Understanding Crohn’s Disease
by Gilles R. G. Monif, M.D.
In medical terms, Crohn’s disease is a chronic granulomatous disease primarily affecting areas within the small bowel.
Crohn’s disease got its name in 1932 when an internist and pathologist described a new disease. Ultimately, the disease became known by the last name of the physician whose name was listed first in the scientific publication.
Inference by Similarity
In the late 1980s and early 1990s, struck by the similarity between Crohn’s disease in humans and a similar condition in cattle (Johne’s disease), the possibility of a shared etiology was entertained. Johne’s disease is caused by a mycobacterium, Mycobacterium avium subspecies paratuberculosis (MAP). Speculation that MAP could be casually related to Crohn’s disease in humans was aided by the knowledge that another bovine mycobacterium, Mycobacterium bovis, had bridged the abyss between domestic animals and humans and produced a chronic destructive disease of the small intestines.
Another mycobacterium, M. bovis, had infected humans by means of its presence in the milk from infected animals. Logic dictated that milk could again be the means by which another mycobacterium bridged the gap between domestic animals and humans. When some MAP infected cows were identified as having viable mycobacteria in their milk, the finding initially went underappreciated. The M. bovis threat to the public health had been aborted when it was demonstrated that pasteurization effectively destroyed M. bovis. When it was conclusively documented that pasteurization, even at temperatures bordering on the denaturation of milk proteins, did not destroy MAP’s infectivity, the first of many panic buttons was pressed. The subsequent demonstration that milk, powdered milk, infant formula and soft cheeses had the potential to contain a documented bovine pathogen had global alarms sounding.
The problem posed for the Food and Drug Administration (FDA) went beyond the Rio Declaration and the World Trade doctrines. The Federal Meat Inspection Act, the Poultry Production Inspection Act and the Federal Food, Drug and Cosmetic Act identify a food as being adulterated “if it contains or bears any deleterious substance which might render it injurious to health and is not neutralized by subsequent processing.” Under these statutes upheld by the Supreme Court, products that are adulterated cannot enter into commerce for food consumption. Confronted with the potential of a disruption of commerce, the FDA referred the issue to Congress.
Quest for an Answer
In 2000-2001, the United States Congress held hearings to determine whether MAP’s potential presence in milk and milk products constituted a hazard to the public welfare. Keeping with recommendations of the United Kingdom’s Food Agency’s recommendation that future decisions be based upon more information, Congress funded $90 million to do just that.
Prior to 2001, both the National Institutes of Health and the Centers for Disease Control and Prevention had expressed interest in exploring an infectious cause for Crohn’s disease. Despite their interest, Congress awarded to the United States Department of Agriculture (USDA) the stewardship of determining whether MAP, potentially embedded in milk and milk products, constituted a public health hazard. The USDA’s avowed mission is the support and promotion of U.S. agribusiness. The USDA chose to apply the money appropriated by Congress to reducing the economic loss from MAP in the production area. In the United States, the quest for the cause of Crohn’s disease and its associated epidemic spread went largely underfunded.
A quick fix to an uncomfortable problem is to study it. In 2002, the USDA instituted the five year Johne’s Disease Prevention Dairy Herd Demonstration Program to reduce the prevalence of MAP. The rationale put forward was that the problem should be dealt with within the production area. According to the USDA’s own figures, from 2001 through 2007, the number of herds containing MAP infected animals increased from 20-30% to 70%. In 2007, 31% of bulk tank milk contained MAP DNA. Today, it is highly probable that there is not a single large dairy herd without MAP-infected animals.
The Autoimmunity Paradigm
The theory of causation embraced by FDA was that Crohn’s disease was an autoimmune disease. Early therapeutic attempts at addressing the signs and symptoms of Crohn’s disease had revealed that, if one used compounds that impaired immune responsiveness, transient remissions of varying lengths could be achieved. The autoimmunity paradigm postulated that the host’s immune system turned against selected areas of its small bowel. The presumed antigen or antigens resided within the small bowel mucosa. As a vertical cut into the horizontal profile of Crohn’s disease, the autoimmune paradigm had apparent validity; but when obligated to explain important facts within the epidemiology of Crohn’s disease, the absence of plausible explanations was damning:
- Why the sudden appearance of a new disease?
- Why its epidemic spread among industrialized nations, but not in nations with third world economics?
- Why disease being limited to but selected areas within the small bowel?
