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Role of lifestyle factors in Inflammatory Bowel Diseases
T. Jayampathi* & S. Jayatilake
Department of Food science and technology, Faculty of Livestock, Fisheries and Nutrition, Wayamba University of Sri Lanka, Makandura, Gonawila (NWP), Sri Lanka


T. Jayampathi
Department of Food Science & Technology, Faculty of Livestock, Fisheries & Nutrition,
Wayamba University of Sri Lanka, Makandura, Gonawila,Sri Lanka 
Telephone number � +94766404873
Fax � 031-2299871
Email address �  HYPERLINK "mailto:tharujayampathi@gmail.com" tharujayampathi@gmail.com
Electronic word count - 4069















Abstract
Inflammatory bowel disease (IBD) is an autoimmune disease of two types as Crohn�s disease (CD) and Ulcerative colitis (UC). It is a multifactorial disease which is manifested when a genetically predisposed individual is exposed to an environmental stimulus which disrupts the normal intestinal commensal flora leading to an inappropriate immune response that causes chronic inflammation. The rapid increase in the incidence of cannot be explained completely by genetics which suggests the strong role played by environmental factors in mediation of the disease, which has been shown demonstrated through twin studies, immigrant studies and epidemiological data. Certain environmental factors affecting IBD are related to the lifestyle changes associated with westernization and industrialization such as smoking, diet, improvement of hygiene, psychological stress and physical inactivity.  Smoking aggravates CD while showing a protective effect on UC. Westernized diet is a risk factor for IBD while fibre rich diets are protective. Improvement in the hygiene is also associated with the IBD risk through the �hygiene hypothesis,� although certain studies show otherwise. There is increasing evidence that psychological stress plays a role in the pathogenesis of IBD and increase the risk of disease flares. Sedentary lifestyles seem to have an effect on IBD, with an improvement in the wellbeing of patients with regular physical activity. Although multiple studies have explored the association between IBD and environmental factors the role of certain factors still remains controversial. This review focuses on the role of lifestyle risk factors in the pathogenesis and progression of IBD. 

Keywords: Crohn�s disease; Ulcerative colitis, Environment; Hygiene hypothesis; Smoking; Diet











Introduction
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder caused by irregular immune responses in individuals who are genetically predisposed to disease [1]. IBD has two types as Crohn�s disease (CD) and Ulcerative colitis (UC) of which the etiology is unknown [2]. It is a multigenetic disease thought to be caused by environmental, genetic, and immunoregulatory factors [3-5]. It is characterized as a chronic inflammation that is manifested when a genetically predisposed individual is exposed to an environmental trigger, which leads to an inappropriate immune system response [6, 7].
IBD was considered as a disease of the West as it was more prevalent in America and Europe compared to developing countries in Asia, however there has been an increase in the incidence with the industrialization [8-12].  Thus the prevalence if inflammatory bowel disease is increasing throughout the world, especially in USA, Europe, Middle East, Asia and South America and therefore has become a global disease of which the prevalence is rising worldwide [13-15]. The rising incidence of IBD in the past few decades in developing regions is associated with the rapidly changing environment and westernized lifestyle suggesting the importance of environmental factors in the pathogenosis of IBD [16, 17], since genetic variations are not significant in such a short period of time [18]. The aberrant immune responses associated with autoimmune diseases such as IBD is perhaps an attempt to adjust to drastic environmental changes for which the body is not adapted [19]. Studies of immigrant populations show that difference in incidence between ethnicities is much more related the influence of environment rather than the difference in the genetics [20]. Migration to high risk areas during a younger age increases risk of developing IBD ain the immigrants as well as their first generation children. It has been found that South Asians who migrated to United Kingdom, particularly from the Indian subcontinent, where IBD was thought to be rare had a higher risk for than whites [21-25]. 
Environmental factors that influence IBD include mode of child birth,  early-life exposures such as breastfeeding, exposure to antibiotics during infancy, lifestyle, smoking and other major life stresses [26]. Factors such as westernized diet [27], saturated fat intake, sleep impairment, low vitamin D levels have also been associated with IBD. Other factors that affect IBD include infectious agents, drugs, appendectomy, oral contraceptives, antibiotics stress and socio-economic factors [28-30]. This review article focuses on the role of lifestyle risk factors which are environmental factors in the pathogenesis and progression of IBDs.


Smoking
Smoking is one of the most important environmental triggers of IBD and has been extensively studied. However the mechanism by which smoking affects IBD still remains quite unclear [31-33]. It has contrasting effects on UC and CD [33]. Evidence suggests that smoking has a protective role on UC and acts as a risk factor for CD [34-36]. This may be due to the fact that cessation of smoking has the ability of increasing the variety and changing the gut micobiota composition [37]. 
Smoking has a positive effect on UC and majority of UC patients are ex-smokers or non-smokers [38]. The relationship between smoking and IBD is dose dependent. A reduction in the risk is seen in smokers with a reduced chance of hospitalization, flares and a lesser need of steroids or colectomies. However ex-smokers have a high risk of developing UC. If a UC patient quits smoking it would lead to the aggravation of disease condition [39]. A large number of studies have confirmed that smoking is a protective factor against UC and that it reduces the risk of disease relapse [40, 41]. During the first year of smoking cessation UC patients show an increase in disease flares and patients who restarted smoking had an improvement in their disease activity [42, 43]. However the effect of smoking on men and women is quite different. The benefits of smoking on UC are mainly observed in males [44, 45]. It has been found that 52% of patients have developed UC within a three year period after they quit smoking [46, 47]. Population studies carried out on the Mormon Church population of England, where smoking is highly discouraged, have shown that there was a five times increase in the incidence of UC, confirming the protective effect of smoking on UC [48]. Pilot studies have indicated that nicotine could induce remission in patients with active UC. However this treatment leads to side effects such as sleep disturbance, nausea and headaches [49]. 
In CD patients smoking leads to the aggravation of disease conditions. It increases the chances of disease flares, requirement of surgery and occurrence after surgery [50]. Smoking can lead to severe cases of disease relapse with the development of fistulae and increase the need for steroids [51, 52]. It is found that CD patients have a higher probability of being exposed to tobacco smoke even before their birth [53]. Cessation of smoking is one of the strategies used in the treatment of CD [54]. Smoking doubles the risk of CD compared to non-smokers [55] and leads to a very aggressive disease course [56] with extreme clinical outcomes [57]. Stopping smoking for a period of six months reduces the risk of disease flares during a period of 12-18 months. The benefits of smoking cessation are more pronounced in women compared to men [58]. A meta-analysis has shown that smoking increases the recurrence of CD by 2.5 times after undergoing surgery [59]. Limited data available on the effects of passive smoking suggest that CD patients who are passive smokers require medications such as inflximib and immunosuppressants more often than patients who do not get exposed to passive smoking. The effects shown by passive smoking on the disease course are much similar to active smoking, however the results are much weaker in the former [60]. Due to the harmful effects of smoking on CD the cessation of smoking is the main therapeutic strategy used for patients who are smokers [61]. 
IBD and smoking follow a dose-response relationship in both cases of disease [62]. In UC patients the highest risk is associated with ex-smokers followed by non-smokers [63] and in CD patients it is current smokers followed by ex-smokers [64]. Smoking cessation increases the risk of UC within a period of 2-5 years and a high risk can be seen up to a period of 20 years [65], on the other hand smoking doubles the risk of CD [66], increases need of steroids [67,68]. The epidemiologic data shows contrasting effects of smoking on UC and CD however the mechanism is unclear. It has been suggested that nicotine in cigarette smoke is responsible for this action, which has been demonstrated through animal models [69]. This may be due to the stimulation of nicotinic acetylcholine receptors found on the mucosal epithelial cells of the bowel [70, 71]. Nicotine replacement therapy in clinical trials has shown inconsistent results, implicating that nicotine alone may not be the component of smoking that affects IBD [72]. Studies also propose that the effects of smoking on IBD may be due to oxidative stress, with a differential effect on CD and UC [73]. Other mechanism state that smoking changes level of cytokines [74] , predispose to development of micro vascular thrombi [75], modify the production of mucus in the colon [76] and modulate cellular immunity [77]. 
