The most indisputable example of the influence of the environment on IBD is tobacco use, specifically, cigarette smoking. Smoking has a strikingly opposite effect on CD as compared to UC, supporting the notion that distinct mechanisms underlie the pathogenesis of each of these forms of IBD [27, 28]. Notably, UC patients are frequently nonsmokers, and furthermore, cessation of smoking increases the risk of developing UC. In fact, nicotine patches are currently being used to treat UC, supporting its protective role in this disease.

The role of passive smoking, particularly in children, as either a risk factor or protective factor for CD and/or UC is still a matter of controversy, with none of the studies having quantitatively assessed passive smoke exposure. The mechanisms underlying the differential effect of smoking in CD or UC are also obscure. However, smoking has been demonstrated to affect both systemic and mucosal immunity, as well as alter a wide range of both innate and adaptive immune functions [29]. For instance, smoking alters the ratio of T-helper to T-suppressor cells, reduces T cell proliferation, modulates apoptosis, and significantly decreases serum and mucosal immunoglobulin levels. In animal models, smoking reduces mucosal cytokine production and promotes adhesion of leukocytes to endothelial cells. Furthermore, it enhances small bowel permeability and colonic mucus production. Interestingly, transdermal nicotine shows some beneficial effect in patients with mild-to-moderate UC. On the other hand, nicotine may be detrimental in CD by contributing to the hypercoagulability state present in this condition. Taken together, these divergent effects of smoking in human IBD indicate a complex interaction between smoking and IBD [30]. In childhood IBD, a concerted effect should be made to study smoking exposure and the risks of IBD development, progression, as well as its interaction with an individual’s genes in determining the eventual outcome.

The search for specific infectious organisms as a cause of IBD has remained very attractive. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents thought to be responsible for CD or UC. Unfortunately, none of these initial reports have ever been reproduced. Several microorganisms have been proposed as having potential etiologic roles, such as Listeria monocytogenes, Chlamydia trachomatis, Escherichia coli, Cytomegalovirus, Saccharomyces cerevisiae, and others. Among those, the role of Mycobacterium avium paratuberculosis (MAP) in CD has been the center of major controversy. This bacterium is the causative agent of Johne’s disease, a chronic granulomatous ileitis in ruminants that closely resembles CD. MAP was initially isolated from a few CD tissues [31], but follow-up studies that tried to culture M. paratuberculosis looked for specific DNA sequences in intestinal samples, or measured serum antibodies against M. paratuberculosis yielding conflicting or inconclusive results. In addition, controlled trials have repeatedly failed to show a therapeutic effect of antituberculous therapy in CD patients [32]. Recently, however, there has been a renewed interest in MAP as a cause of CD following the isolation of MAP by PCR in milk sold in supermarkets in California and Wisconsin [33].

In addition to bacteria, a few have proposed a viral etiology as the cause of IBD and specifically for CD. The finding of paramyxovirus-like particles in CD endothelial granulomas has led to the suggestion that CD is a chronic vasculitis caused by the persistence of the measles virus in the mucosa [34]. In support of this hypothesis, an association between perinatal measles and predisposition to CD was also advanced based on some epidemiological and serologic data [35]. Despite these preliminary findings none were confirmed by later investigations [36].

Importantly, the progressive decline of measles virus infection in the last decades with the concomitant rise of CD during the same period of time, speaks largely against an etiologic role of measles in CD. The hypothesis that the measles vaccination, rather than measles infection, might be a risk factor for CD, has also been raised but again subsequent studies failed to confirm any association [37].

Over the past decade, there has been an exponential increase in interest about commensal bacteria as etiological agents of IBD. Based on fairly solid data, a substantial body of evidence has accumulated suggesting that the normal enteric flora plays a key role in the development of IBD [38]. In addition, the following clinical observations support this hypothesis: (1) that the beneficial effect of antibiotics in the treatment of CD, and to a lesser extent UC, has been appreciated for years; (2) diversion of the fecal stream from inflamed bowel loops has been known to induce symptomatic improvement in CD patients, while relapse often occurs upon restoration of intestinal continuity; and (3) pouchitis, a chronic inflammation of a surgically constructed ileo-anal pouch, develops in a considerable proportion of UC patients after proctocolectomy, and is associated with a dysbiosis caused by the contact of the once near sterile small bowel mucosa with a rich colon-like flora repopulating the pouch after surgery [39]. Furthermore, the more recent demonstration that probiotics (primarily lactic acid bacteria), defined as live microbial feeds, beneficially affect the host by modulating gut microbial balance, and improves both human IBD and experimental colitis, adds an important dimension to the role of gut flora in IBD. In addition, much larger numbers and concentrations of bacteria make up the biofilm covering the intestinal epithelium of IBD patients compared to the epithelium of healthy subjects [40]; and loss of immune tolerance against the autologous enteric aerobic and anaerobic flora has been reported [41]. Finally, and probably the most convincingly, is that, in the majority of animal models of IBD, intestinal inflammation fail to develop when they are kept in a germ-free environment [42]. Why there is an abnormal response to normal endogenous gut bacteria in IBD is not clear, but the recent discovery that CD is genetically associated with mutations of the NOD2 gene, whose products are bacteria-recognizing proteins, points to a link between gut inflammation and abnormal bacterial sensing [43]. Many other identified genes are also actively involved in regulating the interface between the intestinal epithelium and gut microorganisms. One model suggests a 3-step scenario in which bacteria penetrate the epithelial barrier, provoking a weak inflammatory response with impaired clearance in certain persons, which in turn causes chronic inflammation, culminating in IBD [44]. The relative importance of commensal organisms vs. intestinal pathogens in the initiation and/or relapse of IBD remains under debate.