- Why the protective effect of breast feeding against the future development of Crohn’s disease?
The uncontested opinion that a relationship existed between MAP and Crohn’s disease did not move governmental agencies to act in keeping with the precautionary approach to an apparent public health dilemma. When pushed away from the comfort area of Crohn’s disease being an autoimmune disease, the FDA countered by citing that the mycobacterium responsible for Johne’s disease in cattle and M. bovis enteritis in humans, and MAP disease in immunocompromised humans could be readily identified using special stains. This was not the case in Crohn’s disease. The backside of this argument was that, if MAP caused Crohn’s disease, it did so by a mechanism that differed from that of direct host-pathogen interactions.
The MAP Paradigm
Medical research conducted in the United Kingdom and Europe ultimately produced the bulk of incriminating evidence that substantiates a relationship between MAP and Crohn’s disease. MAP or MAP DNA could be demonstrated predominately in diseased small bowel tissue and in the blood of individuals afflicted with Crohn’s disease. The significance of these findings was conflicted by the presence of MAP or MAP DNA in the tissue and blood of a small number of control subjects. Such observations were becoming more frequent with the passage of time. The counter thesis presented was that the USDA, by not preventing the spread of MAP into uninfected herds and by allowing MAP infected animals to be transported across state lines and national borders, had created an unintended human experiment on a massive scale. MAP receptor sites line the entire small bowel. Given the currently growing prevalence of MAP within the human food chain, the probability of a given individual being infected or not infected became a function of diet and time.
The American Academy of Microbiologists stated in their 2008 report on MAP that “the association of MAP and CD (Crohn’s disease) is no longer in question. The unanswered question is whether MAP caused Crohn’s disease or is only incidentally present.” A governing principle within these doctrines of international law on food safety is reflected in the words “The importance of the precautionary measures should not be played down on the grounds that the risk is not proven.” Items to consider would be the dissemination of MAP in the world’s food supply, the protective effect of breast feeding, the frequent presence of MAP in infant formula and the near absence of Crohn’s disease in third world economies.
The FDA had been forced to impose warning labels on tobacco and tobacco products by, not conclusive evidence, but by the preponderance of evidence. Presumably to preclude being again put between a hard place and a rock, the agency auto-engendered an internal regulation whereby, for a substance to be identified as a potential public health hazard and to be so identified, the agreement needed to be conclusive. More simply stated, a single scientific publication expressing a conflicting opinion precluded the need to comply with the precautionary principle within international law. Indirectly, federal food safety acts confirmed this regulation when they were upheld by the United States Supreme Court. The collateral damage from not adhering to the precautionary principle is partially reflected in the numbers. In 1998, the number of Crohn’s disease afflicted individuals numbered 358,000. In 2006, this number was 560,000. In 2010, it was an estimated 800,000. In 2015, crude estimates place the figure above a million. If irritable bowel syndrome is conclusively proven to be a form fruste of Crohn’s disease, the prevailing number becomes four million.
The Hruska Postulate within the MAP Paradigm
Scientists, primarily Europeans, addressed the scientific flaws within the autoimmune paradigm. Karl Hruska and co-workers in the Czech Republic demonstrated the presence of MAP DNA in infant formula and powdered milk. In 2005, 49% of 51 brands of infant formula manufactured by 10 different producers in seven different countries contained MAP DNA. In 2011, Hruska proceeded to craft what would become the Hruska Postulate. The embedded theory would ultimately interlink into a unified theory of causation.
The 2015 expanded Hruska Postulate states that Crohn’s disease is the interaction of two immune responses to MAP occurring in different time frames. The first immunological interface with MAP creates the potential for disease; the second produces the disease. At birth, a baby’s immune system is comparable to that of a germ-free animal. If MAP infection occurs when its acquired immunity is incomplete, to arrest MAP’s continued replication, the baby’s inherent immunity becomes so challenged that its inflammatory response to MAP becomes fixed within immunological memory. Every time thereafter when present with MAP’s antigens, the immune system would respond as if it had never previous processed those antigens. The now intact immune system re-encounters MAP, it again attacks the organism’s antigenic array. The elicited cytotoxic cytokines would target MAP where it attached to intestinal mucosa and where its antigens were being processed. When MAP infection is acquired after the neonatal period, the immune system responds to re-exposure by exhibiting immune tolerance. A pro-inflammatory response to MAP is not elicited.
