Inflammatory bowel disease (IBD) refers to a group of chronic inflammatory diseases that affect the gastrointestinal tract and includes ulcerative colitis (UC) and Crohn’s disease (CD). UC is restricted to the mucosa of the colon, whereas the lesions in CD are often discontinuous, occur across the entire wall of the organ (transmural), and involve any part of the gastrointestinal tract from mouth to anus. Infectious etiologies have been investigated since CD was first described in 1932. In their seminal paper, Oppenheimer, Ginzberg, and Crohn describe in detail the culture conditions they used to demonstrate that CD is neither intestinal tuberculosis nor a disease caused by bacterial pathogens [1]. Over the years, the search for infectious causes of IBD has continued and even dabbled in controversy. In 1993, before his foray into the antivaccine movement with studies claiming an association between the measles, mumps, and rubella (MMR) vaccine and autism, the gastroenterologist Andrew Wakefield published that measles virus particles could be found in tissue specimens from CD patients [2]. The results were never reproduced [3]. On the other hand, early life antibiotic usage has been associated with IBD, and somewhat paradoxically, antibiotics are sometimes used as adjunctive treatment in IBD, implicating bacteria in the disease [4]. It has now been over 80 years since CD was described, and the role of microbes in IBD remains unclear. While a single causative agent has remained elusive, the origin of IBD may be explained by an aberrant response to the community of microbes that reside in the gut, the microbiota. Other excellent reviews have articulated how shifts in bacterial communities occur and subsequently sustain IBD. However, this role for the microbiota does not preclude the possibility that specific infectious agents contribute to IBD as key members of the microbiota with a disproportionate effect akin to a pathogen, and nonbacterial agents have not received sufficient consideration. In this pearl, we review the myriad microbes that have been interrogated in patients and laboratory models for their roles in IBD pathogenesis, highlighting the central importance of understanding host–microbe interactions. Infectious triggers The existence of a pathogen trigger is intriguing because the intestinal pathology of IBD is similar to that which occurs during infection by Mycobacterium, Yersinia, Salmonella, Shigella, and Campylobacter species [5]. For instance, CD and intestinal tuberculosis share a predilection for the terminal ileum and the presence of granulomas by histopathology, and Mycobacterium avium paratuberculosis (MAP) causes Johne’s disease in ruminants, which bears a striking resemblance to CD. Multiple groups have tested thousands of IBD samples for MAP without reaching a definitive conclusion [6]. Rather than directly initiating IBD, pathogens may be responsible for exacerbating or sustaining disease. Clostridium difficile colonization and cytomegalovirus (CMV) reactivation are associated with IBD flares, though likely as a consequence of inflammation or medications. In addition to classical pathogens, commensal organisms with disease-causing potential, referred to as pathobionts, have received attention, including Bacteroides fragilis, Helicobacter hepaticus, and Enterococcus faecalis. In particular, adherent-invasive Escherichia coli (AIEC) isolated from ileal tissue of CD patients has received attention [7]. AIEC and other Enterobacteriaceae species utilize electron acceptors such as nitrate that are byproducts of the host inflammatory response, which can aggravate inflammation and cause specific disease manifestations, such as colorectal cancer [8, 9]. Targeting the respiratory pathways in pathobionts may be a reasonable intervention strategy [10]. The role of infectious agents may be to incapacitate host protective mechanisms, thereby lowering the threshold for subsequent inflammation to occur (Fig 1). Episodes of acute gastroenteritis, most commonly Salmonella and Campylobacter, precede the onset of IBD in some patients [11]. Interestingly, recurrent cycles of Salmonella infection and resolution in mice lead to chronic intestinal inflammation via loss of a protective mechanism of lipopolysaccharide detoxification [12]. Also, acute infection by the protozoan Toxoplasma gondii leads to a break in immune tolerance toward commensal bacteria by inducing the differentiation of microbiota-reactive T cells [13]. Thus, while IBD does not appear to be transmissible, intestinal microbes likely play active roles in inducing IBD. Open in a separate window Fig 1 Model for the role of microbes in IBD pathogenesis. Variable changes to the microbiome, whether by an infectious agent, emergence of a pathobiont, or loss of protective commensals, affect an individual who is susceptible via genetic risk alleles or environmental factors, including diet or lifestyle such as smoking. These episodes cause host responses to the enteric microbes (blue spikes) that over time eventually immobilize host protective mechanisms such that the threshold for intestinal inflammation (orange line) declines to the point of crossing the threshold for symptomatic clinical disease (dashed red line), thereby resulting in IBD. IBD, inflammatory bowel disease.
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Open Access
Mar 12, 2019
Kun Yang + 31
