Crohn’s disease is a chronic inflammatory gastrointestinal disease that is characterized by diarrhea, abdominal pain, and a progressive course in the absence of therapy. In the 1930s, Crohn’s disease was a medical rarity. Today, Crohn’s disease has attained epidemic proportions, affecting between 1,000, 0000 – 1,200,000 individuals in the United States. Why has Crohn’s disease attained epidemic proportions within industrialized nations? A Why unanswered becomes four letter words.
Temporary remission of signs and symptomology of Crohn’s disease can be attained by a number of compounds that disrupt key elements of the inflammatory response. Why? Target-specific compounds termed biologics disrupt key components within the inflammatory response. By so doing, they produce closure of the diseased gastrointestinal mucosa. The remissions induced are contingent upon continued administration [1-3].
Crohn’s disease occurs in a specific area of the small bowel, the ileocecal area. This fact alone had put causation due to autoimmunity to rest. If the mucosa of the gastrointestinal tract were the target organ, location of disease would be markedly less restricted and not the entire small bowel. The question arises as to why, in the absence of prior surgery to remove diseased bowel, is this selective the selected site of disease?
The ability to prevent Crohn’s disease has long been known [1,4]. Retrospective analysis of risk factors for Crohn’s disease and prospective assessment of the progression of Crohn’s disease within nations and subpopulations have demonstrated that breast feeding markedly reduces the risk of the future development of Crohn’s disease:
Corrao G et al.  International Journal of Food Epidemiology 1998. Lack of breastfeeding was associated with an increased risk of UC and CD” (Crohn’s disease).
Klement E et al.  American Journal of Clinical Nutrition. American Journal of Clinical Nutrition. 2004.” … meta-analysis supports the hypothesis that breastfeeding is associated with lower risks of Crohn’s disease and ulcerative colitis.
Thompson NP et al.  European Journal of Gastroenterology & Hepatology. 2000. “…those with Crohn’s disease were more likely not to have breast-fed.
Shamir R  Journal of Pediatric Gastroenterology and Nutrition 2009 “Finally, nutrition may play a role in IBD via the protective effect of breastfeeding against UC and CD. …. The current evidence (meta-analysis) demonstrates a possible protective effect for breast milk in the early development of IBD.
This observation was buttressed by the rarity of Crohn’s disease in economically challenged populations [9,10]. The question is Why? The appearance of Crohn’s disease within relatively insulated populations not only substantiated the protective effect of breast feeding, but also provided a linkage to Mycobacterium avium subspecies paratuberculosis (MAP). Once Crohn’s disease began to appear within the general populations, subpopulations within Israel and the Czech Republic that retained breast feeding as the prime source of infant nutrition failed to exhibit a comparable incidence of Crohn’s disease [11,12]. In Iceland and The Czech Republic, MAP had to become widespread among the milk-producing herds before Crohn’s disease appeared in the general population.
In the 1990s, Chiodini  noted the similarities between Crohn’s disease and a chronic inflammatory gastrointestinal disease in cattle (John’s disease). He subsequently identified MAP as being almost exclusively in the feces of afflicted individuals. Another bovine pathogen, Mycobacterium bovis, had previously bridged the gap between humans and domestic animals using milk as the transport mechanism.
This threat to the public welfare was eliminated by the ability
of pasteurization to inactivate M. bovis. Even when subjected to
higher temperatures, MAP is not neutralized by pasteurization.
The 2001 United Kingdom Food Standard Agency Report
stated that “There is undoubtedly sufficient cause for concern
(relative to MAP being the cause of Crohn’s disease) for further
action to be urgently determined ...” Confronted with a possible
threat to the public health constituted by the presence of MAP
in pasteurized milk, infant formula, powdered milk, and related
milk products, the U.S. Congress gave the responsibility of
determining the validity of such a possibility to the Department
of Agriculture (USDA).
