In this edition of The Journal of Travel Medicine, Nair and colleagues report that a significant percentage of patients experience persistent gastrointestinal (GI) symptoms, specifically abdominal pain and change in bowel habits, following an episode of travelers' diarrhea (TD). What makes the Nair study unique is the pathogen-specific survey identifying the first direct evidence suggesting enterotoxigenic Escherichia coli (ETEC) as a trigger of post-TD functional abdominal symptoms. Equally important is the evaluation of a multitude of GI symptoms post-TD, rather than the more circumscribed syndrome of postinfectious irritable bowel syndrome (PI-IBS). The accumulation of such specific data on many and varied GI symptoms resists a common and limiting tendency to focus on a single disease diagnosis, such as that of PI-IBS. Instead, it allows us to look at a panoply of symptoms which may be directly related to a pathogenic microorganism, or which may be indirectly related, or even, perhaps, not related at all. The study also frames the challenges inherent in the attribution of disease causation for a subjectively defined illness with an often unidentified exposure.
One of the major challenges of such studies is accounting for the large number of individuals who have preexisting GI disease prior to their travels. For example, IBS affects up to 15% of individuals in industrialized countries, many of which may not have been previously diagnosed. Thus, in any evaluation of subjects with post-TD GI symptoms, a clear and accurate determination of the status of each subject's GI tract prior to travel and after the episode of TD is imperative. Was the subject truly symptom-free prior to travel? Even patients who report no previous history of IBS may, upon further or more directed questioning, report symptoms that, in fact, fall under the rubric of IBS. Furthermore, as there are no serologic or diagnostic tests for IBS, excluding IBS as a precondition may in fact be subjective and difficult. If the patient was, in fact, symptom-free prior to travel, another consideration would be whether he or she has an underlying GI disorder, such as celiac disease or inflammatory bowel disease (IBD), which may have been unmasked by an episode of infectious diarrhea, or has acquired a protozoal infection which may be the cause. The authors acknowledge the uncertainty of these factors as a limitation to their study. Indeed, further evaluation of such possibilities in subsequent studies would provide us with additional insights into the nature, incidence, and phenotypic expression of post-TD functional disorders.
This study represents the first in which ETEC, specifically heat-labile toxin ETEC (LT-ETEC), is implicated as an etiological trigger of chronic functional bowel disease. Among healthy travelers at 6 months follow-up, 18 of the 169 (11%) were noted to have had an LT-ETEC infection, whereas 13 of the 64 (20%) with a functional abdominal disorder at 6 months had an LT-ETEC TD episode (risk ratio 1.7, p = 0.0526). While the borderline association did not hold true for the other toxin phenotypes, this may be an important signal in that ETEC is the leading cause of TD and,[3, 4] thus, represents an important specific disease inducing exposure (not unlike Shigella spp. and Campylobacter jejuni) should this observation be confirmed in future studies. It is interesting that LT-ETEC and not heat-stable toxin ETEC (ST-ETEC) was found to be associated; an observation which draws scrutiny to the potential adverse effects of LT which may lead to pathogenic mechanisms of dysbiosis, barrier dysfunction, and/or aberrant immune response at the level of the gut. There is biological plausibility for such an effect given the polyfunctional effects of this toxin that have been described. In addition to secretory effects through induction of cAMP and chloride channel activation resulting in acute watery diarrhea, LT (and cholera toxin) has additional notable functions including gut barrier disruption,[6, 7] immune system activation, and abrogation of tolerance. As was elegantly detailed in a recent small animal model, it is possible that in humans who are host to a large and diverse population of commensal bacteria, LT-ETEC (and other infections) could induce loss of tolerance to commensals, and microbiota-specific T cells may be activated and differentiate into inflammatory effector and memory cells with responses that parallel antipathogen responses. Interestingly, an additional line of evidence which implicates ETEC and the potential importance of preventing the chronic sequelae associated with infection comes from a pilot phase 2 LT patch randomized, double-blind, placebo-controlled field trial among travelers to Mexico and Guatemala, where at 6-month follow-up of evaluable subjects, 0 of 8 subjects in the LT vaccine group who had diarrhea developed incident IBS, whereas 3 of 17 (17.6%) in the placebo group that developed diarrhea went on to have incident IBS (non-significant).[11, 12] While the follow-on phase 2 and 3 studies using the same LT patch vaccine failed to meet primary endpoints for efficacy against all-cause ETEC,[13, 14] the trials collected data on incident postinfectious functional bowel disorders at 6 months after returning from travel, and present an untapped opportunity to understand the potential expanded value of an ETEC vaccine in prevention of postinfectious functional bowel disorders. The investigators and sponsor of these trials are urged to fully explore and report on these data which have been collected and may contribute to important generalizable knowledge.
The Nair study also directs our attention to novel conceptual approaches in our thinking about TD and its sequelae. This is primarily because our view of TD has not changed appreciably in the 40 years since bacteria were first recognized as the predominant etiologic agents. Diarrhea attack rates for travelers remain at approximately 40% in those areas of the world where hygiene and sanitation are suboptimal. What has changed is the epidemiology of TD insofar as areas of the world that are considered high risk are now fewer than they were 40 years ago. Our concept of TD as one bug causing one disease treated by one drug needs to be reconsidered as we learn more about the contribution of the role of the microbiome in health and disease. Certainly when pathogenic bacteria such as Shigella, Salmonella, Campylobacter, and ETEC are isolated from those with acute diarrhea, treatment with appropriate antibiotics not only eradicates carriage of the microorganism but also results in symptomatic improvement, thus fulfilling Koch's postulates. However, what remains unexplained, is the fact that in at least 50% of cases of presumed bacterial diarrhea, no specific bacterial pathogen can be identified, and some individuals go on to develop postinfectious symptoms and not others. Perhaps, with the advent of more sensitive and specific high-throughput stool DNA analyses, these presumed pathogens will be identified. Another possibility, however, is that somehow the relationship between the microorganism and microbiome might be more complicated, leading to perturbations which cause GI symptoms.
Regardless of these acknowledged challenges in attributing chronic illness to acute infections, more effort is needed to explore mechanisms of acute infection and identify treatment strategies which might mitigate these postinfectious sequelae in travelers. Whatever the mechanism(s), the accumulation of evidence implicating acute enteric infection as a trigger of chronic functional disorders in susceptible individuals calls for a reemphasis on primary prevention of these infections, including development of TD vaccines, effective hand washing, and possibly a reconsideration of antimicrobial chemoprophylaxis. Furthermore, while this study lacked exploration of treatment effects on minimizing or enhancing risk of PI-IBS, questions remain as to whether early short course (eg, single dose) antimicrobial treatment, and/or concomitant use of probiotics, prebiotics, or synbiotics might mitigate the pathological effects of these infections and should be considered in well-controlled trials.