In spite of the fact that smoking is considered as a main risk factor in the pathogenesis of IBD, the highest prevalence if IBD is seen in countries with low smoking, such as Canada [78, 79]. However South Korea which has a higher prevalence of smoking has a lesser prevalence of IBD. Also majority of smokers do not develop CD and most CD patients are non-smokers. Thus the effect of smoking in the development is multifactorial [80]. Studies further show that the habit of smoking is less prevalent UC patients rather than the non-UC population [81].  
Although smoking is considered the most consistent environmental factor affecting IBD [82], a European study has that the higher prevalence of IBD in Northern Europe may not be explained by the high prevalence of smoking or higher education levels [83]. 


Diet 
Diet is considered to be one of the most common environmental factors affecting IBD [84, 85]. A correlation has been found between the changes towards westernized diets and the increase of prevalence of CD in Asia and Eastern Europe [86]. Western diets with low fiber, high animal fat and carbohydrates have been said to increase the risk of IBD [84, 87].  The gut microbiota is affected by the nutrition that an individual receives. Thus the gut microflora of African children who consume higher fiber diet is much different from European children consuming diets rich in protein, fat and sugar [88, 89]. Western diet maybe a risk factor affecting IBD, however it is probable that it involves a combination of other environmental risk factors that it is part of a modernized lifestyle as well.  
Fruits and Vegetables  
High intake of fruits and vegetables which are rich in dietary fiber has been associated with a reduction in the incidence of IBD [90-93]. It has been found that children consuming larger amounts of fruits and vegetables had a lower risk of developing CD, in a dose dependent manner [91]. Prospective studies done using adult populations have shown strong inverse relationships between fiber intake and IBD. However it is noted that this relationship is stronger with CD. The source of fiber seems to have an impact on the protective effect against IBD. It has been found that dietary fiber from fruits and vegetable, specially cruciferous vegetables  is able to reduce the incidence of IBD, while insoluble fiber from whole grains and bran do not show such effect [94]. Consumption of more than five citrus fruits per week has been associated to reduction in the risk of UC. It is also found that low consumption of raw fruits and vegetables is common in IBD patients [95]. A Japanese study has indicated that fiber reduces the inflammation of bowels and it is suggested to consume fiber rich food such as fruits, vegetables, dried mushrooms and seaweeds [96]. 
Sugars
Consuming higher amounts of processed carbohydrate and sugar containing foods such as pastries, chocolates, dessert mixes with sugar and fizzy drinks have been associated with an increase in the incidence of CD as well as UC [97-99]. It was found that CD patients usually consume foods rich in refined sugars [100, 101]. In addition high sugar consumption has been associated of increase of CD in both North American and Asian populations [102, 103]. 
Fat
Dietary fat has a great impact on the gut microbiota and possesses the ability to initiate UC [23]. Diets rich in fat increase the inflammation in chronic UC conditions, which have also been demonstrated through animal model [104, 105]. CD has been associated with total dietary intake of fats [91], while UC has been associated with increased consumption on monounsaturated and polyunsaturated fatty acids [106]. High intakes of mega-6 long chain fatty acids such as arachidonic acid and linoleic acids has led to a four-fold and two-fold increase of UC respectively [107-110]. On the other hand omega-3 fatty acids such as docosahexaenoicacid (DHA), eicosapentaenoic acid (EPA) and total n-3 intake were inversely associated with risk of UC, indicating a protective role against UC [111-113]. Also high consumption of trans fatty acids over a prolonged period has been positively related to the development of IBD [113]. 
Animal protein 
Many studies have shown that the consumption of animal protein is positively associated to the development of CD [114-116]. Meat and fish are found to significantly increase IBD although there is no such association found with dairy or eggs [117]. Consumption of red meat, protein and alcohol has been associated with increase in the incidence of relapses in CD patients [118]. 
Breastfeeding
Breastfeeding has the ability of protecting infants against many immune diseases including IBD. It has been shown to play protective role against IBD in both childhood and adulthood [119] particularly for CD and also prevents early onset of IBD [120]. This may be due to the development of oral tolerance to microflora and food antigens [121] and also due to the presence of lactoferrin in breast milk, which possess anti-inflammatory characteristics [122]. 

Hygiene
Hygiene hypothesis can be a probable explanation of the rise in the incidence of IBD in both developing and developed countries which has coincided with the improvement of hygiene and sanitary facilities in the 20th century [123, 124]. It has been suggested as a factor contributing for increase in allergic, autoimmune and inflammatory conditions [125, 126]. This theory states that a child who lives in an environment with improved hygiene could be overprotected from common infectious agents in the environment and when they come into contact with pathogens later in life, they exhibit inappropriate immune responses which may cause abnormal inflammatory processes such as IBD [127, 128]. Thus poor hygiene and increased exposure to childhood infections is considered to provide protection from diseases occurring later in life [129].
It has been found that childhood infections help the establishment of a balance between pro-inflammatory and tolerance-inducing regulatory T cells, thus preventing inappropriate immune responses to antigenic stimuli [130]. This has been supported by low incidence of disease in developing countries where there is a higher exposure to infections compared to developed Northern countries [131], ability of parasitic infections in disease modulation [132], and the difference of incidence between rural and urban areas [133]. Improvement in the general hygienic conditions such as free access to clean water, running hot water, smaller family size [134], less crowding, non-contaminated food, hygiene products such as toothpaste [135, 136], cleaner environment, lower exposure to farm animals [137, 138], vaccinations, chewing gum which are parts of modern lifestyle are suggested to be related to an increased incidence in IBD [139]. However some studies do not support association of improved hygiene with IBD [140]. It has been found that CD is five times more common in patients whose childhood home had a fixed hot water tap and separate bathroom. However no association was found between IBD and access to flush toilets. There was no association between domestic hygiene factors as UC [141]. Similarly another study found that hot water taps at home before age of 11 was associated with CD but other domestic factors were not associated with UC or CD [142]. However some other studies do not show significant associations between availability of hot water, number of bathrooms, drinking water source, bed and risk for CD [143]. Domestic crowding and bedroom sharing have been associated with an increase in risk of UC [144]. Increase in risk of CD has also been associated with frequent use of public swimming pools [145]. Living in crowded homes and infrequent use of personal towels were found to be related to higher risk of CD [146]. Frequency tooth brushing, use of dental floss, breath freshener was higher in IBD patients.  It may suggest that oral hygiene practices may change the microbiome of the oral mucosa which causes dysbiosis of gut microbiota [147]. 
Larger family size indicates a higher chance of overcrowding and an increased chance of IBD. Having older siblings was associated with an increased risk of UC [148], probably because older siblings may expose younger siblings to infections at higher doses or at an early age. Similarly small number of siblings in the family and higher birth order was associated with an increased risk [149]. In contrast having younger siblings showed a protective effect particularly when the younger sibling was born within two years of patient�s birth [150].  However in contrast some studies show that there is no significant association between sibship size and sib rank with IBD risk [135].  
The �Measles hypothesis� suggests that there us a higher risk of IBD in patients who have been given live attenuated measles vaccine in early childhood [151]. This is due to the ability of childhood vaccinations to change the maturation of intestinal and immune systems which have been implicated in IBD [152]. A study in UK showed a 3-fold and 2.5-fold more likeliness to develop CD and UC respectively [153]. 
Pet ownership [146] and animal exposure during childhood [137, 154] has been associated with an increased risk of CD. Day care attendance during first six months of life has been associated with an increase in their risk of CD as it has a higher chance of exposing children to larger infections [137]. However other studies have not shown a significant difference between IBD cases and control in regards to pre-school attendance[135].Several studies show that a higher incidence of IBD in urban populations than rural populations [155, 156].

 Stress 
Psychological stress has for a long time been considered to affect the disease course of IBD. Many studies have shown an association between chronic stress, anxiety, depression, psychological disorders and adverse life events with IBD [157-164]. Due to many early studies showing a relationship between IBD and psychological disorders, it was considered as a psychosomatic disorder in around the 1950s [165].