Naser and co-workers at the University of South Florida
isolated MAP from the breast milk of women with Crohn’s
disease and primarily, but not exclusively, from the blood of
afflicted individuals [14-16]. In the United Kingdom, Dr. John
Hermon-Taylor’s group subsequently enhanced the possibility
of a relationship between MAP and Crohn’s disease by
demonstrating the presence of MAP DNA in primarily diseased
tissue from individuals with Crohn’s disease [17-20]. By 2008,
the circumstantial case linking MAP and Crohn’s disease had
developed such that the American Academy of Microbiologists
stated that “the association of MAP and Crohn’s disease is no
longer in question. The critical issue today is whether MAP
causes Crohn’s disease or is incidentally present” .
The question of whether MAP infection caused Crohn’s
disease was crippled by four pertinent sets of data. When MAP
produces gastrointestinal disease in domestic animals and human
disease in immunocompromised individuals, MAP can be both
isolated and, using special stains, visually identified. Despite the
documented presence of MAP DNA, MAP can neither be isolated
nor demonstrated by special stains from diseased tissue. The
occasional identification of MAP DNA in non-diseased tissue or
in the white blood cells of health control subjects represented
a serious impediment to accepting causation. Finally, both
steroids and biologics that can induce temporary remissions
potentiate the pathogenicity of mycobacteria. If Crohn’s disease
is the consequence of MAP, the disease process would exacerbate
rather than ameliorate.
MAP receptors line the entire small bowel . Given the
current widespread presence of MAP in milk, infant formula,
cheeses and other milk-based products, it is more probable than
not that the vast majority of individuals within industrialized
nations have been infected by MAP. In 2007, the National Health
Monitoring System study of 515 dairy farms identified that
31.2% of the participating dairy farms had bulk tank milk that
tested positive for MAP DNA . The probability of human
MAP infection has become just a function of time and diet. The
disparity between the number of individuals presumed to have
been infected and the number of individuals afflicted with Crohn’s
disease supports the contention that MAP is a weak pathogen for
humans with intact immunity. The occasional demonstration of
MAP in normal gastrointestinal tissue reflects the prevalence of
MAP in the food supply. The rare presence of MAP in the blood
of a healthy individual identifies a person with recently acquired
That powdered milk and infant formula can be adulterated by
MAP is an established fact [24-29]. As early as 2005, 49% of 51
brands of baby formula manufactured by 10 different producers
in seven different countries were demonstrated to contain MAP
DNA . The significant presence of MAP in powdered milk
and infant formula answers the Whys? of 1. Why breastfeeding
conferred protection against the future development of Crohn’s
disease and 2. Why the epidemic spread of Crohn’s disease
gained a foundation.
Breastfeeding reduces potential exposure of a baby to MAP
within its period of incomplete acquired immunity. Aggressive
marketing of infant formula coupled with USDA’s failure to
prevent the spread of MAP infection among the nation’s milkproducing
animals have been instrumental in the creation of the
Crohn’s disease epidemics within industrialized nations.
The protective effect of breast-feeding focused analysis on
the neonatal period. What defines the immediate neonatal period
is the absence of gut derived acquired immunity. Congenital and
postpartum viral infections had documented the importance
of cell-mediated immunity in determining the consequences of
infection. If infection occurs in the absence of acquired immunity,
viral infections that produce minimal or no symptomology
or residual sequelae in individuals with complete immunity
(rubella and the cytomegaloviruses) now resulted in widespread
systemic disease and in organs of limited regenerative capacity,
permanent alteration of structure and function.
When a person first encounters a microbial organism, the
body’s immune system aggressively takes its inventory. When
the host is re-exposed to it, the immune system gives the bacteria
a pass from Th1 responsiveness. The absence or ineffective
acquired immunity makes aborting an organism’s replication
more difficult, particularly if the organism is a documented
pathogen. If the MAP challenge load is sufficient, the resident
inherent immune system may become so taxed, that in order
to suppress continuing MAP replication, its pro-inflammatory
attack response to MAP becomes fixed in immunological
memory. When again challenged by MAP, the body’s immune
system finds itself locked into a perpetuation of its initial proinflammatory
response against MAP. Upon re-exposure to MAP,
the now complete immune system’s response is still one of attack
rather than one of “so-what” (immunological antigen tolerance).
