Assessing environmental risk factors affecting the inflammatory bowel diseases: A joint workshop of the Crohnʼs & Colitis Foundations of Canada and the USA

Canadian Program Organizers: Andrew Stadnyk (Dalhousie University, Halifax, NS), Charles Bernstein (University of Manitoba, Winnipeg, MB), John Marshall (McMaster University, Hamilton, ON), and Devendra Amre (University of Montreal, Montreal, QC). American Program Organizers: Jonathan Braun (UCLA, Los Angeles, CA), Balfour Sartor (University of North Carolina, Chapel Hill, NC), and Scott Snapper (Massachusetts General Hospital, Boston, MA). It is widely considered that chronic idiopathic inflammatory bowel diseases (IBDs) occur due to an aberrant immune response to luminal antigens in persons who are genetically predisposed. While remarkable advances have been made in identifying specific genetic linkages that underlie this predisposition, these have not explained the disease etiology. In addition, striking epidemiological observations implicate environmental influences on genetic predisposition. Nevertheless, the epidemiology of environmental risk factors in IBD is incompletely understood and in need of further study. Few associations with the environment or lifestyle have been linked confidently with either susceptibility or disease course in IBD. An outstanding example is the paradoxical effect of smoking, wherein quitting smoking is a risk factor for ulcerative colitis while continued smoking is a risk factor for Crohn's disease. Otherwise, inconsistencies among other associations, such as diet, prenatal or perinatal exposures, drinking water, etc., have given rise to more questions than answers. To begin to address these gaps in our knowledge, the Crohn's and Colitis Foundations of Canada and the USA jointly hosted a day-long workshop in Toronto, Ontario, on measuring environmental risk factors as they may pertain to the etiology and severity of chronic human disease. The primary objective was to explore innovative approaches and strategies to identifying and measuring environmental risk factors for IBD. The strategy was to learn from the experience and progress made by researchers studying and treating other human chronic illnesses and apply this knowledge to studies in IBD. In addition to stakeholders in IBD research, experts from various disease disciplines undertaking comprehensive studies of environmental risk factors were invited to share their strategies and progress. The proceedings follow. Organizers' comment: Dr. Bonini presented the hygiene hypothesis as it relates to asthma and allergic disorders, suggesting that it can be applied to IBD as well. He suggested that using probiotics or bacterial extracts to provide the immune system with the microbial education that was missed in childhood because of cleaner living conditions might be a strategy to reverse IBD. Noninfectious agents such as allergens, pollution, diet, and exercise, as well as infectious agents all play a role in asthma. There is a growing interest in the relationship between infections and allergy, and the ‘hygiene hypothesis.’ The general understanding of the mechanisms of allergic respiratory disease includes processes related to allergens and IgE—leading to the accumulation of mucus, vasodilation, contraction of smooth muscle, and late-phase allergic reactions. However, there can also be inflammation independent of IgE. Like allergy, IBD is a multifactorial and polygenic disease. The hygiene hypothesis stems from epidemiological studies of associations between disease and environment and studies of mechanisms underlying these associations (such as the effects of infections on innate and adaptive immunity; role of GI microbiota, etc.). It suggests that exposure to less hygienic environments facilitates immune responses early in life that can be protective against antigens experienced later in life. A corollary to this is that in developed nations the lower exposure to infections early in life has rendered immune responses incapable of protecting or being tolerant of foreign antigens later in life. National Health and Nutrition Examination Surveys (NHANES) data show stronger associations with allergic disease among people who are hepatitis-negative than those who are positive. Exposure to infectious agents can be a marker for disease and risk—but general environment and exposures need to be taken into account. Genetic–environmental interactions can happen in different ways. This can range from food-borne microbes, viral infections, and more. Developing countries have lower rates of allergic disorders. Their environment includes larger family size, more exposure to livestock, low antibiotic use, intestinal microbiota that are variable and transient, high helminth burden, poor sanitation, and high rates of orofecal transfer. In contrast, Western countries have higher rates of allergic disorders. Their environment includes small family size, high antibiotic use, low or absent helminth burden, good sanitation, and low rates of orofecal transfer. Could mimicking the microbial ‘education’ of the immune system be used as a strategy to reverse the epidemic trend of atopy and allergic asthma? Some evidence suggests probiotics and bacterial extracts might be useful for this, but more studies need to be done. Organizers' comment: Dr. Rewers presented a process for assembling very large prospectively enrolled cohorts of children at risk for developing diabetes. Such cohort selection can allow an assessment of dietary factors. Studies show that the timing of the introduction of certain foods to infants can affect the risk of developing celiac and diabetic autoimmunity. This may also be relevant in IBD. A similar prospective study, using biomarkers specific to preclinical IBD and including first-degree relatives of IBD patients could potentially help disentangle these factors in the etiology of the disease. The incidence of type-1 diabetes is rising