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Gilles R. G. Monif, M.D. | How MAP Becomes Crohn’s Disease

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How MAP Becomes Crohn’s Disease

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This opinion piece was initially published in the March 2016 edition of the International Association for Paratuberculosis newsletter. It is reprinted here with permission. The International Association for Paratuberculosis is a non-profit organization devoted to the advancement of knowledge and scientific achievement towards the eradication of paratuberculosis in domestic livestock and other species affected by Mycobacterium paratuberculosis. For more information, visit their website at www.paratuberculosis.net.


Dairyby Gilles R. G. Monif, M.D.

Any claim for causation of Crohn’s disease must address four key issues:

  1. Why the sudden onset of disease in the twentieth century;
  2. Why its epidemic spread;
  3. Why limited sites of involvement within the gastrointestinal tract; and
  4. Why the significant variability with respect to the age of onset.

An answer to each of these questions resided within the Hruska Postulate (1,2). The mechanisms by which Mycobacterium avium subspecies paratuberculosis (MAP) produces Johne’s disease in cattle and diarrhea in humans with advanced retro-virus infection and that by which it produces Crohn’s disease and possibly irritable bowel syndrome are significantly different.

The Hruska Postulate 
The Hruska Postulate states that Crohn’s disease is the consequence of the body’s fixed pro-inflammatory immune response when represented with MAP (1). Creation of a population at risk for the future development of Crohn’s disease and the induction of disease by MAP are said to occur through two synergistically functioning processes (1,2).

First, MAP must infect newborns within the first weeks of the neonatal period. At that time, a baby’s acquired immunity is largely absent. In terminating MAP’s replication, immune tolerance to MAP’s antigenic array is lost. Inherent immunity’s pro-inflammatory response to MAP becomes fixed within immunological memory (2). Every time the body’s immune system is re-challenged by MAP, it again responds by elaborating pro-inflammatory cytokines. The cytotoxic cytokines attack MAP at its sites of intestinal attachment and antigen processing.

Why the Sudden Appearance of Crohn’s Disease?
The answer resides in the superimposition of two events: MAP infection in the relative absence of gut acquired immunity and the widespread dissemination of MAP within a nation’s food supply. Documentation of the period of vulnerability for disease induction resides with well  documented studies demonstrating the protective effect of breastfeeding against the future  development of Crohn’s disease (3-8). In populations where breast feeding is an economical necessity, Crohn’s disease is rare (1,2).

Given the regenerative capacity of the gastrointestinal tract’s lining mucosa, occasional antigen challenges by MAP would be of limited significance. Frequent, closely spaced challenges are theorized to be requisites for mucosa denudement. Loss of this anatomical barrier allows the gastrointestinal microbiota access to the underlying tissues. As illustrated in the United States, the epidemic of Crohn’s disease in the general population appeared after widespread dissemination of MAP within a country’s milk producing herds.

Why the Epidemic Spread of Crohn’s Disease?
The epidemic expansion of Crohn’s disease is theorized to be the consequence of  recruitment of a population at risk by the use of MAP adulterated baby formula for early infant feeding (9-11). MAP is not neutralized by pasteurization. Milk, powdered milk, cheese, and infant formula have the potential to be adulterated by MAP (11-14). Progressive substitution of infant formula in lieu of breast feeding and its administration during the neonatal period are postulated to have created an expanding population at risk for the future development of Crohn’s disease. In 2005, 49% of 51 brands of baby formula manufactured by different producers in seven different countries were demonstrated to contain MAP DNA (9,10).  The widespread presence of MAP within the U.S. milk-based food supply is argued to be the catalyst that transforms the potential for Crohn’s disease into clinical disease.

Why Limited Sites of Tissue Disease within the Gastrointestinal Tract?
The predominant sites of cytokine-induced tissue destruction reside in those areas that achieve maximum fecal stasis. If Crohn’s disease was the product of an autoimmune process directed against the lining epithelium, the resultant histopathology would be widespread throughout the gastrointestinal tract.

Why the Variability in Onset of Disease?
Disease is the consequence of an inoculum size modified by the pathogen’s virulence that surmounts host immunity. The variability between the amount of MAP that establishes neonatal infection and the genetically determined capacity of host immunity modulates the intensity of the elicited pro-inflammatory response to MAP and hence the intensity of cytokine elaboration severity of clinical expression. The frequency of MAP is the other variable that determines age of onset. Given the absence of plausible alternate theories of causation, the Hruska Postulate becomes the template for breaking the cycle of events that fuel the global Crohn’s disease epidemic.

References

  1. Hruska K, Pavlik I, 2014. Crohn’s disease and related inflammatory diseases: from many single hypotheses to one ”superhypothesis”. Veterinarni Medicina, 59:583-630.
  2. Monif GRG, 2015. The Hruska Postulate of Crohn’s Disease. Med. Hypoth. doi:10.1016/j.mehy.2015.09. 019.
  3. Barclay AR, Russell RK, Wilson ML, Gilmour WH, Satsangi J, Wilson DC, 2009. Systemic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease. J. Pediat. 155:421-426.
  4. Bergstrand O, Hellers G, 1983. Breastfeeding during infancy in patients who later develop Crohn’s disease. Scand. J. Gastroenterol. 18:903-906.
  5. Hornell A, Lagstrom H, Lande B, Thorsdottri I, 2013. Breastfeeding, introduction of other foods affect on health a systematic literature review for the 5th Nordic Nutrition Recommendations. Food Nut Res., 57-61.
  6. Klement E, Cohen RV, Boxman J, Joseph A, Reif S, 2004. Breastfeeding and risk of inflammatory bowel disease: a systemic review with meta-analysis. Am J. Clin. Nutr. 80:1342-1352.
  7. Mikhailov TA, Fumer SE, 2009. Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children. World J. Gastroenterology 15:270-279.
  8. Ponsonby AL, Catto-Smith AG, Pezic A, Dupuis S, 2009. Association between early-life factors and risk of childhood onset of Crohn’s disease among Victorian children born 1983-1998: a cohort study. Inflam. Bowel Dis. 15:656-866.
  9. Hruska K, Baros M, Kralik P, Pavlik I, 2005. Mycobacterium avium subspecies paratuberculosis in powdered infant milk: paratuberculosis in cattle – the public health problem to be solved.  Veterinarni Medicina 50:327-335. 
  10. Hruska K, Slana J, Kralik P, Pavlik I, 2011. Mycobacterium avium subsp. paratuberculosis in powdered milk: F57 competitive real time PCR. Veterinarni Medicina 226-230.
  11. Donaghy JA, Johnston J, Rowe MT, 2011. Detection of Mycobacterium avium ssp. paratuberculosis in cheese, milk powder, and milk using IS900 and f57-based qPCR assays. J. Appl. Microbiol. 110:479-489.
  12. Grant IR, Ball HJ, Neill SD, Rowe MT, 2002. Incidence of Mycobacterium avium subspecies paratuberculosis in bulk raw and pasteurized milk from approved dairy processing establishments in the United Kingdom. Appl. Envir. Micriobiol. 68:2428-2435.
  13. Ellingson JL, Anderson JL, Koziczkowski JJ, Radcliff RP, Sloan SJ, Allen SE, Sullivan NM, 2005. Detection of viable Mycobacterium avium subspecies paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J. Food Prot. 68:966-972. 
  14. Clark DL, Anderson JL, Kozickowski JJ, Ellingson JLE, 2006. Detection of Mycobacterium avium subspecies paratuberculosis in cheese curds purchased in Wisconsin and Minnesota. Molecular Cell. Probes 2006; 20:197-202.

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