The light of evolution points toward reconstitution of the biome as the only reasonable therapy for a wide range of immune-associated disorders, including allergy, autoimmunity and perhaps autism.

By William Parker, Duke University

It is now widely appreciated that humans did not evolve as a single species, but rather that humans and the microbiomes associated with us have co-evolved as a “super-organism”, and that our evolution as a species and the evolution of our associated microbiomes have always been intertwined. This co-evolution has biological consequences that are readily apparent. For example, decades of work with gnotobiotic (microbe-free) animals consistently demonstrate that the painstaking separation of a mammal from its associated microbiome results in an underdeveloped immune system that is a mere shadow of its naturally occurring counterpart.

The vital role of the microbiome in shaping the development of the immune system is, thankfully, becoming widely appreciated and the subject of more intensive inquiry. On the other hand, it is less well appreciated that, like the microbiome, a wide range of our fellow eukaryotes have co-evolved with us and have become intertwined with the development of our immune system. All mammalian species with the exception of humans in post-industrial societies and their domesticated animals co-exist with a wide range of intestinal worms, called helminths. Unfortunately, we are only now beginning to appreciate the consequences of our deceptively painless separation from these animals.

The co-evolution of helminths and the organisms they colonize can be traced back far deeper than the evolution of mammals, to the beginnings of immune systems. From this view, the immune system can be seen as having evolved as an interface with symbiotic organisms more so than as a defense against invading organisms, although defense against invading organisms was almost certainly a part of that interface. The co-evolution of helminths and their host’s immune systems has shaped the biology of both parties. Helminths have evolved to secrete dozens if not hundreds of molecules that exquisitely turn down the host immune system.  Mechanisms by which several of these helminth-derived immunosuppressive “drugs” function have been elucidated, and generally appear to be adapted for specific host species.  It is unreasonable to hope that host immune systems have not, in turn, adapted to the presence of helminths.  The idea that natural selection has left us dependent on the immunosuppressive  drugs produced by our evolutionary partners seems not only likely, but unavoidable.

The “hygiene hypothesis” was first proposed more than 20 years ago, and, having undergone an evolution of its own, is now more appropriately termed “The Lost Friends Theory” or “The Biome Depletion Theory”.  This theory, in its present form, describes the medical impact of separating us from our partners in co-evolution by means of widely appreciated medical care in combination with technology that we now take for granted, including running water and toilets. The Biome Depletion Theory embodies the central idea that epidemics of immune-related diseases associated with post-industrial society are due to a pathologically over-reactive immune response, which in turn is caused by a loss of components of our biome that normally interact with our immune system. These diseases include essentially all allergies and autoimmune disease, as well as appendicitis. The incidence of these diseases is staggering, with as much as 40% of the population suffering from allergies, 8% suffering from autoimmunity of some sort, and 6% undergoing appendectomy following inflammation of the appendix. Although components of the biome other than helminths may be important in this plague of diseases, a wide range of studies in rodents and emerging observations in humans demonstrate consistently that helminths are the component of the biome that is most missed by our immune system in post-industrial culture (Capron et al. 2004; Wilson and Maizels 2004; Fumagalli et al. 2009; Rook 2009).

The Depleted Biome Theory does not suppose that biome depletion is the single cause of allergies and autoimmune disease. Indeed, evidence is incontrovertible that such hyper-immune associated diseases are connected with genetic and epigenetic factors that predispose to disease as well as environmental “triggers” which initiate pathogenesis. The Biome Depletion Theory does, however, state that it is the change in the biome that is responsible for the epidemic nature (i.e. the increased incidence) of the disease. Unfortunately, failure to appreciate this distinction has been a source of confusion. The identification of genetic factors or a “trigger” (often a viral infection or some other environmental stimulus) does not invalidate the applicability of The Biome Depletion Theory to a particular disease. Rather, it is the incidence of a particular disease in post-industrial countries and in developing countries, in conjunction with the presence of an immune component of disease, which is indicative of the involvement of biome depletion in pathogenesis.

The potential complexity of the biological effects of biome depletion is staggering. Not only must the effects of biome depletion on a particular generation be considered, but the epigenetic effects on future generations may be profound. Further, the fact that biome depletion is not an all-or-nothing proposition adds vast complexity to the potential down-stream effects. Even more concerning is the obvious fact that the immune system and our biome did not evolve in isolation. Other organs, including our brain, were evolving at the same time, and are intertwined with our immune system in ways that are only beginning to be understood (Bilbo et al. 2005; Davis 2008). The implications are potentially far reaching. For example, the association of autism with inflammation (Ashwood et al. 2006; Braunschweig et al. 2008; Ashwood et al. 2009; Patterson 2009) and the epidemic nature of this disease in post-industrial societies (Becker 2007) point toward The Biome Depletion Theory. The identification of viral “triggers” which may be involved in autism (Lintas et al. 2010) is consistent with the idea that epidemics of autism (although, almost paradoxically, not autism, per se) are a result of biome depletion.