A higher level of stress has been associated with relapse of UC [166] and CD [167]. It has also been shown to play a role in diseases flares of both UC and CD [168-170]. A prospective study has shown that better coping mechanisms and low stress levels were associated with a reduction in the risk of disease flares [171]. Poor coping strategies and stress handling has been associated with early relapse of disease in CD patients as demonstrated by a prospective study [172]. In addition depression and anxiety has been related to higher risk of surgery in CD patients [173-175]. Adverse life events also have been associated with the relapse of IBD [176]. However events occurring during a period of 6 months from the onset of IBD have not been associated to increased risk of developing IBD as shown by a questionnaire �based study carried out in France [177]. There is a significant role played by depression and anxiety on the aggravation of the disease condition [178]. Stress is found to be the only independent predictor of increased risk for disease flare [179] and is found to change the course of the disease [180]. 
Immune function is affected by chronic and acute stress which affects the course of IBD [181, 182]. Experiments done using animal models have demonstrated that chronic stress could aggravate the disease by increasing permeability of intestinal epithelium and promoting damage to the mucosa, thereby reducing its ability to act as a barrier against microbial invasion [183, 184]. Stress also leads to the reduction of mucus secretion and increases the permeability of the colon of mice in both CD and UC [185]. 
There is insufficient data on whether management of stress, anxiety and depression improves the disease course of IBD [186]. It has been shown through a retrospective observational study that requirement of steroids and relapse of symptoms was reduced by anti-depressant therapy [187]. However certain other studies have not found any beneficial effect of psychological interventions on IBD [188]. Thus there is some controversy over the effect of such treatment on disease conditions of IBD patients, in spite of the fact that psychological interventions have improved the quality of life of UC patients [186].

Physical activity
Studies have shown that physical activity is associated with a lower risk of CD but such results have not been seen of UC. This may be due to induction of autophagy or modulation of innate immunity [189], improvement of psychological health [190], physical health [191], reduction of stress [192] and changes in local neuro-immunoendocrine effects [193] 
It has been found that active women who had a physical activity of at least 27 metabolic equivalent task (MET) hours had a 44% reduction in the risk of CD in comparison to women who had less than 3 MET hours per week. It was observed that sedentary CD patients were able to tolerate low intensity exercises for moderate duration and that it was able to show improvements in their physical and psychological conditions [194]. A similar pilot study using a smaller study group had shown that low intensity exercises of moderate duration were able to improve physical health and fitness, decrease stress, and improve general wellbeing, quality of life and CD symptoms. Also it was not associated with the excaberation of disease symptoms in patients with mildly active or inactive disease. It was seen that physical activity is not harmful for IBD patients although there was an acute increase in levels of activated neutrophils and serum malondialdehyde levels [195]. It was found in a German study that workers who engaged in physically demanding jobs had a lower risk of IBD compared to those who engaged in sedentary jobs. However occupational risks could also be associated with other factors such as lower access to medical care, socioeconomic status as well as family history. As well as less demanding occupations may have attracted the chronically ill However it can be speculated that physical activity as a protective effect on IBD [196]. A case-control study based on activity reported over a 5 year period also shows that there was an inverse relationship between Crohn�s disease development and regular physical activity participation [197]. A lower relative risk was found in both men and women who had daily or weekly exercise with a relative risk of 0.5 and 0.6 respectively. However this effect was not seen in UC patients [198]. In contrast another case control study found benefits of physical activity on both UC and CD [199]. 
Glucocorticoid medications taken by IBD patients causes osteoporosis, osteopenia, muscle atrophy and weakness therefore it is beneficial to promote regular physical activity among them [200]. 
Conclusion
Environmental factors play an important role in the development and progression of IBD. Understanding the mechanisms by which different factors affect the disease would be an effective means of prevention as well as management of disease. The changes in lifestyle associated with westernization seem to be a major reason for increase of incidence of IBD in developing regions particularly in Asia, however the impact of certain factors on disease course still remains controversial.  
Prospects for future research
Although the prevalence and environmental factors affecting IBD have been widely studied in the much developed countries, there is a lack of good quality epidemiological data on developing Asian countries, particularly in the Indian subcontinent where there is a major change in the lifestyle during the past decade. It is important to carry out large prospective studies and collect accurate data regarding the disease incidence of those regions, which would help to identify the environmental risk factors mostly associated with their rapidly changing lifestyles. 

References
Targan, S. R., & Shih, D. Q. (2009). Insights into IBD pathogenesis. Current Gastroenterology Reports. http://doi.org/10.1007/s11894-009-0072-9
Karlinger, K., Gyorke, T., Mako, E., Mester, A., & Tarjan, Z. (2000). The epidemiology and the pathogenesis of inflammatory bowel disease. European Journal of Radiology, 35(3), 154�167. http://doi.org/Doi 10.1016/S0720-048x(00)00238-2
Hanauer, S. B. (2006). Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflammatory Bowel Diseases, 12 Suppl 1(January), S3�S9. http://doi.org/10.1097/01.MIB.0000195385.19268.68
Lakatos PL, Fischer S, Lakatos L, Gal I, PappJ: Current concept on the pathogenesis ofIBD: crosstalk between genetic and microbialfactors. Pathogenic bacteria, altered bacterialsensing or changes in mucosal integritytake �toll�? World J Gastroenterol 2006;12: 1829�1840.
Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis.Gastroenterology 1998;115:182�205.
Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, MeyerzumB�schenfelde KH. Tolerance exists towards resident intestinalflora but is broken in active inflammatory bowel disease (IBD) ClinExpImmunol 1995; 102: 448-455 [PMID: 8536356 DOI: 10.1111/j.1365-2249.1995.tb03836.x]
Abraham C, Cho JH. Inflammatory bowel disease. N Engl JMed 2009; 361: 2066-2078 [PMID: 19923578 DOI: 10.1056/NEJMra0804647]
Loftus EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004; 126: 1504-1517 [PMID: 15168363 DOI: 10.1053/j.gastro.2004.01.063]
Ng SC. Emerging leadership lecture: Inflammatory bowel disease in Asia: emergence of a �Western� disease. J GastroenterolHepatol 2015; 30: 440-445 [PMID: 25469874 DOI: 10.1111/jgh.12859]
Ng SC, Tang W, Ching JY, Wong M, Chow CM, Hui AJ, Wong TC, Leung VK, Tsang SW, Yu HH, Li MF, Ng KK, Kamm MA, Studd C, Bell S, Leong R, de Silva HJ, Kasturiratne A, Mufeena MN, Ling KL, Ooi CJ, Tan PS, Ong D, Goh KL, Hilmi I, Pisespongsa P, Manatsathit S, Rerknimitr R, Aniwan S, Wang YF, OuyangQ,Zeng Z, Zhu Z, Chen MH, Hu PJ, Wu K, Wang X, Simadibrata M, Abdullah M, Wu JC, Sung JJ, Chan FK. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn�s and colitis epidemiology study. Gastroenterology 2013; 145: 158-165.e2 [PMID: 23583432 DOI: 10.1053/j.gastro.2013.04.007]
Zhao J, Ng SC, Lei Y, Yi F, Li J, Yu L, Zou K, Dan Z, Dai M, Ding Y, Song M, Mei Q, Fang X, Liu H, Shi Z, Zhou R, Xia M, Wu Q, Xiong Z, Zhu W, Deng L, Kamm MA, Xia B. First prospective, population-based inflammatory bowel disease incidence study in mainland of China: the emergence of �western� disease. InflammBowel Dis 2013; 19: 1839-1845 [PMID: 23669403 DOI: 10.1097/ MIB.0b013e31828a6551]
Park SJ, Kim WH, Cheon JH. Clinical characteristics and treatment of inflammatory bowel disease: a comparison of Eastern and Western perspectives. World J Gastroenterol2014; 20: 11525-11537 [PMID: 25206259 DOI: 10.3748/wjg.v20.i33.11525]
Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Kaplan, G. G. (2012). Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review - Gastroenterology. YGAST, 142, 46�54.e42.
Crohn�s& Colitis Foundation of America. (2014). The Facts About Inflammatory Bowel Diseases. Inflammatory Bowel Diseases, 2(2), 1. http://doi.org/10.1097/00054725-199606000-00001
Kaplan, G. G. (2015). The global burden of IBD: from 2015 to 2025. Nature Reviews. Gastroenterology&Hepatology,12(12),720�  HYPERLINK "http://doi.org/10.1038/nrgastro.2015.150" http://doi.org/10.1038/nrgastro.2015.150
Thia KT, Loftus Jr EV, Sandborn WJ, Yang SK. An update on theepidemiology of inflammatory bowel disease in Asia.Am JGastroenterol. 2008;103:3167�82.
