Understanding the Pathogenesis of Crohn's Disease and the Hruska Postulate

THE PATHOGENESIS of CROHN S DISEASE GILLES R. G. MONIF, MD

THE HRUSKA POSTULATE Med. Hypothesis 2015; 85:878-881. Crohn s disease is the consequence of two interdependent mechanisms created by Mycobacterium avium ss. paratuberculosis

To create the potential for the future development of Crohn Disease, MAP infection must occur in the relative absence of acquired immunity. To arrest MAP replication, inherent immunity is so challenged that the elicited pro-inflammatory response becomes fixed in immunological memory.

Re-challenges by MAPs antigenic array results in reissuance of a pro-inflammatory Cytokine cascade rather than conversion to a TH2 response. To arrest continued MAP replication, inherent immunity is so challenged that the elicited pro-inflammatory response become fixed within immunological memory and immunological tolerance is lost.

For targeted, immune mediated responsiveness to translate into disease, the intensity of MAP challenges must overwhelm the regenerative capacity of the gastrointestinal mucosa. Loss of mucosa integrity permits the gastrointestinal microbiota to insert additive mechanisms for tissue destruction.

Using the Plato vs. Socrates debate format, The essence of the Hruska Postulate that MAP is the cause of Crohn s diseases will be challenged and defended by two voices from the past: Robert Koch and Louis Pasteur.

ROBERT KOCH My position will be that MAP is NOT the cause of Crohn s disease. 1 - MAP disease in humans is basically limited to individuals with congenital or acquired immune system impairment. In these settings, MAP can be readily both cultured and demonstrated using special stains.

2- The gastrointestinal pathology of Johnes disease and Crohn s disease are NOT comparable! Mycobacterium receptor sites line the entire small bowel. MAP disease in herbivores and Mycobacterium bovis in humans involves the entire small intestines. NOT SO in Crohn s disease! In Crohn s disease, small bowel pathology involves primarily to the ileocecal area.

3-MAP DNA can occasionally be demonstrate in healthy small bowel specimens and in the WBCs of non-Crohn s disease afflicted individuals. 4- Given MAP s widespread presence within the U.S. food supply by MAP, it is more probable than not that the number of MAP infected individuals in the United States is between one and two hundred million. The corresponding number of individuals with Crohn s disease is less than1% of this figure.

5- Biologics and steroids enhance the pathogenicity of microbes whose replication containment is governed by cell-mediated immunity. If MAP was the causative agent of Crohn s disease, the disease process should deteriorate rather than ameliorate with such therapies. MAP is NOTthe cause of Crohn s disease! Respectfully, Robert Koch

LOUIS PASTEUR Your statements of facts are honored, but, not your interpretation. What you have documented is that, If MAP causes Crohn s disease, it does so by a different mechanism from that by which it produces disease in animals and immunocompromised human beings. Here are the arguments as to why MAP IS the CAUSEof Crohn s disease.

A - That MAP can neither be cultured nor demonstrated is because what primers identify as MAP DNA is MAP s spheroclastic form. Spheroclasts lack stainable cell walls and are not recoverable using standard culture technology.

B - Why is initial tissue destruction is relegated primarily to the ileocecal area? The ileocecal region is the site of maximum fecal stasis. Fecal stasis facilitates augmentation of MAP attachment. the magnitude of cytokine assault is proportional to the eliciting antigen mass.

C- With respect to MAP DNA, MAP DNA is predominately demonstrated in white blood cells and diseased small bowel tissue specimens taken from individuals afflicted with Crohn s disease, and exclusively in breast milk of women with Crohn s disease. Given the large number of individuals with active subclinical MAP infection at any given moment, the occasional demonstration of MAP DNA in WBC and in non-diseased small bowel is to be anticipated.

D- I agree that there is a numerical disconnect between individual who experience MAP as an infectious disease and those who experience it as an immune-mediated disease. E-Biologics and steroids work precisely because Crohn s disease is immune-mediated disease and NOT an infectious disease

HAVING ADDRESSED YOUR REASON, I WILL STATE MY CASE. Fact - Longitudinal epidemiologic studies have shown that MAP must become widespread in the milk-producing herds before Crohn s disease appears in the corresponding population. Fact - In the United States, the increase in the number of cases of Crohn s disease parallels the increase in the number of MAP infected dairy herds.

Fact - Domestic MAP infected animal can periodically shed MAP into their milk. Fact - Unlike M. bovis, MAP s viability in milk is not effectively destroyed by pasteurization. Fact - Viable MAP organisms have been demonstrated in pasteurized milk and milk-based infant formulas. Adulterated milk-based foods constitute the zoonotic bridge linking MAP-infected animals and humans.