Although it may be impossibly difficult at the present time to sort out the potential effects of biome depletion, it has thus far proven surprisingly simple to restore the balance of nature for those suffering from biome depletion. Laboratory rodents, of course, were the first to benefit from such restoration, with a number of studies showing that colonization with helminths prevents adverse immune reactions associated with allergy and autoimmune disease (Capron et al. 2004; Wilson and Maizels 2004; Fumagalli et al. 2009; Rook 2009).  Studies in humans demonstrate that colonization with helminths provides an effective cure for many patients with inflammatory bowel disease that had proven untreatable with modern medicine (Summers et al. 2003). Even more exciting are data showing that the progression of multiple sclerosis is halted by helminth colonization (Correale and Farez 2007). Perhaps we should not be surprised.  Co-evolution can easily lead to co-dependency.

Although I take for granted the presence of a toilet in my house, it was only very recently, less than 100 year ago, that the toilet was imported to the United States. My father and all of my grandparents were born in houses with no indoor plumbing, although the concept of no toilet is foreign to me at my age of less than 50 years.  We seem to have forgotten that it was only a very few generations ago, at most, that our ancestors first acquired indoor plumbing and access to modern medicine, which effectively eliminate helminth reproduction. Connecting this recent history of hygiene with the epidemiology of disease, the evolution of our species, and the potential effects of epigenetics through time, it is possible to arrive at a remarkably simple conclusion that can account for a wide range of post-industrial disease: Biome depletion has left us with an overly reactive immune system. William of Ockham, the founder of Occam ’s razor, would approve. The frightening aspect of this conclusion is that we do not yet know if the effects of biome depletion have reached a climax. On the other hand, we can be reassured that biome reconstitution as a means of resolving the problems associated with biome depletion gives every indication of being quite feasible.

The idea of intentionally introducing organisms classified as parasites into the human population might seem, at first glance, repulsive. To some, hayfever seems a worthwhile price to pay for avoiding these co-evolutionary partners. Crohn’s disease and multiple sclerosis are certainly less tolerable, but therapies which usually alleviate the symptoms of these diseases at least to some extent are available. Despite the high costs of many pharmaceuticals, the general consensus may be that some disease can be tolerated as a side effect of being parasite free. This view, however, is undermined by two arguments. First, we do not yet know the extent of disease that must be tolerated in order to avoid our co-evolutionary partners. Certainly autism, if indeed it is associated with biome depletion, seems to cross over a reasonable line. This disease affects our very humanity…our cognition. The bottom line is that we are not at all certain of the price we are currently paying for biome depletion, and we are left in an uneasy “wait-and-see” position, not knowing what immune-associated epidemics are yet to come. Secondly, although helminth infections extract a horrible toll in developing countries, this price need not be paid by any post-industrial society that wishes to enjoy the benefits of colonization with helminths. In developing countries, one or more of the following three scenarios are necessary ingredients for morbidity and mortality associated with parasitic infection:

1. The presence of starving and malnourished populations.
2. The absence of water treatment facilities and sewer systems.
3. The presence of parasites that are not well adapted to the host (e.g. ones that hurt or harm a healthy host).

These three factors are simply not considerations in over-nourished, post-industrial societies. Individuals with pre-existing conditions that would be contraindications for helminth therapy (e.g. anemia or clotting abnormalities) are easily identified. Given a proper selection of helminths for colonization, uncontrolled infections are impossible in the face of modern sewer systems and water treatment facilities. Finally, adverse reactions can be readily reduced to far below acceptable levels by careful biomedical research in advance of widespread therapeutic application. After all, helminths represent a potential therapeutic that is readily reversible and that has been trained by hundreds of millions of years of natural selection not to encumber the host. No pharmaceutical company can boast that record for any drug. We have the luxury of selecting controlled colonization with helminths, not pathologic infection. The natural products are readily available and cost effective, with no need for expensive therapies. The technology and clinical implementation of the treatment should prove no more difficult than immunization during a routine visit to the doctor’s office, with follow-up visits to confirm immunity.

The learned thinking pattern for medical professionals and biomedical researchers is to envision isolation and characterization of the individual components produced by helminths, with the goal of creating new helminth-inspired drugs to treat disease. On the one hand, this approach is consistent with the general practice of modern medicine and the common approach used to find new drugs today. On the other hand, recapitulating the effects of an integral member or members of the biome using a single or even a handful of pharmaceuticals may prove extremely difficult.  Indeed, given the complex and continuous nature of the interactions between host and helminth that have evolved over hundreds of millions of years, the design of therapeutics to entirely and effectively recapitulate this interaction may prove impossible. In support of this idea, our laboratory, using a wild-caught rat versus laboratory rat model, has found that biome depletion potentially throws a wide range of parameters associated with cellular and humoral responses into disarray (Devalapalli et al. 2006; Lesher et al. 2006). Ongoing research in our lab using the same model indicates that biome depletion can affect the overall maturation of the immune system as well as the fundamental nature of both the adaptive and innate immune responses. Traditional paradigms associated with allergy and autoimmune disease (e.g. Th1 versus Th2 versus Th17) simply do not address this effect. We as immunologists are now faced with the unsettling realization that the immune system we have spent all of our effort and energy studying over in the past fifty years has turned out to be dramatically different than the system derived by natural selection. We find that “normal” is not helminth-free, and that our co-evolutionary partners must be included if we want to address the “normal” state of things. From a medical perspective, it is difficult to imagine that we will be able to restore the immune system to normal using a pharmaceutical that is directed at one cog in the immune apparatus, when in fact the entire apparatus is entirely out of sync with nature. Such an approach is tantamount to treating a despondent widow or widower with a topical ointment containing the recombinantly expressed MHC II complex of the absent partner. Pharmaceuticals do not effectively recapitulate biology derived by hundreds of millions of years of natural selection.