Ng SC, Bernstein CN, Vatn MH, Lakatos PL, Loftus EV, Tysk C,O�Morain C, Moum B, Colombel JF. Geographical variability andenvironmental risk factors in inflammatory bowel disease. Gut 2013;62: 630-649 [PMID: 23335431 DOI: 10.1136/gutjnl-2012-303661]
Wills-Karp M, Santeliz J, Karp CL. The germless theory ofallergic diseases: revisiting the hygiene hypothesis. Nat Rev2001;1:69� 75.
Straub RH, Besedovsky HO. Integrated evolutionary, immunological,and neuroendocrine framework for the pathogenesisof chronic disabling inflammatory diseases. FASEB J 2003; 17:2176� 83.
Bernstein CN, Shanahan F. Disorders of a modern lifestyle:reconciling the epidemiology of inflammatory bowel diseases.Gut 2008; 57: 1185-1191 [PMID: 18515412 DOI: 10.1136/ gut.2007.122143]
Pinsk V, Lemberg DA, Grewal K, Barker CC, Schreiber RA,Jacobson K. Inflammatory bowel disease in the South Asian pediatric population of British Columbia. Am J Gastroenterol2007; 102: 1077-1083 [PMID: 17378907 DOI: 10.1111/j.1572-0241.2007.01124.x]
 Probert CS, Jayanthi V, Pinder D, Wicks AC, Mayberry JF.Epidemiological study of ulcerative proctocolitis in Indian migrantsand the indigenous population of Leicestershire. Gut 1992; 33:687-693 [PMID: 1307684 DOI: 10.1136/gut.33.5.687]
Carr I, Mayberry JF. The effects of migration on ulcerative colitis:a three-year prospective study among Europeans and first- andsecond- generation South Asians in Leicester (1991-1994). Am JGastroenterol 1999; 94: 2918-2922 [PMID: 10520845]
Benchimol EI, Mack DR, Guttmann A, Nguyen GC, To T,Mojaverian N, Quach P, Manuel DG. Inflammatory bowel disease inimmigrants to Canada and their children: a population-based cohortstudy. Am J Gastroenterol 2015; 110: 553-563 [PMID: 25756238 DOI: 10.1038/ajg.2015.52]
Barreiro-de Acosta M, Alvarez Castro A, Souto R, IglesiasM, Lorenzo A, Dominguez-Mu�oz JE. Emigration to westernindustrialized countries: A risk factor for developing inflammatorybowel disease. J Crohns Colitis 2011; 5: 566-569 [PMID: 2211537 DOI: 10.1016/j.crohns.2011.05.009]
Ananthakrishnan, A. N. (2015). Epidemiology and risk factors for IBD. Nature Reviews. Gastroenterology & Hepatology, 12(April), 205�217.  HYPERLINK "http://doi.org/10.1038/nrgastro.2015.34" http://doi.org/10.1038/nrgastro.2015.34
Cashman KD, Shanahan F: Is nutrition anaetiological factor for inflammatory boweldisease? Eur J GastroenterolHepatol 2003;15: 607�613.
Jantchou, P., Monnet, E., & Carbonnel, F. (2006). [Environmental risk factors in Crohn�s disease and ulcerative colitis (excluding tobacco and appendicectomy)]. Gastroenterol Clin Biol, 30(6-7), 859�867.
Lakatos PL: Recent trends in the epidemiologyof inflammatory bowel diseases: up or down? World J Gastroenterol 2006; 12: 6102�6108
Lakatos PL. Environmental factors affecting inflammatory bowel disease:have we made progress? Dig Dis 2009;27:215�25.
Tuvlin JA, Raza SS, Bracamonte S, Julian C, Hanauer SB, NicolaeDL, King AC, Cho JH. Smoking and inflammatory bowel disease:trends in familial and sporadic cohorts. Inflamm Bowel Dis 2007; 13:573-579 [PMID: 17345609]
Cosnes J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract Res Clin Gastroenterol. 2004;18:481�96.
Cosnes J. What is the link between the use of tobacco and IBD? Inflamm Bowel Dis. 2008;14 Suppl 2:S14�5. 
Corrao G, Tragnone A, Caprilli R, Trallori G, Papi C, Andredi A, Di-Paolo M, Riegler G, Rigo GP, Feran O, Mansi C, Ingrosso M, Valpiani D. Risk of in�ammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: a nationwide case control study. Cooperative investigators of the Italian group for the study of the colon and rectum (GISC). Int J Epidemiol 1998;27:397�404.
Parkes GC, Whelan K, Lindsay JO. Smoking in inflammatorybowel disease: impact on disease course and insights into the aetiology of its effect. J Crohns Colitis 2014; 8: 717-725 [PMID: 24636140 DOI: 10.1016/j.crohns.2014.02.002]
Naito T, Kida H, Yokoyama H, Koshino Y, Tomosugi N, Hattori N, Kobayashi K. A case of diffuse panbronchiolitis (DPB) with benign monoclonal IgA gammopathy and IgA nephropathy with monoclonal IgA deposition.Jpn J Med 1989; 28: 503-505 [PMID: 2509771 DOI: 10.5114/pg.2014.43577]
Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989;34:1841-54.
Biedermann L, Zeitz J, Mwinyi J, Sutter-Minder E, Rehman A, Ott SJ, Steurer-Stey C, Frei A, Frei P, Scharl M, Loessner MJ, Vavricka SR, Fried M, Schreiber S, Schuppler M, Rogler G. Smoking cessation induces profound changes in the composition of the intestinalmicrobiota in humans. PLoS One 2013; 8: e59260 [PMID: 23516617 DOI: 10.1371/journal.pone.0059260]
  Boyko EJ, Koepsell TD, Perera DR, Inui TS. Risk of ulcerative colitis among former  and current cigarette smokers. N Engl J Med 1987;316:707-10.
Cosnes J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract Res Clin Gastroenterol2004; 18: 481-496 [PMID: 15157822 DOI: 10.1016/ j.bpg.2003.12.003]
Lakatos PL, Szamosi T, Lakatos L. Smoking in inflammatory bowel diseases: good, bad or ugly? World J Gastroenterol2007; 13: 6134-6139 [PMID: 18069751 DOI: 10.3748/wjg.13.6134]
Odes HS, Fich A, Reif S, Halak A, Lavy A, Keter D, Eliakim R, Paz J, Broide E, Niv Y, Ron Y, Villa Y, Arber N, Gilat T. Effects of current cigarette smoking on clinical course of Crohn's disease and ulcerative colitis. Dig Dis Sci. 2001;46:1717�21. 
 Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre JP, Cosnes J. Impact of cessation of smoking on the course of ulcerative colitis. Am J Gastroenterol2001; 96: 2113-2116 [PMID: 11467641 DOI:10.1111/j.1572-0241.2001.03944.x]
Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a meta-analysis. Mayo ClinProc2006; 81: 1462-1471 [PMID: 17120402 DOI:10.4065/81.11.1462]
 Cosnes J, Nion-Larmurier I, Afchain P, Beaugerie L, Gendre JP. Gender differences in the response of colitis to smoking.Clin GastroenterolHepatol2004; 2: 41-48 [PMID: 15017631 DOI: 10.1016/S1542-3565(03)00290-8]
Jha P, Ranson MK, Nguyen SN, Yach D. Estimates of global and regional smoking prevalence in 1995, by age and sex. Am J Public Health 2002; 92: 1002-1006 [PMID: 12036796 DOI: 10.2105/AJPH.92.6.1002]
Motley RJ, Rhodes J, Ford GA, Wilkinson SP, Chesner IM, AsquithP, Hellier MD, Mayberry JF. Time relationships between cessation of smoking and onset of ulcerative colitis. Digestion 1987; 37: 125-127 [PMID: 3622939 DOI: 10.1159/000199478]
Penny WJ, 19. Penny E, Mayberry JF, Rhodes J. Prevalence of inflammatory bowel disease amongst Mormons in Britain and Ireland. SocSci Med 1985; 21: 287-290 [PMID: 3875900 DOI: 10.1016/0277-9536(85)90103-0]
Thomas GA, Rhodes J, Ragunath K, Mani V, Williams GT, Newcombe RG, Russell MA, Feyerabend C. Transdermal nicotine compared with oral prednisolone therapy for active ulcerative colitis. Eur J GastroenterolHepatol1996; 8: 769-776 [PMID: 8864674]
 Bastida G, Beltr�n B. Ulcerative colitis in smokers, non-smokers and ex-smokers. World J Gastroenterol2011; 17: 2740-2747 [PMID: 21734782 DOI: 10.3748/wjg.v17.i22.2740]
Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre J. Effects of cigarette smoking on the long-term course of Crohn�s disease. Gastroenterology 1996;110:424-31.
