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27-10-2016Academy Laureates
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Antibacterial Development Conference

Executive Summary

Crohn’s Disease (CD) is a devastating illness in search of a cause and a cure. More than 800,000 people in North America suffer from CD, a gastrointestinal disorder characterized by severe abdominal pain, diarrhea, bleeding, bowel obstruction, and a variety of systemic symptoms that can impede the ability to lead a normal life during chronic episodes that span months to years. Researchers and clinicians agree that onset of CD requires a series of events; implicated are certain inherited genetic traits, an environmental stimulus, and an overzealous immune and inflammatory response. The combination of these factors contributes to a disease whose course is variable among patients and whose symptoms range from mild to devastating on any given day. The economic and social impact of this disease is substantial for the patient, the family, the community, and the healthcare system.

Long considered an autoimmune and chronic inflammatory disorder, current CD therapies are designed to treat symptoms of overactive inflammation in the gut. Chronic inflammation, however, does not generally induce itself. Inflammation is normally caused by a “foreign body,” an inanimate object (i.e., splinter) or animate objects like rogue cells (i.e., cancer) or microorganisms (i.e., bacterium, virus, or fungus). Until the cause of inflammation is eliminated, the body continues to send in its clean-up crew, the white blood cells of inflammation whose job it is to expel the tissue invader. Inflammation only subsides when the causative agent is finally banished.

There is suspicion, supported by reports of genetic inability to interact appropriately with certain bacteria or bacterial products in some patients, that CD may have a currently unrecognized infectious origin, perhaps environmentally derived. That CD is a set of wide-ranging symptoms, more like a syndrome than a specific disease, suggests that if its origin is microbial, more than one etiologic agent may ultimately be identified. Bacterial suspects at the moment include a Mycobacterium and a variant of the normal bacterial flora of the gut, Escherichia coli. The possibility of more than one infectious cause that leads to a similar set of symptoms confounds the research agenda to find both a cause and a cure for CD.

One acknowledged potential microbial agent of CD is Mycobacterium avium subspecies paratuberculosis (MAP), a microorganism that causes a gastrointestinal disease similar to CD in ruminants, including dairy cattle, called Johne’s disease (or paratuberculosis). People with CD have 7:1 odds of having a documented presence of MAP in blood or gut tissues than those who do not have CD, thus the association of MAP and CD is no longer in question (see Figure 1, page 11). The critical issue today is not whether MAP is associated with CD, but whether MAP causes CD or is only incidentally present, not an inciter or participant in the disease process.

If MAP is involved in the disease process of CD or other gastrointestinal disorders, then we need to determine how people are exposed to this microorganism, how to prevent that exposure, and how to treat the infection.

Despite its prevalence in the U.S. population in numbers that exceed most cancers, CD is not a focus of research attention in the same way as these other feared diseases. The American Academy of Microbiology convened a colloquium with experts in medicine, microbiology, veterinary pathology, epidemiology, infectious diseases, and food safety to describe the state of knowledge about the relationship between MAP and CD and to make recommendations for effective research that will move the field forward.

The general consensus of the assembled experts was that there are certainly reasons to suspect a role for MAP in CD:

  • MAP persists in contaminated soil and water, which links the environmental factor of CD to the disease.
  • MAP has a cell wall that contains muramyl dipeptide (MDP). One genetic trait that is affiliated in certain patients with CD is the NOD2 gene, which regulates ability to respond appropriately to MDP, thus the link between the genetic trait and MAP, or other bacteria.
  • MAP causes Johne’s disease, an illness of cattle and other ruminants that has many similarities with CD. The similarities of MAP disease in animals, for which the etiologic agent is known, and CD, for which the etiologic agent is unknown, provide a symptomatic link between agent and disease.
  • MAP can survive standard milk pasteurization processes and has been identified in off-the-shelf milk in retail grocery stores in the U.S. and the European Union (E.U.). There is increasing concern that MAP can also be found in cheese made from the milk of MAP-infected cattle and meat from Johne’s diseased animals. These observations could provide the exposure route of CD patients to MAP.
  • Treatment of some CD patients with antibiotics that have activity on certain other Mycobacteria, although not specifically selected for their activity against MAP, provides short-term or long-term relief or remission of symptoms.

Circumstantially, these observations appear to make a compelling case for MAP as involved in CD. On the other hand, the ability to definitively identify MAP as the cause of CD, or the cause of a significant number of CD cases, has been stymied by the elusive characteristics the organism itself, the lack of broadly available and validated clinical tools to easily and definitively identify MAP in accessible tissues, and the late symptomatic stage at which CD is finally diagnosed, where the origin of the destructive inflammation could have been years before the patient sought medical care. Most important, however, is the lack of resources, financial and scientific, to generate the tools that clinicians and patients need to determine whether MAP is involved in the disease process or not.

Several important clinical trials of antibiotics have been attempted in CD patients, with variable results. Treating CD patients with existing antibiotics with activity against other Mycobacteria (M. tuberculosis, which causes TB, and M. avium complex, or MAC, which is pathogenic in immune compromised persons) have either failed to provide relief (TB drugs) or produced promising outcomes for some patients, but not all (MAC drugs). Confounding these clinical results is the lack of information about which patients in the clinical trial population were actually infected with MAP, and whether any MAP organisms in infected patients were susceptible to the antibiotics used in the trials. Without sensitive and specific diagnostics that can detect early MAP infection, knowledge of how and where to isolate MAP for antibiotic susceptibility studies, and drugs that are known to be active against MAP itself, alone or in combination, the role of MAP in CD will remain circumstantial and the controversy over CD etiology will continue.

There is little known about where exactly viable MAP can be found in human tissues or, since most pathogenic Mycobacteria are intracellular, in which cells MAP can live and grow in humans. While the site of infection and tissue pathologies of MAP in animals can be assessed at necropsy, there is enough dissimilarity between digestive processes of ruminants and humans that this information may not necessarily inform studies in humans.

Of concern from a public health perspective is the ongoing presence of MAP disease in commercial livestock that supply the U.S. with dairy and meat products. If, in fact, CD is a zoonotic infection (one that is passed from animals to humans) and MAP is the (or one) cause of CD, then early identification of MAP disease in veterinary practice and appropriate management of these animals to safeguard the food supply will be critical to guard the public health.

Even in animals, it is nearly impossible to diagnose Johne’s disease in the early stages of disease. Diagnosis is by a combination of clinical observation (wasting and reductions in milk production in dairy cattle, for instance) and microbiological, histopathological, and immunological testing of Johne’s disease suspects. Although efforts to eliminate Johne’s disease and MAP from livestock herds are ongoing, the lack of an accurate and easily-administered diagnostic for early disease onset is hampering these efforts. The results are mixed, and food products containing MAP or MAP DNA can be found on supermarket shelves. Veterinary diagnostics that are sensitive (detect MAP at early stages of infection) and specific (identify MAP and not other microorganisms) will be necessary to eliminate Johne’s disease from the commercial food supply. Research to discover and validate these techniques may also shed light on diagnosis of human disease.

Colloquium participants agreed that research to elucidate the role of MAP in CD must address two major unknowns: (1) whether MAP from livestock and other animals is transmissible to humans and how it is transmitted and (2) whether humans are susceptible to infection and disease after exposure to MAP. No single study will fill all the gaps in our understanding of the possible relationship between MAP and CD. Furthermore, participants agreed that validated, reproducible biological markers confirming human MAP infection are desperately needed. If MAP can be causally associated with CD using reproducible analytical techniques, appropriate patient populations can be treated with antibiotics that are selected for their MAP activity. Then, at least MAP-infected CD patients will have both a cause and a cure.