by 3% to 5% annually. This growth rate cannot be explained by genetic models alone. Most causal models of diabetic pathogenesis accept that an environmental agent stimulates the immune system and triggers chronic inflammation of the islets of Langerhans, typically over a long period of development. The Diabetes Autoimmunity Study in the Young (DAISY) was launched in 1993. At-risk nondiabetic children were enrolled if a sibling or 1 parent had diabetes. In addition, over 30,000 babies born at a Colorado hospital underwent HLA screening, and over 1500 children with high-risk genotypes were enrolled. Overall, DAISY has followed over 2500 high-risk infants and over 120 have already developed diabetes or biological markers for islet autoimmunity. Although the timing and frequency of testing can affect accuracy, the idea was to relate development of islet autoantibodies and diabetes to environmental exposures measured prospectively before diabetes developed. Islet autoantibodies are powerful predictors of diabetes. DAISY also assessed celiac disease because there is a shared genetic susceptibility with type-1 diabetes and availability of a sensitive and specific serologic test. Up to 1% of children in Colorado develop celiac disease. Similar studies are being done by a consortium of research groups from 4 countries, the Environmental Determinants of Diabetes in The Young (TEDDY). The purpose of TEDDY is to identify gene–environment interactions which cause prediabetic autoimmunity and type-1 diabetes. Started in 2004, the project will screen over 350,000 newborns from the general population, including 3400 first-degree relative infants with high-risk genotypes. Approximately 40% of the cohort has already been enrolled and will be reassessed at least annually. At each visit, both infections and noninfectious exposures (e.g., diet, toxins, psychosocial factors) will be evaluated. Assessment will likely be conducted more than once per year. Dietary factors are of interest as studies show that the timing of the introduction of certain foods to infants can affect the risk of developing celiac and diabetic autoimmunity. Organizers' comment: Dr. Perl presented evidence of a certain geographic location associated with the development of neurodegenerative disease through the presence of heavy metals. If such a strong link is present, migration patterns and IBD epidemiology may help unearth clues to disease etiology. Alzheimer's disease (AD) includes the development of neurofibrillary tangles associated with a loss of cognitive function and dementia. Studies show aluminum can induce experimental neurofibrillary degeneration and that the Alzheimer brain has excessive amounts of aluminum in neurons with tangles. Since aluminum is not used by biological systems, its presence in tissues implies an environmental source. Following World War II, large numbers of cases of amyotrophic lateral sclerosis (ALS) and a disease similar to Parkinson's disease with severe dementia were identified among the native population living on Guam. Brains of ALS/PDC cases showed neurofibrillary tangles identical to those seen in AD, but with aluminum levels that were 10 times higher than are seen in AD. ALS/PDC has changed over the past 25 years with observation of more pure dementia cases, fewer ALS cases, and a 10-year increase in age of onset. Such rapid changes in a disease suggest an environmental etiology. Furthermore, Filipino migrants to Guam are at high risk of developing ALS/PDC, but only after they have lived on the island for 20 years or more. Although there has been a large military presence in Guam since World War II, people temporarily stationed on the island do not develop ALS/PDC. While there are genetic features leading to ALS/PDC susceptibility, the specifics are not known. Either ALS/PDC results from long-time exposure to an environmental factor on Guam, or there is early exposure followed by a long period of latency. Both aluminum and iron are present in neurofibrillary tangles of AD as well as damaged nerve cells in Parkinson's disease. While there is an iron and aluminum association in these diseases, causation has not been established. IBD and neurodegenerative diseases appear to arise as the result of interactions between environmental and genetic factors. Due to the issues of timing, the nature of exposure, and complex interactions, identifying relevant environmental factors is much more difficult than studying genetic ones. Because they are modifiable, environmental factors are arguably more important. Studies of etiological factors influencing neurodegeneration suggest the importance of the phenomenon of latency. Organizers' comment: Dr. Lang presented large projects under way through NIH that are assessing the effects of environmental factors on humans. The NIEHS studies factors in the environment (traditionally chemical toxicology) that can adversely affect human health. In the US, about 70%–90% of diseases are not accounted for by genetic predisposition, but rather by reversible behaviors and environmental exposures. The Environmental Protection Agency (EPA) uses NIEHS data to help develop risk assessment, standards, public health policies, and more. NIEHS research ranges from basic biology to public health. There are in environment can affect health. Some can be as lifestyle and play a disease and age can affect is from different disciplines to environmental factors may by This is by with and have a effect on the of the the of Similar may the risk for NIEHS The This at and human genetic models for the effects of environmental factors on humans. are used to learn about the mechanisms of The and Health The is at factors such as lifestyle and environmental exposures. A is to to these factors and they to human health. Exposure is on developing of The This is a of the microbial at using from the human is it could be to good health. 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