 Lunney PC, Kariyawasam VC, Wang RR, Middleton KL, Huang T, Selinger CP, Andrews JM, Katelaris PH, Leong RW. Smoking prevalence and its influence on disease course and surgery in Crohn�s disease and ulcerative colitis. Aliment PharmacolTher 2015; 42: 61-70[PMID: 25968332 DOI: 10.1111/apt.13239]
Picco MF, Bayless TM. Tobacco consumption and disease duration are associated with fistulizing and stricturingbehaviors in the first 8 years of Crohn�s disease. Am J Gastroenterol2003; 98: 363-368 [PMID: 12591056 DOI: 10.1111/j.1572-0241.2003.07240.x]
Mahid SS, Minor KS, Stevens PL, Galandiuk S. The role of smoking in Crohn�s disease as defined by clinical variables. Dig Dis Sci2007; 52: 2897-2903 [PMID: 17401688 DOI: 10.1007/s10620-006-9624-0]
Johnson GJ, Cosnes J, Mansfield JC. Review article: smoking cessation as primary therapy to modify the course of Crohn�s disease. Aliment PharmacolTher2005; 21: 921-931 [PMID: 15813828 DOI:10.1111/j.1365-2036.2005.02424.x]
Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci1989; 34: 1841-1854 [PMID: 2598752DOI: 10.1007/BF01536701]
Nos P, Dom�nech E. Management of Crohn�s disease in smokers: is an alternative approach necessary? World J Gastroenterol2011; 17:3567-3574 [PMID: 21987601 DOI: 10.3748/wjg.v17.i31.3567]
Higuchi LM, Khalili H, Chan AT, Richter JM, Bousvaros A, Fuchs CS. A prospective study of cigarette smoking and the risk of inflammatory bowel disease in women. Am J Gastroenterol2012;107: 1399-1406 [PMID: 22777340 DOI: 10.1038/ajg.2012.196]
Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn�s disease: an intervention study. Gastroenterology 2001; 120: 1093-1099 [PMID: 11266373 DOI: 10.1053/gast.2001.23231]
Reese GE, 31. Nanidis T, Borysiewicz C, Yamamoto T, Orchard T, Tekkis PP. The effect of smoking after surgery for Crohn�s disease: a meta-analysis of observational studies. Int J Colorectal Dis 2008; 23: 1213-1221 [PMID: 18762954 DOI: 10.1007/s00384-008-0542-9]
van der Heide F, Dijkstra A, Weersma RK, Albersnagel FA, van der Logt EM, Faber KN, Sluiter WJ, Kleibeuker JH, Dijkstra G. Effects of active and passive smoking on disease course of Crohn�s disease and ulcerative colitis. Inflamm Bowel Dis 2009; 15: 1199-1207 [PMID: 19170191 DOI: 10.1002/ibd.20884]
Rubin DT, Hanauer SB. Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12:855-62.
Jones DT, Osterman MT, Bewtra M, Lewis JD. Passive smoking and inflammatory bowel disease: A meta-analysis. Am J Gastroenterol 2008;103:2382-93.
Persson PG, Ahlbom A, Hellers G. Inflammatory bowel disease and tobacco smoke � a case-control study. Gut 1990;31:1377-81.
Franceschi S, Panza E, Vecchia CL, Parazzini F, Decarli A, Porro GB. Nonspecific inflammatory bowel disease and smoking. Am J Epidemiol 1987;125:445-52
Higuchi LM, Khalili H, Chan AT, Richter JM, Bousvaros A, Fuchs CS. A Prospective Study of Cigarette Smoking and the Risk of Inflammatory Bowel Disease in Women. American Journal of Gastroenterology (in press) 2012.
Birrenbach T, Bocker U. Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis. 2004;10:848�59.
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785�94.
Richardson CE. Effect of smoking and transdermal nicotine on colonic nicotinic acetylcholine receptors in ulcerative colitis. QJM 2003;96:57-65.
Razani-Boroujerdi S, Boyd RT, Davila-Garcia MI, et al. T cells express {alpha}7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response. J Immunol 2007;179:2889-98.
Birrenbach T, B�cker U. Inflammatory bowel disease and smoking. A review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis 2006;10:848-59.
Nikfar S, Ehteshami-Ashar S, Rahimi R, Abdollahi M. Systematic review and metaanalysis of the efficacy and tolerability of nicotine preparations in active ulcerative colitis. Clin Ther. 2010;32 (14):2304�15. Review. 
Bergeron V, Grondin V, Rajca S, Maubert MA, Pigneur B, Thomas G, Trugnan G, Beaugerie L, Cosnes J, Masliah J, Sokol H, Seksik P, Bachelet M. Current smoking differentially affects blood mononuclear cells from patients with Crohn's disease and ulcerative colitis: relevance to its adverse role in the disease. Inflamm Bowel Dis. 2012;18:1101�11.
Sher ME, Bank S, Greenberg R, et al. The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease. Inflamm Bowel Dis 2007;5:73-8.
 Sawyerr AM, Wakefield AJ, Hudson M, Dhillon AP, Pounder RE. The pharmacological implications of leucocyte-endothelial cell interactions in Crohn�s disease. Aliment Pharmacol Ther 1991;5:1-14.
Cope GF, Heatley RV, Kelleher JK. Smoking and colonic mucus in ulcerative colitis. BMJ (Clinical research edn) 1986;293:481.
Miller L, Goldstein G, Murphy M, Ginns L. Reversible alterations in immunoregulatory T cells in smoking. Analysis by monoclonal antibodies and flow cytometry. Chest 1982;82:526-9.
Shields M. Smoking bans: Influence on smoking prevalence. Health reports / Statistics Canada, Canadian Centre for Health Information = Rapports sur la sant� / Statistique Canada, Centre canadien d�information sur la sant�. 2007;18:9-24.
Bernstein CN, Wajda A, Svenson LW, et al. The epidemiology of inflammatory bowel disease in Canada: A population-based study. Am J Gastroenterol 2006;101:1559-68
Ouyang Q, Tandon R, Goh K-L, Ooi CJ, Ogata H, Fiocchi C. The emergence of inflammatory bowel disease in the Asian Pacific region. Curr Opin Gastroenterol 2005;21:408-13.
Lindberg E, Tysk C, Andersson K, Jarnerot G. Smoking and in�ammatory bowel disease. A case control study. Gut 1988;29:352 7.
Russel MG, Stockbrugger RW. Epidemiology of in�ammatory bowel disease, an update. Scand J Gastroenterol 1996; 31:417  27.
Shivananda S, Lennard-Jones J, Logan R, EC-IBD Study Group. Incidence of in�ammatory disease across Europe: is there a difference between north and south? Results of the European collaborative study on in�ammatory bowel disease (EC-IBD), Gut 1996;39:690 697. 
Chapman-Kiddell CA, Davies PS, Gillen L, Radford-Smith GL. Role of diet in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2010;16:137�51. 
Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol 2011;106:563�73. Comprehensive review of the role of diet in the pathogenesis of inflammatory bowel diseases. 
 Lakatos PL: Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J Gastroenterol 2006;  1 2:   6102� 6108
Chapman-Kiddell CA, Davies PS, Gillen L, Radford-Smith GL. Role of diet in the development of inflammatory bowel disease. Inflamm Bowel Dis 2010; 16: 137-151 [PMID: 19462428 DOI: 10.1002/ibd.20968]
O�Sullivan M, O�Morain C: Nutrition in inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2006;   20:   561�573. 
Muegge BD, Kuczynski J, Knights D, Clemente JC, Gonz�lez A, Fontana L, Henrissat B, Knight R, Gordon JI. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 2011; 332: 970-974 [PMID: 21596990 DOI: 10.1126/science.1198719]
 De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010; 107: 14691-14696 [PMID: 20679230 DOI: 10.1073/pnas.1005963107]
Russel MGVM, Engels LG, Muris JW, Limonard CB, Volovics A, Brummer RJ, Stockbrugger RW: �Modern life� in the epidemiology of inflammatory bowel disease: a case-control study with special emphasis on nutritional factors. Eur J Gastroenterol Hepatol 1998;  1 0:   243�249. 
