The document summarizes research presented at the 10th International Colloquium on Paratuberculosis regarding the potential link between Mycobacterium avium subspecies paratuberculosis (MAP) infection and Crohn's disease in humans. While early research yielded conflicting results, more recent studies have found MAP DNA and viable bacteria in human tissues and blood. Genetic factors may influence susceptibility to MAP infection. Some studies suggest MAP is able to actively invade and persist in the human gastrointestinal tract. Certain drug therapies for Crohn's disease may inhibit MAP culture but not necessarily clear infection.

1. Is Map one of the causes of Crohn’s Disease? A review of papers from 10 th International Colloquium on Paratuberculosis Peter Mullowney

2. The Public Health Perspective Carol Nacy

6. Singh,(2009)

7. Singh,(2009)

9. Olsen, (2009)

10. Proliferation of T-cell clones from two different CD patients Olsen, (2009)

11. Cytokine production from T-cell clones in response to MAP Olsen, (2009)

17. Greenstein, (2009)

18. Greenstein, (2009)

19. Greenstein, (2009)

24. MAP in early onset CD 140 patients: 2 – 16 yrs age Prospective samples no medication Optimised DNA extraction Controlled, MAP specific PCR Long term culture for MAP (Kirkwood; Inflamm. Bowel Dis.2009) Bull, (2009) 0% 8% 16% PBMC PCR 0% 32% UC 0% 15% Non-IBD 40% 39% CD Biopsy Culture Biopsy PCR

30. MAP and HD5 HD5 expression is significantly reduced in the gut of CD patients. HD5 inhibits entry of MAP into human macrophage cell lines NOD2 mutation leads to HD5 depletion leads to MAP infection? Bull, (2009)

31. MAP Detection “ The association of MAP and Crohn’s disease, based on PCR or ELISA testing is well established” MAP +ve are 7 fold more likely in CD than Normals 10 – 40% presence of MAP in Non-STERILE and STERILE samples from Normals MAP is chronically and actively invading humans Bull, (2009)

32. MAP culture and VNC phenotype Viable Non-Culturable (lag) phase increases with repeated cycles of heat shock. Bull, (2009)

33. MAP culture and VNC phenotype MAP infection into human macrophages leads to Viable Non-Culturable (VNC) phenotype. Bull, (2009)

34. MAP culture and VNC phenotype MAP becomes Viable Non-Culturable (VNC) on intracellular entry Some Crohn’s Disease therapies are inhibitory to culture Immunotherapy (which aggravates MTB infection) does not promote MAP growth Negative MAP culture is NOT necessarily indicative of Negative MAP infection CD patients on some long term therapies may not be suitable for MAP culture studies Bull, (2009)

35. Summary MAP can and does Infect and persist in Crohn’s patients Respond to anti-MAP therapeutics in Crohn’s patients Exploit CD susceptibility gene defects to promote chronic persistence Generate a Th17 biased immune dysregulation that COULD lead to Crohn’s Disease Bull, (2009)

36. Verdict Viable chronic MAP infection is present in most patients with Crohn’s Disease MAP infection can cause the immune dysregulation that is the major predisposing factor to the development of Crohn’s Disease Bull, (2009)

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