Conclusions and Directions Forward

Although there are many recognizable similari­ties between paratuberculosis and Crohn’s dis­ease, several inconsistencies exist. There have been ~200 papers published on the potential aetiological role of MAP in the development of Crohn's disease since the first edition of this chapter.

Epidemiological research is limited by the many challenges involved in associating MAP exposure to disease outcomes, includ­ing its slow growth rate and the multifactorial nature of Crohn's disease. Although clusters of Crohn's disease have been described in the population, how these relate to MAP is un­certain. Future studies would benefit from implementing bacterial genotyping in order to establish a transmissible infection from the suggested source of exposure. Additionally, the majority of research investigating a rela­tionship between occupational exposure and disease development have not found an as­sociation with direct contact with livestock. However, the notion that occupational risk should be considered a defining point for es­tablishing an aetiological relationship is not consistently found in other types of intestinal infection. Therefore, whether this argument should play a significant role in evaluating this theory going forward should be considered. Studies seeking to detect MAP in humans have demonstrated a positive association between MAP and Crohn's disease as described by mul­tiple systematic reviews.

Key knowledge gaps exist in our under­standing of the immunology of MAP infection in humans, which limits our ability to determine its involvement in the development of Crohn's dis­ease. Recent research has broadly established the potential for a MAP-induced Th1∕Th17 immune response in humans. Future studies should aim to delineate the role of TNF-α as a host defence mechanism or as a response initiated by MAP to modulate the host immunity to promote its own infection. This may provide evidence to explain the counterintuitive host responses to Crohn's disease immunosuppressive therapies if MAP is implicated in disease aetiology. Additionally, many of the genes positively associated with dis­ease are involved in innate immune responses to intracellular bacterial infection such as with MAP. However, no relationship with MAP­positive status has been established with a num­ber of susceptibility genes. As research in this field has been primarily focused on searching for MAP, we may be overlooking other potential candidates, which involve similar host immune responses.

In addition to the need for further bench­level research, incoming data from the recently concluded RHB-104 phase III trial will be a key piece of information in determining how the elimination of MAP infection affects outcomes of Crohn's disease.

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