Amre DK, D'Souza S, Morgan K, Seidman G, Lambrette P, Grimard G, Israel D, Mack D, Ghadirian P, Deslandres C, Chotard V, Budai B, Law L, Levy E, Seidman EG. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children. Am J Gastroenterol. 2007;102:2016�25. 
 Reif S, Klein I, Lubin F, Farbstein M, Hallak A, Gilat T. Pre-illness dietary factors in inflammatory bowel disease. Gut 1997;40:754-60.
 Russel MG, Engels LG, Muris JW, et al. Modern life in the epidemiology of inflammatory bowel disease: A case-control study with special emphasis on nutritional factors. Eur J Gastroenterol Hepatol 1998;10:243-9.
Maconi G, Ardizzone S, Cucino C, Bezzio C, Russo AG, Bianchi Porro G. Pre-illness changes in dietary habits and diet as a risk factor for inflammatory bowel disease: a case-control study. World J Gastroenterol 2010; 16: 4297-4304 [PMID: 20818813]
Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, de Silva P, Korzenik JR, Fuchs CS, Willett WC, Richter JM, Chan AT. A prospective study of long-term intake of dietary fiber and risk of Crohn�s disease and ulcerative colitis. Gastroenterology 2013; 145: 970-977 [PMID: 23912083 DOI: 10.1053/j.gastro.2013.07.050]
 Russel MG, Engels LG, Muris JW, Limonard CB, Volovics A, Brummer RJ, Stockbr�gger RW. Modern life� in the epidemiology of inflammatory bowel disease: a case-control study with special emphasis on nutritional factors. Eur J Gastroenterol Hepatol 1998; 10: 243-249 [PMID: 9585029]
 Kowal-Vern A, McFadden J. Pseudomonas aeruginosa pneumonia as a presenting entity in an AIDS patient. Clin Pediatr (Phila) 1989; 28: 403 [PMID: 2504528 DOI: 10.3904/kjim.2014.29.4.409]
Bianchi Porro G, Panza E. Smoking, sugar, and inflammatory bowel disease. Br Med J (Clin Res Ed) 1985; 291: 971-972 [PMID: 3929989]Hansen TS, Jess T, Vind I, Elkjaer M, Nielsen MF, Gamborg M, Munkholm P. Environmental factors in inflammatory bowel disease: a case-control study based on a Danish inception cohort. J Crohns Colitis 2011; 5: 577-584 [PMID: 22115378 DOI: 10.1016/ j.crohns.2011.05.010]
Jakobsen C, Paerregaard A, Munkholm P, Wewer V. Environmental factors and risk of developing paediatric inflammatory bowel disease -- a population based study 2007-2009. J Crohns Colitis 2013; 7: 79-88 [PMID: 22748696 DOI: 10.1016/j.crohns.2012.05.024]
Martini GA, Brandes JW. Increased consumption of refined carbohydrates in patients with Crohn�s disease. Klin Wochenschr 1976; 54: 367-371 [PMID: 1271690]
Mayberry JF, Rhodes J, Newcombe RG. Increased sugar consumption in Crohn�s disease. Digestion 1980; 20: 323-326 [PMID: 7390057]
  Sakamoto N, Kono S, Wakai K, et al. Dietary risk factors for inflammatory bowel disease: A multicenter case-control study in Japan. Inflamm Bowel Dis 2005;11:154-63.
 Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Dietary-fat- induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 2012; 487: 104-108 [PMID: 22722865 DOI: 10.1038/nature11225]
 Teixeira LG, Leonel AJ, Aguilar EC, Batista NV, Alves AC, Coimbra CC, Ferreira AV, de Faria AM, Cara DC, Alvarez Leite JI. The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation. Lipids Health Dis 2011; 10: 204 [PMID: 22073943 DOI: 10.1186/1476-511X-10-204]
Geerling BJ, Dagnelie PC, Badart-Smook A, Russel MG, Stockbr�gger RW, Brummer RJ. Diet as a risk factor for the development of ulcerative colitis. Am J Gastroenterol 2000;95:1008-13.
  Shoda R, Matsueda K, Yamato S, Umeda N. Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am J Clin Nutr 1996; 63: 741-745 [PMID: 8615358]
 Hart AR, Luben R, Olsen A, Tjonneland A, Linseisen J, Nagel G, Berglund G, Lindgren S, Grip O, Key T, Appleby P, Bergmann MM, Boeing H, Hallmans G, Danielsson A, Palmqvist R, Sjodin H, Hagglund G, Overvad K, Palli D, Masala G, Riboli E, Kennedy H, Welch A, Khaw KT, Day N, Bingham S. Diet in the aetiology of ulcerative colitis: a European prospective cohort study. Digestion 2008; 77: 57-64 [PMID: 18349539 DOI: 10.1159/000121412]
 de Silva PS, Olsen A, Christensen J, Schmidt EB, Overvaad K, Tjonneland A, Hart AR. An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis. Gastroenterology 2010; 139: 1912-1917 [PMID: 20950616 DOI: 10.1053/j.gastro.2010.07.065]
 Tjonneland A, Overvad K, Bergmann MM, Nagel G, Linseisen J, Hallmans G, Palmqvist R, Sjodin H, Hagglund G, Berglund G, Lindgren S, Grip O, Palli D, Day NE, Khaw KT, Bingham S, Riboli E, Kennedy H, Hart A. Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case�control study within a European prospective cohort study. Gut. 2009;58:1606�11.
 Kono H, Fujii H, Ogiku M, Tsuchiya M, Ishii K, Hara M. Enteral diets enriched with medium-chain triglycerides and N-3 fatty acids prevent chemically induced experimental colitis in rats. Transl Res 2010; 156: 282-291 [PMID: 20970751 DOI: 10.1016/ j.trsl.2010.07.012]
 John S, Luben R, Shrestha SS, Welch A, Khaw KT, Hart AR. Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: a UK prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22:602�6. 
 Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, de Silva P, Fuchs CS, Willett WC, Richter JM, Chan AT. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn�s disease. Gut 2014; 63: 776-784 [PMID: 23828881 DOI: 10.
 D�Souza S, Levy E, Mack D, Israel D, Lambrette P, Ghadirian P, Deslandres C, Morgan K, Seidman EG, Amre DK. Dietary patterns and risk for Crohn�s disease in children. Inflamm Bowel Dis 2008; 14: 367-373 [PMID: 18092347 DOI: 10.1002/ibd.20333]
Asakura H, Suzuki K, Kitahora T, Morizane T. Is there a link between food and intestinal microbes and the occurrence of Crohn�s disease and ulcerative colitis? J Gastroenterol Hepatol 2008; 23: 1794-1801 [PMID: 19120872 DOI: 10.1111/ j.1440-1746.2008.05681.x]
 Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol 2011; 106: 563-573 [PMID: 21468064 DOI: 10.1038/ajg.2011.44] 
 Jantchou P, Morois S, Clavel-Chapelon F, Boutron-Ruault M-C, Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: The E3N prospective study. Am J Gastroenterol 2010;105:2195-201
 Jowett SL, Seal CJ, Pearce MS, Phillips E, Gregory W, Barton JR, Welfare MR: Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut 2004;  5 3:  1 479�1484. 
Klement E, Cohen RV, Boxman J, Joseph A, Reif S. Breastfeeding and risk of inflammatory bowel disease: A systematic review with meta-analysis. Am J Clin Nutr 2004;80:1342-52. 
Barclay AR, Russell RK, Wilson ML, Gilmour WH, Satsangi J, Wilson DC. Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease. J Pediatr 2009; 155: 421-426 [PMID: 19464699 DOI: 10.1016/ j.jpeds.2009.03.017]
 Koloski N-A, Bret L, Radford-Smith G. Hygiene hypothesis in inflammatory bowel disease: A critical review of the literature. World J Gastroenterol 2008;14:165-73
 Brock JH. The physiology of lactoferrin. Biochem Cell Biol 2002;80:1-6
Askling J, Grahnquist L, Ekbom A, Finkel Y. Incidence of paediatric Crohn's disease in Stockholm, Sweden. Lancet 1999; 354: 1179
Yao T, Matsui T, Hiwatashi N. Crohn's disease in Japan:diagnostic criteria and epidemiology. Dis Colon Rectum 2000; 43: S85-S93
Stange EF, Travis S, Vermeire S, Reinisch W, Goebes K, Barakauskiene A, et al. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohn's Colitis 2008;2:1�23.