Neonatal MAP infection creates only the potential for subsequent development of disease. For Crohn’s disease to actually develop requires frequent and closely spaced dietary MAP antigen challenges. The magnitude and intensity of these cytokine assaults on MAP’s sites of mucosal attachments need to be such that they overwhelm the mucosa’s regenerative capacity. Once mucosal integrity has been breached, the bacteria within the gastrointestinal microbiota penetrate the underlying tissues and produce the second titer of Crohn’s disease.
To appropriate the mantle of validity, the Hruska Postulate of the MAP paradigm had to address the very questions that resulted in the discarding of the autoimmune paradigm:
Question: Why the sudden appearance of Crohn’s disease?
Answer: Prior to 1960, the presence of MAP in the human food chain was not sufficient to cause enough immune-mediated destruction to overwhelm the regenerative capacity of the small bowel mucosa in individuals that had experienced neonatal MAP infection.
Question: Why the current global epidemic of Crohn’s disease?
Answer: Substitution of adulterated infant formula for breast feeding within industrialized nations and the widespread dissemination of MAP in selected areas of the human food chain create a population at risk to develop Crohn’s disease. The expansion of MAP in the human food chain translated potential into disease.
Question: Why the relative absence of Crohn’s disease among nations with third world economies?
Answer: The reliance of breast feeding to provide infant nutrition.
Question: Why do only selective areas of the small bowl manifest with disease?
Answer: The sites of disease correlate with areas of maximum fecal stasis and concentration of MAP attachment.
Question: Why do biologics work?
Answer: Biologics abort or impede selected pro-inflammatory cytokines elicited by MAP challenges to the immune system.
Question: Why does anti-MAP therapy work?
Answer. Therapy directed against MAP destroys the template required for a pro-inflammatory response to MAP and/or its antigenic array.
Question: Theoretically, why doesn’t every neonatally MAP infected baby develop Crohn’s disease?
Answer: Variations in genetic makeup. Whether infection or disease ensues is determined by a simple equation: Amount of the organism times its virulence countered by host immunity. About one third of individuals afflicted with Crohn’s disease have a genetically predetermined susceptibility for develop disease. Evidence that irritable bowel syndrome is an incomplete expression (forme fruste) of Crohn’s disease suggests that a spectrum of possible outcomes following neonatal MAP infection exists.
Question: Can the Crohn’s disease epidemic be stopped?
Answer: Yes. The pathogenesis of Crohn’s disease, as defined in the Hruska Postulate, identifies the one simple step that the FDA can take to stem the ongoing epidemic. All that the FDA needs to do is make certain that infant formula used within the neonatal period is MAP free and advocate that women should breast feed their babies for the first four weeks of life.
A Lingering Why
Going against the then autoimmunity paradigm, Prof. Thomas Borody in Australia and Dr. William Chamberlin in the United States committed to a leap of faith. Without awaiting scientific delineation of mechanism by which MAP produced disease, they incorporated anti-MAP antimicrobial therapy into their respective treatment regimens for Crohn’s disease. To specifically target MAP ran contrary to what was then, and still is the standard of care for Crohn’s disease: biologics with or without antibiotics. They respectively were able to achieve more prolonged remission compared to what had been reported with other therapeutic regimens. In 2010, they published a meta-analysis of anti-MAP therapy for Crohn’s disease. The analysis substantiated their contention that anti-MAP therapy needed to be an integral part of treatment of Crohn’s disease.
The rational for incorporation of anti-MAP therapy seemed illogical. Anti-MAP therapy does not directly target cellular immunity. The majority of anti-MAP antimicrobials advocated are of limited efficacy against the majority of invading bacteria that cause the dysbiosis described in Crohn’s disease. The answer to why they have been able to achieve longer remissions is theorized to reside with the template theory of antibody production. For continued synthesis and release of target specific antibodies, the eliciting antigen must be present. Destruction of the template aborts continuation of the immune response. Rather than blocking the effects of cytotoxic cytokines or diminishing the amount of cytokines produced, anti-MAP therapy targets turning off the anti-MAP directed response.
Gilles R. G. Monif, M.D. is a former assistant dean at a United States medical school, a special consultant in infectious diseases to the American College of Obstetricians and Gynecologists, an Editor of the leading source book on Infection diseases in Obstetrics and Gynecology and has published over one hundred per reviewed articles dealing with infectious diseases.