The Hruska Postulate argues that, in the absence of effective
acquired immunity, the immune system elaborates a cascade of
substances that attack MAP at its sites of attachment and antigen
processing . Disease is contingent on MAP antigen overload.
For the resultant immune-mediated mechanism to overcome
the regenerative capacity of the gastrointestinal mucosa, MAP
challenges need to be sufficiently repetitive and concentrated in
order to create a localized loss of mucosal integrity .
What is underappreciated is that the clinical spectrum of
Crohn’s disease is the composite of two inter-related disease
processes: an immune-mediated disease and an infectious
disease . Once focal mucosal integrity is lost, the intraluminal
gastrointestinal microbiota has sustained open access to
the lamina propria and submucosa. The invading gastrointestinal
microbiota creates a polymicrobial infection. The mechanisms
by which polymicrobial infections produce divergent patterns
of disease follow the dictates of the anaerobic progression.
Submucosa infection dominated by the Enterobacteriaceae
results in healing by fibrosis. If antibacterial therapy is not
comprehensive, bacteria whose spectrums of susceptibility are
not addressed will re-align themselves within the anaerobic
progression. As long as the gastrointestinal microbiota has open
portal access, antibiotic administration has the potential to
select for antibiotic resistance. Stricture formation, submucosal
fibrosis, loop-to-loop fistula, and bowel perforations are not
the consequence of the immune-mediated disease, but rather
documentation of infectious disease induced tissue damage.
Twenty-five percent of afflicted individuals developed fistula.
Using the Hruska Postulate, a number of the four- lettered
whys embedded in the natural history of Crohn’s disease become
a) Why the sudden appearance of a new disease: The
combination of neonatal MAP infection in the absence of
acquired immunity and widespread prevalence of MAP in a
nation’s food supply.
b) Why the long period between initial MAP infection and
disease: The regenerative capacity of the gastrointestinal
c) Why the initial localization of disease in the ileocecal
region: The ileocecal area is the site of maximum fecal stasis
thereby increasing the probability of MAP binding to its
complimentary intestinal binding site.
d) Why the efficacy of steroids and biologics to effect
temporary remissions through mucosal healing: Steroids
and biologics prevent the cytokines elaborated by the host’s
immune system from affecting their targets.
e) Why do biologics fail to achieve permanent remissions:
They do not destroy the immune template that sustains a
dysfunctional immune response.
f) Why do selected anti-MAP drugs produce apparently
sustained remissions and other anti-mycobacterium drugs
do not? Persisting in its spheroclastic form, MAP is the
template for the dysfunctional pro-inflammatory response.
To affect spheroclasts, drugs must disrupt ribosomal
function, Current anti-MAP therapy include compounds
impact on ribosomal function (
Why biologics can’t cure Crohn’s disease: Biologics fail
to destroy the immune template that sustains the dysfunction
pro-inflammatory response against MAP.
h) Why do only selected a limit number of antimycobacterial
drugs appear to induced sustained remissions:
The MAP DNA identified in disease tissue represents MAP
in its spheroclast form (an organism without its cell wall).
The absence of a cell wall is why MAP can’t be identified
with special stains Anti-mycobacterial compounds whose
mechanism of action is contingent on disruption of cell wall
synthesis have minimal efficacy. The anti-MAP regimens now
advocated include agents that that inhibit selected critical
internal cell functions within MAP spheroclasts.
i) Why have exclusion diets with targeted supplementation
produced rare, sustained remissions: Reduction of MAP
embedded in adulterated foods coupled with the upgrading
of host immunity.
j) Why is it not an ethical imperative to move therapy
beyond plication of disease to its cure; Why?