Rook GA, Adams V, Hunt J, et al. Mycobacteria and other environmental organisms as immunomodulators for immunoregulatorydisorders. Springer SeminImmunopathol 2004;25:237�55.
Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J. Too clean, or not too clean: the hygiene hypothesis and home hygiene. ClinExp Allergy 2006; 36: 402-425
Forbes A, Kalantzis T. Crohn's disease: the cold chain hypothesis. Int J Colorectal Dis 2006;21:399�401.
Bresciani M, Parisi C, Manghi G, et al. The hygiene hypothesis:Does it function worldwide? CurrOpin Allergy ClinImmunol 2005;5:147�51.
Pinchbeck BR, Kirdeikis J, Thomson AB. Inflammatorybowel disease in northern Alberta. An epidemiologic study.J ClinGastroenterol 1988;10(5):505�15.
 Armitage EL, Aldhous MC, Anderson N, et al. Incidenceof juvenile-onset Crohn�s disease in Scotland: Associationwith northern latitude and affluence. Gastroenterology 2004;127:1061�7.
Elliot DE, Li J, Blum A, et al. Exposure to schistosomeeggs protects mice from TNBS-induced colitis. Am J Physiol2003;284:G385�91.
Loftus ER Jr, Silverstein MD, Sandborn WJ, et al.Crohn�s disease in Olmstead County, Minnesota, 1940�1993: Incidence, prevalence, and survival. Gastroenterology1998;114(6):1161�8.
Kiloski N, Bret L, Radford-Smith G. Hygiene hypothesis in inflammatory bowel disease: a critical review of the literature.World J Gastroenterol 2008;14:165�73.
Feeney MA, Murphy F, Clegg AJ, Trebble TM, Sharer NM, Snook JA. A case-control study of childhood environmental risk factors for the development of inflammatory bowel disease. Eur J GastroenterolHepatol2002; 14: 529-534
Sullivan SN. Hypothesis revisited: toothpaste and the cause of Crohn's disease. Lancet 1990; 336: 1096-1097
 Bernstein CN, Rawsthorne P, Cheang M, et al. A population-basedcase control study of potential risk factors for IBD. Am J Gastroenterol. 2006;101:993�1002.
Radon K, Windstetter D, Poluda AL, et al. Contact with farm animals in early life and juvenile inflammatory bowel disease: a case control study. Pediatrics. 2007;120:354�361.
Lakatos L, Mester G, Erdelyi Z, Balogh M,Szipocs I, Kamaras G, Lakatos PL: Striking elevation in incidence and prevalence of inflammatory bowel disease in a province of western Hungary between 1977�2001. WorldJ Gastroenterol 2004; 10: 404�409.
Gilat T, Hacohen D, Lilos P, et al. Childhood factors inulcerative colitis and Crohn�s disease: An international collaborative study. Scand J Gastroenterol 1987;22:1009�24.
Gent AE, Hellier MD, Grace RH, SwarbrickET, Coggon D: Inflammatory bowel disease and domestic hygiene in infancy. Lancet1994; 343: 766�767.
Duggan AE, Usmani I, Neal KR, et al. Appendicectomy,childhood hygiene, Helicobacter pylori status, and risk ofinflammatory bowel disease: A case control study. Gut1998;43:494�8.
Hampe J, Heymann K, Krawczak M, Schreiber S. Association of inflammatory bowel disease with indicators for childhood antigen and infection exposure. Int J Colorectal Dis 2003; 18:413-417
Baron S, Turck D, Leplat C, et al. Environmental risk factors in paediatric inflammatory bowel diseases:A population based case control study. Gut 2005;54:357�63.
Castiglione F, Diaferia M, Morace F,  Labianca  O, Meucci C , Cuomo A,  Panarese A, Romano M, Sorrentini I, D'Onofrio C,  Caporaso N, Rispoa A. Risk factors for inflammatory bowel diseases according to the �hygiene hypothesis�: A case�control, multi-centre, prospective study in Southern Italy; Journal of Crohn's and Colitis 2012; 6: 324�329
Amre DK, Lambrette P, Law L, et al. Investigating the hygiene hypothesis as a risk factor in pediatric onset Crohn�s disease: A case-control study. Am J Gastroenterol 2006;101:1005�11.
Singhal S,Dian D,  Keshavarzian A, Fogg  L, Fields JZ, Farhadi A. The Role of Oral Hygiene in Inflammatory Bowel Disease. Dig Dis Sci 2011; 56:170�175
Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev 2004; 3: 394-400
Klement E, Lysy J, Hoshen M, Avitan M, Goldin E, Israeli E: Childhood hygiene is associated with the risk for inflammatory bowel disease: a population-based study. Am J Gastroenterol 2008; 103: 1775�1782.
Montgomery SM, Lambe M, Wakefield AJ, Pounder RE, Ekbom A. Siblings and the risk of inflammatory bowel disease. Scand J Gastroenterol2002; 37: 1301-1308
Thompson NP, Montgomery SM, Pounder RE, Wakefield AJ. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet 1995; 345: 1071�74.
Corrao G, Tragnone A, Caprilli R, Trallori G,Papi C, Andreoli A, Di Paolo M, Riegler G, Rigo GP, Ferrau O, Mansi C, Ingrosso M, Valpiani D: Risk of inflammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: a nationwide case-control study. Cooperative Investigators of the Italian Group for the Study of the Colon and the Rectum (GISC).Int J Epidemiol 1998; 27: 397�404.
Ghosh S, Armitage E, Wilson D, Minor PD,Afzal MA: Detection of persistent measlesvirus infection in Crohn�s disease: currentstatus of experimental work. Gut 2001; 48:748�752.
 Subhani J, Montgomery S, Thompson N, Wakefield AJ, Ebrahim S, Pounder R. Childhood risk factors for inflammatory bowel disease using a twin case-control method. Gastroenterology 1997; 112: A1099
Blanchard JF, Bernstein CN, Wajda A, Rawsthorne P. Smallarea variations and sociodemographic correlates for theincidence of Crohn's disease and ulcerative colitis. Am J Epidemiol2001; 154: 328-335
Ekbom A, Helmick C, Zack M, Adami HO. The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden. Gastroenterology 1991; 100: 350-358
Mawdsley JE, Rampton DS. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut 2005; 54: 1481-1491 [PMID: 16162953 DOI: 10.1136/gut.2005.064261]
Reber SO. Stress and animal models of inflammatory bowel disease--an update on the role of the hypothalamo-pituitary-adrenal axis. Psychoneuroendocrinology 2012; 37: 1-19 [PMID: 21741177 DOI: 10.1016/j.psyneuen.2011.05.014]
Ennaifer R, Elleuch N, Cheikh M, Hefaiedh R, Romdhane H, Ben Nejma H, Belhadj N. Risk factors of psychological disorders in inflammatory bowel disease in a tunisian survey. Results of a cross- sectional study. Tunis Med 2014; 92: 723-726 [PMID: 25879596]
Bannaga AS, Selinger CP. Inflammatory bowel disease and anxiety: links, risks, and challenges faced. Clin Exp Gastroenterol 2015; 8: 111-117 [PMID: 25848313 DOI: 10.2147/CEG.S57982]
Goodhand JR, Wahed M, Mawdsley JE, Farmer AD, Aziz Q, Rampton DS. Mood disorders in inflammatory bowel disease: relation to diagnosis, disease activity, perceived stress, and other factors. Inflamm Bowel Dis 2012; 18: 2301-2309 [PMID: 22359369 DOI: 10.1002/ibd.22916]
Long MD, Kappelman MD, Martin CF, Chen W, Anton K, Sandler RS. Risk factors for depression in the elderly inflammatory bowel disease population. J Crohns Colitis 2014; 8: 113-119 [PMID: 23932782 DOI: 10.1016/j.crohns.2013.07.002]
Szigethy EM, Youk AO, Benhayon D, Fairclough DL, Newara MC, Kirshner MA, Bujoreanu SI, Mrakotsky C, Bousvaros A, Srinath AI, Keljo DJ, Kupfer DJ, DeMaso DR. Depression subtypes in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2014; 58: 574-581 [PMID: 24345836 DOI: 10.1097/ MPG.0000000000000262]
Ananthakrishnan AN, Gainer VS, Perez RG, Cai T, Cheng SC, Savova G, Chen P, Szolovits P, Xia Z, De Jager PL, Shaw SY, Churchill S, Karlson EW, Kohane I, Perlis RH, Plenge RM, Murphy SN, Liao KP. Psychiatric co-morbidity is associated with increased risk of surgery in Crohn�s disease. Aliment Pharmacol Ther 2013; 37: 445-454 [PMID: 23289600 DOI: 10.1111/apt.12195])
Alexander T: An objective study of psychological factors in ulcerative colitis in children. Lancet 1965;   85:   22�24. 
