal disease prediction for IBD. The implication is that, if our understanding of disease causation is to be complete—and by extension, if disease prediction is to be accurate—we need to ascertain the other factors that are not genetically determined; namely, environmental factors. The task of comprehensively identifying environmental risk factors for complex diseases seems daunting. Consider all the possible environmental exposures one may encounter. The water we drink contains a multitude of trace elements, microorganisms, and organic and inorganic compounds, each in various concentrations. The foods we eat may vary in their total caloric content, nutrients, micronutrients, additives, microbes, and pollutants. Even the same food item may not be standardized in its composition, depending on when, where, and how the component ingredients were raised. Life in the developed world also includes exposures to drugs and immunizations throughout the lifespan, if not prenatally. Our exposure to air pollutants varies according to where one works and lives. There are dermal exposures to chemicals, bacteria, and light. And finally, there is increasing recognition of the impact of physical and psychological exposures: ionizing radiation, noise, psychological stress, and factors that limit energy expenditure (ie, exercise). All such environmental factors may play a role in the onset of disease, as well as influence the course of disease. The sheer number of possible exposures, and their interactions with host factors such as genetics, makes the identification of environmental risk factors for disease a challenge far greater than unraveling the human genome. One hesitates to mention that the timing and duration of these exposures (ranging from in utero to old age) add yet another layer of complexity. Empiric observation and confirmation in classically designed cohort studies have revealed just a handful of environmental risk factors for IBD, including smoking (a risk for CD, protective for ulcerative colitis),7Lakatos P.L. Szamosi T. Lakatos L. Smoking in inflammatory bowel diseases: good, bad or ugly?.World J Gastroenterol. 2007; 13: 6134-6139Crossref PubMed Scopus (147) Google Scholar breastfeeding (protective),8Barclay A.R. Russell R.K. Wilson M.L. et al.Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease.J Pediatr. 2009; 155: 421-426Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar oral contraceptives (a risk factor),9Boyko E.J. Theis M.K. Vaughan T.L. et al.Increased risk of inflammatory bowel disease associated with oral contraceptive use.Am J Epidemiol. 1994; 140: 268-278Crossref PubMed Scopus (69) Google Scholar and antibiotics (a risk factor).10Shaw S.Y. Blanchard J.F. Bernstein C.N. Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis.Am J Gastroenterol. 2011; 106: 2133-2142Crossref PubMed Scopus (185) Google Scholar In the current model of investigation, novel hypotheses regarding environmental risk factors are seldom generated, and establishing causality is even more difficult. Just as genetics research has benefited from a paradigm shift, moving from positional cloning of candidate genes based on a prior hypothesis to unbiased genetic discovery with GWAS, research into the environmental contributions to illness seems poised to experience a similar change in experimental approach. In a commentary published in 2005, Wild coined the term “exposome” to describe the environmental analog of the genome.11Wild C.P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1847-1850Crossref PubMed Scopus (1355) Google Scholar This concept is gaining momentum in environmental health science. Proponents of the exposome concept distinguish this approach as being a broad-based assessment of exposures, as opposed to the traditionally parochial approach of environmental scientists looking at one toxin or class of exposures at a time. Environmental scientists are divided in their approach to unraveling the exposome. A “bottom-up” strategy seeks to broadly measure the external sources of the individual exposome at multiple time points.12Rappaport S.M. Smith M.T. Epidemiology Environment and disease risks.Science. 2010; 330: 460-461Crossref PubMed Scopus (578) Google Scholar This approach may benefit from recent innovations in global information systems, remote sensing, and even personal sensing devices. By contrast, a “top-down” approach to the exposome focuses on the internal milieu as reflected in the blood, using a variety “-omics” technologies, including transcriptomics, proteomics, and metabonomics.12Rappaport S.M. Smith M.T. Epidemiology Environment and disease risks.Science. 2010; 330: 460-461Crossref PubMed Scopus (578) Google Scholar Such unbiased measurements have, in a few early examples, revealed distinct signatures associated with specific environmental exposures.13Patel C.J. Butte A.J. Predicting environmental chemical factors associated with disease-related gene expression data.BMC Med Genomics. 2010; 3: 17Crossref PubMed Scopus (23) Google Scholar As a growing number of signatures of environmental exposures accumulate, one may envision the development of high-throughput, multiplex assays to register individual environmental exposures. An early demonstration of this was the first reported environment-wide association study, which discovered novel associations between type 2 diabetes mellitus and specific chemical exposures.14Patel C.J. Bhattacharya J. Butte A.J. An environment-wide association study (EWAS) on type 2 diabetes mellitus.PLoS One. 2010; 5: e10746Crossref PubMed Scopus (425) Google Scholar Bottom-up and top-down strategies will ultimately need to be cross-validated to understand how external exposures are related to internal exposures and disease. We should recognize that gastroenterology sits at a major frontier of the exposome. The gastrointestinal tract is a major portal for the outside world. Our lifelong oral encounter with the environment is reflected in all that we ingest, and in the rich internal environment of the gut microbiome. Advances in exposomic approaches could lead to major advances in understanding not only IBD, but also a variety of liver diseases, gastrointestinal cancers, and functional disorders of the gut that do not have very obvious genetic causes. Unraveling the exposome, in all its complexity, may be critical in understanding not only GI diseases, but also a panoply of diseases outside the digestive system. Already evident are surprising demonstrations of the role of gut flora in obesity15Turnbaugh P.J. Ley R.E. Mahowald M.A. et al.An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (8684) Google Scholar and, independently, in bile acid metabolism as a risk factor for cardiovascular disease.16Wang Z. Klipfell E. Bennett B.J. et al.Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011; 472: 57-63Crossref PubMed Scopus (3734) Google Scholar Although great progress is being made in characterization of the microbiome, connecting the microbiome to the active compounds elaborated by the microbiome are not as advanced. Unbiased evaluations of truly exogenous factors, such as ingested bioactive compounds, lag even further behind. A comprehensive approach to the exposome cannot help but embrace the gastrointestinal tract. Is gastroenterology itself ready to embrace the exposome?