Environmental Risk and Protective Factors

Introduction

Although patients with inflammatory bowel disease (IBD) may have genetic predispositions to develop such diseases, this alone does not appear to be sufficient for the onset of inflammation. An important role for environmental factors in disease onset is suggested by higher incidence rates in industrialized countries as well as rising incidence rates in less developing countries. Environmental factors may also explain rural vs urban and latitudinal (i.e., north vs south) variations in IBD frequency. Although many environmental factors have been investigated as being contributory in the pathogenesis of ulcerative colitis (UC), few have been found to have well-defined influences. The most important environmental influences, such as tobacco smoking, appendectomy and microbial exposure will be discussed in this section.

Tobacco Smoking

Of the environmental factors, tobacco smoking has possibly the strongest association with IBD and paradoxically, is a significant risk factor for Crohn’s disease (CD) but is a protective factor for UC. While not completely understood, some have suggested this is due to changes of mucosal permeability and cytokine responses. Smoking, including early-life and second-hand exposure, is associated with approximately a 2-fold increase in the risk of developing CD. Smokers with CD also have more aggressive disease, earlier onset, higher disease recurrence, increased need for immunosuppression and increased need for surgery. In contrast, non-smokers are at approximately three times greater risk for developing UC compared to smokers (OR=2.9). However, ex-smokers are at approximately 1.7 times greater risk for developing UC than never-smokers and smoking cessation may lead to disease exacerbation. Furthermore, like active smoking in CD, ex-smokers with UC have a more aggressive disease course, require more frequent hospitalization and are twice as likely to require colectomy compared to never-smokers. As such, any protective effects of smoking in the context of UC benefit only active smokers. The benefits of active smoking in UC patients appear to be dose dependent and consistent across geographic regions. In addition to protecting against the onset of UC, active smoking is associated with a better disease course compared to never-smokers, reduced need for immunosuppressants, and is protective against colectomy, colorectal cancer, sclerosing cholangitis and pouchitis.

The relationship between active smoking and UC course and severity presents a clinical conundrum for treating physicians and gastroenterologists, since outside the context of UC, smoking cessation has overwhelming benefits, cardiovascular, oncologic and otherwise. However, given the debilitating nature of UC, the benefits of quitting smoking should be weighed against further exacerbating the disease. At the very least, the risks of smoking vs its protective benefits should be discussed with the patient. Unfortunately, nicotine replacement in UC does not appear to mimic the benefits of active smoking. Although the mechanism underlying the divergent effects of smoking on the two subtypes of IBD is not understood, the complex relationship suggests unique pathophysiological profiles for both UC and CD.

Appendectomy

While the etiology is unclear, appendectomy appears to confer protection against the development of UC, especially if performed before age 20 and particularly when surgery is done for inflammation of the appendix. In contrast, appendectomy is a risk factor for CD, reinforcing the uniqueness of these two inflammatory conditions. Appendectomy is estimated to reduce the risk of developing UC by 69% (OR=0.31). Furthermore, some data suggest that appendectomy may also reduce the rate of recurrence and need for immunosuppressive medications and colectomy, thus affecting the clinical course of UC.

Microbial Exposure: The Hygiene Hypothesis

Similar to asthma, rheumatoid arthritis and multiple sclerosis, IBD demonstrates an inverse relationship with degree of sanitation, that is, greater microbial exposure appears to protect against the development of IBD. Large family size, lack of running water, living on a farm, consumption of unpasteurized milk, and early exposure to pets are all associated with a reduced risk for IBD. Elevated infection rate due to overcrowding may also be protective. In contrast, higher socioeconomic status extends an increased risk for IBD. The mechanism by which sanitation affects disease onset is still uncertain, but one hypothesis is that it reduces exposure to certain key beneficial microbes, such as the firmicutes.

Specific types of infections have been investigated as being risk factors for development of IBD. Such pathogens have included Clostridioides difficile, salmonella, campylobacter, measles virus and cytomegalovirus. However, to date, no definitive causal link between them and IBD has been established.

Occupation

The prevalence of both UC and CD is higher among white-collar workers, such as those with managerial, clerical and sales positions, compared to those with blue-collar professions, such as farmers and construction workers. This has been proposed to be due to the outdoor, physically-demanding nature of blue-collar professions, which may protect against the development of IBD.

Weight

Adipose tissue, made up of connective tissue and adipocytes, has endocrine functions and is an important mediator of inflammation. Overweight or obese patients with UC experience higher rates of colectomy, an increased requirement for permanent ileostomy, longer hospital stays, higher rates of ileoanal pouch anastomosis and incisional hernia, increased inflammation of the colon, among other complications. Weight-related complications have also been observed in CD patients, including more rapid progression of disease and time to first surgical intervention compared to underweight patients.

Diet

Most studies which have evaluated the link between diet as a risk factor for the development of IBD have been inconclusive. However, there is some evidence that an elevated intake of refined carbohydrates can increase the risk for IBD. Newly diagnosed IBD patients are also observed to consume less fruit, dietary fiber and vegetables compared to healthy individuals. One population-based case-control study found that consumption of fast food at least two times a week was associated with an increased relative risk of 3.4 for CD and 3.9 for UC.

Other Environmental Factors

A variety of other environmental factors have been suggested in limited studies to be associated with an increased risk for UC, including urban living, a history of gastroenteritis, use of certain medications (including oral contraceptives, hormone replacement therapy and nonsteroidal anti-inflammatory drugs), disruptive sleep patterns, and stress, anxiety and depression. Although these have been suggested to be associated with the onset of UC in some studies, causality has not been established. Depression and anxiety have also been associated with more severe disease, a higher rate of surgery, decreased quality of life and decreased response to immunosuppressants. Breastfeeding, on the other hand, appears to decrease the risk for UC.