Levenstein S, Prantera C, Varvo V, Scribano ML, Andreoli A, Luzi C, Arc� M, Berto E, Milite G, Marcheggiano A. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 2000; 95: 1213-1220 [PMID: 10811330 DOI: 10.1111/j.1572-0241.2000.02012.x
Bitton A, Dobkin PL, Edwardes MD, Sewitch MJ, Meddings JB, Rawal S, Cohen A, Vermeire S, Dufresne L, Franchimont D, Wild GE. Predicting relapse in Crohn�s disease: a biopsychosocial model. Gut 2008; 57: 1386-1392 [PMID: 18390994 DOI: 10.1136/ gut.2007.134817]
Maunder RG. Evidence that stress contributes to inflammatory bowel disease: evaluation, synthesis, and future directions. Inflamm Bowel Dis. 2005;11:600�8. 
 Mawdsley JE, Rampton DS. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut. 2005;54:1481�91.
Mawdsley JE, Rampton DS. The role of psychological stress in inflammatory bowel disease. Neuro immunomodulation. 2006;13:327�36. 
Bitton A, Dobkin PL, Edwardes MD, Sewitch MJ, Meddings JB, Rawal S, Cohen A, Vermeire S, Dufresne L, Franchimont D, Wild GE. Predicting relapse in Crohn's disease: a biopsychosocial model. Gut. 2008;57:1386�92. 
 Bitton A, Dobkin PL, Edwardes MD, et al. Predicting relapse in Crohn�s disease: A biopsychosocial model. Gut 2008;57:1386-92
Kaname S, Uchida S, Ogata E, Kurokawa K. Autocrine secretion of transforming growth factor-beta in cultured rat mesangial cells. Kidney Int 1992; 42: 1319-1327 [PMID: 1474764 DOI: 10.1038/ ki.1992.423]
Graff LA, Walker JR, Bernstein CN. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis 2009; 15: 1105-1118 [PMID: 19161177 DOI: 10.1002/ibd.20873]
Ananthakrishnan AN, Long MD, Martin CF, Sandler RS, Kappelman MD. Sleep disturbance and risk of active disease in patients with Crohn�s disease and ulcerative colitis. Clin Gastroenterol Hepatol 2013; 11: 965-971 [PMID: 23376797 DOI: 10.1016/j.cgh.2013.01.021]
Vidal A, G�mez-Gil E, Sans M, Portella MJ, Salamero M, Piqu� JM, Pan�s J: Life events and inflammatory bowel disease relapse: a prospective study of patients enrolled in remission. Am J Gastroenterol 2006;  1 01:  7 75� 781.
Lerebours E, Gower-Rousseau C, Merle V, Brazier F, Debeugny S, Marti R, Salomez JL, Hellot MF, Dupas JL, Colombel JF, Cortot A, Benichou J: Stressful life events as a risk factor for inflammatory bowel disease onset: a population-based case-control study.
Camara RJ, Schoepfer AM, Pittet V, Begre S, von Kanel R. Mood and nonmood components of perceived stress and exacerbation of Crohn's disease. Inflamm Bowel Dis. 2011;17:2358�65
Bernstein CN, Singh S, Graff LA, Walker JR, Miller N, Cheang M. A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol 2010; 105: 1994-2002 [PMID: 20372115 DOI: 10.1038/ajg.2010.140]
Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: The role of environmental factors. Autoimmun Rev 2004;3:394-400.
Lerebours E, Gower-Rousseau C, Merle V, et al. Stressful life events as a risk factor for inflammatory bowel disease onset: A population- based case-control study. Am J Gastroenterol 2007;102:122-31..
S�derholm JD, Yang PC, Ceponis P, et al. Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 2002;123:1099-108.
Mazzon E, Sturniolo GC, Puzzolo D, Frisina N, Fries W. Effect of stress on the paracellular barrier in the rat ileum. Gut 2002;51:507-13.
Am J Gastroenterol 2007;  1 02:  1 22�131. 9 1 O�Sullivan M, O�Morain C: Nutrition in inflammatory bowel disease. Best Pract
Collins SM. Stress and the Gastrointestinal Tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance. Am J Physiol Gastrointest Liver Physiol 2001; 280: G315-G318 [PMID: 11171612]
Boye B, Lundin KE, Jantschek G, Leganger S, Mokleby K, Tangen T, Jantschek I, Pripp AH, Wojniusz S, Dahlstroem A, Rivenes AC, Benninghoven D, Hausken T, Roseth A, Kunzendorf S, Wilhelmsen I, Sharpe M, Blomhoff S, Malt UF, Jahnsen J. INSPIRE study: does stress management improve the course of inflammatory bowel disease and disease-specific quality of life in distressed patients with ulcerative colitis or Crohn�s disease? A randomized controlled trial. Inflamm Bowel Dis 2011; 17: 1863-1873 [PMID: 21287660 DOI: 10.1002/ibd.21575]
Goodhand JR, Greig FI, Koodun Y, McDermott A, Wahed M, Langmead L, Rampton DS. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective casematched observational study. Inflamm Bowel Dis. 2012; 18(7):1232�9. 
Timmer A, Preiss JC, Motschall E, R�cker G, Jantschek G, Moser G. Psychological interventions for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2011;16(2):CD006913.
Nehlsen-Cannarella SL, Nieman DC, Balk-Lamberton AJ, et al. The effects of moderate exercise training on immune response. Med Sci Sports Exerc 1991;23:64 �70. 
King AC, Taylor CB, Haskell WL, DeBurk RF. Influence of regular aerobic exercise on psychological health: A randomized controlled trial of healthy middle-aged adults. Health Psychol 1989;8:305�24.
Traeger-Mackinnon L. Current challenges and future expectations in exercise immunology: Back to the future. Med Sci Sports Exerc 1994;26:191� 4.
Brown JD. Staying fit and staying well: Physical fitness as a moderator of life stress. J PersSocPsychol 1991;60:555� 61.
S�rensen VZ, Olsen BG, Binder V. Life prospects and quality of life in patients with Crohn�s disease. Gut 1987;28:382�5.
Khalili H , Ananthakrishnan AN, , Konijeti GG, ,1  Liao X, Higuchi LM, Fuchs CS, Spiegelman D, Richter JM, Korzenik JR, Chan AT.Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses� Health Study cohorts. BMJ 2013; 347:12
Loudon CP, Corroll V, J Butcher J ,  Rawsthorne P, Bernstein CN. The Effects of Physical Exercise on Patients With Crohn�s Disease. Am. Coll. of Gastroenterology 1999; 94: 697-703
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&Fd�a$gdR�Sonnenberg A. Occupational distribution of inflammatory bowel disease among German employees. Gut 1990;31:1037�40.
d�Inca R, Mestriner C, Varnier M, et al. Effect of mild exercise on ilealCrohn�s Disease (CD) in remission. Gut 1996; 39(Suppl 3):A167.
Persson PG, Leijonmarck CE, Bernell O, Hellers G, Ahlbom A. Risk Indicators for Inflammatory Bowel Disease.Int J  Epidemiol 1993; 22:2:269.
Klein I, Reif S, Farbstein H, et al. Preillness non-dietary factors and habits in inflammatory bowel disease. Ital J GastroenterolHepatol1998;30:247�51
D�Inca R, Varnier M, Mestriner C, et al. Effect of moderate exercise onCrohn�s disease patients in remission. Ital J Gastroenterol Hepatol 1999;31:205�10.


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