A synthesis of evolutionary biology, epidemiology, modern medicine, and immunology strongly suggests that biome reconstitution and maintenance should be a major thrust of the medicine of the future. Old paradigms of pharmaceuticals as a cure for immune-associated disorders are potentially as inferior to biome reconstitution as anti-cholesterol drugs are inferior to a healthy diet and adequate exercise. We cannot escape the biology imposed by our evolution, and the medical science of the future will take that fact fully into account.  At present, we need to direct intensive research toward biome reconstitution. The approach needs to be devised systematically rather than piecemeal. We need to know which organisms to utilize, and when and how to utilize them. We need to know the safety and efficacy of biome reconstitution for various conditions, including which hyper-immune conditions can be cured versus which can be prevented but not cured by biome reconstitution. We need to know the effects of biome reconstitution not only on one generation, but on subsequent generations. We must determine if new technologies are needed to reduce potential side effects of helminth colonization. In short, we need to know how to reconstitute our biome and keep that biome healthy. It is time for a paradigm shift in the enterprise of biomedical research and subsequently of medicine. Our evolution and our resulting biology require it.

References:

Ashwood, P., J. Schauer, I. N. Pessah, and J. V. de Water. 2009. Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. Journal of Neuroimmunology 208:130-135.

Ashwood, P., S. Wills, and J. Van De Water. 2006. The immune response in autism: a new frontier for autism research. Journal of Leukocyte Biology 80:1-15.

Becker, K. G. 2007. Autism, asthma, inflammation, and the hygiene hypothesis. Medical Hypotheses 69:731-740.

Bilbo, S. D., J. C. Biedenkapp, A. Der-Avakian, L. R. Watkins, J. W. Rudy, and S. F. Maier. 2005. Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. Journal of Neuroscience 25:8000-8009.

Braunschweig, D., P. Ashwood, P. Krakowiak, I. Hertz-Picciotto, R. Hansen, L. A. Croen, I. N. Pessah, and J. Van de Water. 2008. Autism: Maternally derived antibodies specific for fetal brain proteins. Neurotoxicology (Amsterdam) 29:226-231.

Capron, A., D. Dombrowicz, and M. Capron. 2004. Helminth infections and allergic diseases. Clinical Reviews in Allergy and Immunology 26:25-34.

Correale, J., and M. Farez. 2007. Association between parasite infection and immune responses in multiple sclerosis. Annals of Neurology 61:97-108.

Davis, M. M. 2008. A Prescription for Human Immunology. Immunity 29:835-838.

Devalapalli, A. P., A. Lesher, K. Shieh, J. S. Solow, M. L. Everett, A. S. Edala, P. Whitt, R. R. Long, N. Newton, and W. Parker. 2006. Increased Levels of IgE and Autoreactive, Polyreactive IgG in Wild Rodents: Implications for the Hygiene Hypothesis. Scandanavian Journal of Immunology 64:125-136.

Fumagalli, M., U. Pozzoli, R. Cagliani, G. P. Comi, S. Riva, M. Clerici, N. Bresolin, and M. Sironi. 2009. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 206:1395-1408.

Lesher, A., B. Li, P. Whitt, N. Newton, A. P. Devalapalli, K. Shieh, J. S. Solow, and W. Parker. 2006. Increased IL-4 Production and Attenuated Proliferative and Proinflammatory Responses of Splenocytes from Wild-Caught Rats (Rattus Norvegicus). Immunology and Cell Biology 84:374-382.

Lintas, C., L. Altieri, F. Lombardi, R. Sacco, and A. M. Persico. 2010. Association of autism with polyomavirus infection in postmortem brains. Journal of Neurovirology 16:141-149.

Patterson, P. H. 2009. Immune involvement in schizophrenia and autism: Etiology, pathology and animal models. Behavioural Brain Research 204:313-321.

Rook, G. A. W. 2009. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology 126:3-11.

Summers, R. W., D. E. Elliott, K. Qadir, J. F. Urban, Jr., R. Thompson, and J. V. Weinstock. 2003. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease.[see comment]. American Journal of Gastroenterology 98:2034-2041.

Wilson, M. S., and R. M. Maizels. 2004. Regulation of allergy and autoimmunity in helminth infection. Clinical Reviews in Allergy and Immunology 24:35-50.

William Parker, PhD.

Department of Surgery

Duke University Medical Center

DUMC Box 2605

Durham, NC 27710

Phone: 919-681-3886

E-mail: [email protected]