WHAT THE HRUSKA POSTULATE FOCUSES ON IS NOT THE ABILITY OF MAP TO CROSS THE ZOONOTIC BRIDGE, BUT WHEN? Fact - For the first weeks of life, functional acquired immunity is basically ineffective. Fact Fetuses totally lack any acquired immunity. When acquired in utero, certain RNA viruses (i.e., rubella) and certain DNA viruses (i.e. the cytomegaloviruses) caused exaggerated systemic destruction; yet when acquired later in life, they produce little in the way of significant illness.

Fact The issue of incomplete acquired Immunity is addressed by the Herpes simplex viruses. Neonatal infection results in an exaggerated disease spectrum that sharply contrasts with what occurs when infection occurs months later. Fact Publications have overwhelming shown that breast feeding confers protection against the future development of Crohn s disease. Where an embedded control population existed, the progressive increase in the number of Crohn s disease occurring in the general population did not translate to that observed in the population that retained breast feeding.

ROBERT KOCH INTERESTING. Maybe even powerful; but, let me challenge you. Question: Why the appearance of a new disease? Answer: The failure to prevent MAP infected milk-producing animals from being transported across state and national boundaries that subsequently resulted in the widespread presence of MAP in milk and milk-based products.

Question: Why the Crohns disease epidemic? Answer: The progressive replacement of breast feeding by infant formulas that have the potential to contain viable MAP.

Question: Why the long delay between the creation of a dysfunctional immune response and development of disease? Answer: The ability of lining mucosa of the gastrointestinal tract to regenerate and the magnitude and frequency of MAP antigenic challenges required to achieve sustained mucosal denudement. Once the mucosal denudement is sustained, microbial invasion from the gastrointestinal microbiota becomes the second mechanism for added pathology. You now have an infectious disease (the anaerobic progression) layered upon an immune-mediated disease entity. That is why antibacterial therapy is needed at initiation of any therapeutic regimen to lessen residual morbidity caused by the anaerobic progression.

Question: Why the progressively earlier age of onset for Crohn s disease? Answer: Progressively greater penetration by MAP into the human food chain resulting in greater frequency and density of ensuing antigen challenges. Question: How do you explain the occasional occurrence of Crohn s disease in an individual who has never been breastfed? Answer: MAP is now pervasive in the water supply whose sources are rivers or lakes that abut to agriculture. Once introduced, MAP persists in biofilm.

Question: A newborn, lacking acquired immunity, becomes infected by a certified bovine pathogen, why don t some of them die with demonstrable disease being present? Answer: First, inherent immunity is intact. Secondly, compared to M. bovis, MAP is a pathogen of reduced virulence, Johne s disease takes months to years before manifesting. While MAP has no difficult crossing species barriers, it does so at a price: loss of virulence. In humans with intact immunity, MAP is of little identified significance. The hundreds of millions of theoretically infected humans stand as evidence of MAP s relative non-virulence for humans.

Question: Is Crohns disease curable? Answer: Absolutely! Destroy the template sustaining the dysfunctional immune response to environmental MAP challenges.

Question: And just how does one destroy the MAP template? Answer: By elimination of potentially MAP adulterated foods via adoption of a semi-vegetarian diet, dietary enhancement of cellular immunity, and administration of selected antimicrobial drugs whose primary mechanism of action disrupts ribosomal function within spheroclasts.

Question: Is there proof that antimycobacterium interventions work? Answer: Ask Thomas Borody, William Chamberlin and others who think outside of the box. Question: Why, in your opinion, is the Hurska Postulate so powerful? Answer: By identifying the events that combine to produce disease, the Hruska Postulate identifies 4 therapeutic intervention points.

1. Exclusion diets to decrease the frequency of antigen challenges 2. Immune nutritional supplementation to correct loss of elements central to host immunity 3. The need for antibacterial therapy that addresses both arms of the anaerobic progression as part of initial therapy 4. The target destruction of the MAP template that sustains the dysfunctional immune reaction

THE HRUSKA POSTULATE IS A GAME CHANGER! Crohn s disease had been considered a classic example of an autoimmune disease. The Hruska Postulate is a sword that impales the myth of autoimmunity by releasing from mind paralysis of the label of autoimmunity, other so-called autoimmune diseases (i.e. psoriasis, rheumatoid arthritis, Hashimoto s thyroiditis, Blau syndrome etc.).