Reaching out for the causative agent in inflammatory bowel disease: is there evidence for Chlamydia pneumoniae as a pathogenic factor?

Abstract

• The role of specific bacterial pathogens as causative agents in inflammatory bowel disease (IBD) has not been defined.
• Chlamydia pneumoniae seems not to play a role in the pathogenesis of IBD.
• The search for causative microorganisms should continue.

In this issue of the Journal, Muller and colleagues attempt to define the role of specific bacterial pathogens, particularly Chlamydia pneumoniae, as causative agents in inflammatory bowel disease. Even if a major role for C. pneumoniae in the pathogenesis of inflammatory bowel disease could be ruled out, our current understanding of inflammatory pathways in Crohn's disease and ulcerative colitis implies that the search for other microorganisms as causative agents should continue.

In a paper published in this issue of the Journal, Müller and colleagues attempt to define the role of specific bacterial pathogens, particularly Chlamydia pneumoniae, as causative agents in inflammatory bowel disease (IBD). At various times during the history of IBD, microorganisms have been suspected of being the cause of Crohn's disease and ulcerative colitis [^1–3]. Numerous pathogens, including the measles virus [⁴] and Mycobacterium paratuberculosis [⁵], have been advanced as co-factors, or even the causative agents of IBD, and are still under investigation. However, a definitive primary aetiological agent has yet to be identified in the disease. The current understanding of the pathogenesis of IBD is that it is multifactorial, with genetic and environmental factors predisposing the host to inappropriate T-cell activation and a loss of tolerance against enteric flora [⁶]. As the understanding of the inflammatory process in IBD progresses, there is also increasing interest in the interaction of proteins involved in bacterial antigen recognition, such as NOD2 and infective agents, or bacteria-derived antigens, acting as a persisting stimulus.

During the last decade, Chlamydia pneumoniae, an obligate, intracellular, Gram negative pathogen, has emerged as an important human bacterium involved not only in the pathogenesis of bronchitis and pneumonia, but also in the aetiology of atherosclerosis and autoimmune disorders such as multiple sclerosis [^7–9]. Various investigations considered C. pneumoniae as a potentially important pathogen in chronic, relapsing, autoimmune disease [¹⁰] and in the aetiology of IBD [^11,12]. So far, C. pneumoniae DNA has been identified in the intestinal mucosa of both IBD patients and healthy controls [¹²], making the role of C. pneumoniae as a causative agent in IBD unlikely. However, the objective of the present study by Müller et al. was to assess a possible relationship between IBD and chlamydial infection both by using DNA analysis of mucosal biopsies and by measuring anti-C. pneumoniae IgG titres in IBD patients with regard to the presence of NOD2/CARD15 gene mutations. The study found that there was no significant difference in the prevalence of anti-C. pneumoniae IgG antibodies between IBD patients, healthy family members and unrelated healthy controls, which is in line with the generally high infection rate during a person's life-time, with 50–70% of all adults exhibiting antibodies. In addition, no statistically significant differences in the presence of C. pneumoniae DNA in intestinal biopsies between IBD patients and healthy controls could be identified, supporting the previous results by Chen et al. [¹²]. Correlating the results with the CARD15 genotype, no association with a higher infection rate could be found. In summary, both studies could not provide any evidence for C. pneumoniae DNA as the direct causative agent in the aetiology of IBD.

However, even if the identification of the primary causative agent of IBD remains elusive after these investigations, the evolving molecular understanding of the interaction between genes, proteins, environmental factors and intestinal flora increasingly emphasizes the importance of intracellular bacteria in the regulation of mucosal immunity. The developing insight into the far-reaching immunological consequences of defective clearance of intracellular pathogens, based on genetic polymorphisms such as CARD15, still keeps alive the theory of microorganisms as causative agents. Further clinical and microbiological experiments will be needed to contribute further data to this unresolved debate. Consider, for instance, that in HIV, Helicobacter pylori or tuberculosis, Nature has followed surprising trails to keep its microbial secrets hidden. Nevertheless, human perseverance has unravelled some of them.