Paradigm Change in Disease Management?
David M. Brady, ND, DC, CCN, DACBN
The genesis of this article was a presentation delivered at the 2011 American Association of Naturopathic Physicians Annual Convention (Phoenix, Arizona) on the topic of autoimmune disease, which resulted in a substantial amount of inquiry and requests for further exploration of the topics presented. There is no doubt that the incidence of autoimmune disorders has been rising sharply over the past several decades in Western industrialized countries, particularly the United States.1 A broad array of disorders that are considered immune dysregulatory and autoimmune in nature are included in this phenomenon. Why has there been such a sharp rise in the incidence of these disorders?
The typical allopathic clinical approach to autoimmune disorders focuses on the management of symptoms with various anti-inflammatory medications and often the use of chemotherapeutics and very potent immunosuppressive agents with harsh potential adverse effects such as leukemia and lymphoma.2 Although these approaches can provide substantial symptomatic relief to the patient, they do not address the cause of these conditions, and some research indicates that these approaches may result in a furthering of the pathological process. However, modern research into the autoimmune phenomenon suggests that radically different approaches may be required to reverse the cited trends, including a strong emphasis on very early detection with predictive autoantibodies, a focus on optimizing gastrointestinal (GI) mucosal immune function and the microbiome, eradication of infectious agent triggers with antimicrobial therapy, and even the seemingly bizarre use of parasitic agents therapeutically. Some of these concepts have a long history in naturopathic and functional models of medicine but now are emerging as key areas of emphasis in allopathic medical research journals and investigative communities in the field of immunology.
The concept of molecular mimicry is a simple one, and it is attracting considerable research related to the genesis of autoimmune disorders. Simply stated, environmental exposure to specific antigens (including dietary peptides and those expressed by microbes) in genetically susceptible individuals can induce cross-reactions with structurally similar amino acid motifs associated with specific host tissues. Multitudes of associations have been firmly established between immune incompatibility with specific dietary-derived antigens, as well as the overgrowth of certain opportunistic and pathogenic GI bacteria, and the presence of specific autoimmune disorders (see Table 1).3-12 While some of these associations have been known for some time, mechanisms of causality are rapidly being elucidated in the research. However, patients with disorders such as rheumatoid arthritis, ankylosing spondylitis, and autoimmune thyroiditis (ie, Hashimoto disease or Graves disease) who visit a rheumatologist or an endocrinologist do not routinely have stool analysis of their GI microbiota or food sensitivity testing performed. This is ironic, particularly in the case of opportunistic microbial overgrowth in the gut, because the allopathic medical paradigm typically assumes an infectious cause. This is perhaps just another example of resistance to significant change in clinical approach within medicine, even in the face of compelling evidence to do so, because it would then require at least a passive admission that something so seemingly simple had been missed for so long.
While these associations may be interesting to researchers, what does this mean to a clinician? Some critics would argue that there is a lack of interventional data to suggest that eradication of these associated organisms or avoidance of these dietary antigens positively affects patient outcomes. This might be true in some instances, but it has been well established (eg, by Ebringer and colleagues6,7) that successful treatment of Proteus urinary tract infection clinically helps patients with rheumatoid arthritis, and dietary elimination of gluten-containing grains is accepted as the most viable intervention in celiac disease. One potential issue in play is that, by the time a patient is diagnosed as having autoimmune disease, substantial host-tissue damage often already exists. Perhaps the horse has already left the barn? However, what if potential triggers were routinely screened for and removed by healthcare providers, particularly in patients with a family history of autoimmune disorders? The entire course of the disease might be favorably altered, and many of these disorders might never emerge clinically. In the naturopathic medicine model, there is a strong emphasis on early detection and interventions that target the basis of pathogenesis and on underlying dysfunction of a disease process. Therefore, in these models the goal is to take clinical actions to reduce the potential for the disease process to progress. This seems to intuitively make sense even in patients who already have established disease. Although you may be unable to undo the damage already done, you can likely (if nothing else) slow down the train. This is particularly true because the interventions required pose little or no risk and are inexpensive, including probiotics, antimicrobial botanicals and volatile oils, mucosal-supporting nutrients and botanicals, and dietary modulation. Substantially improved molecular methods to assess the GI microbiota using polymerase chain reaction DNA analysis are available to clinicians at low cost, with rapid turnaround time.13
The Hygiene Hypothesis
The concept of the hygiene hypothesis is simple, with the complexity being in the details. The thought that we have induced dysregulation into our immune systems by virtue of living in too clean of an environment and have overeradicated infection is not new, but it has gained favor with researchers who have begun to work out exactly why this may be the case. Some of these concepts were elegantly addressed by Weiss14 in an editorial in The New England Journal of Medicine entitled “Eat Dirt: The Hygiene Hypothesis and Allergic Disease.” There is no doubt that modern public health measures such as adequate sewage systems, water treatment, the use of antibiotic agents, and various other aspects of hygiene have lessened deadly infectious outbreaks and have prevented unnecessary deaths. However, as with most topics, there is a yin and a yang. This “new clean world” has likely resulted in a lack of adequate sampling of our environment, including a lack of exposure to all the microbes with which we share our planet, particularly when we are young and our immune systems are developing the delicate balance between adequate defense and tolerance.15
The Role of Parasites
As reported by David Gutierrez16 in NaturalNews, researchers in a study conducted at the University of Nottingham (Nottingham, England) point out that humans and GI parasites might have coevolved in such a way that the parasites help regulate the human immune system to prevent allergies. They believe that over the course of millions of years GI parasites have evolved the ability to suppress the human immune system as a survival mechanism. Because parasitic infestation has been so common throughout human evolutionary history, the human immune system has in turn evolved to compensate for this effect. This means that if the parasites are removed the immune system may function too strongly, resulting in maladaptive immune responses such as asthma, allergies, and eczema.
With issues such as the hygiene hypothesis and the role of parasites in immune function in mind, colleagues of gastroenterologist and researcher Joel Weinstock, originally at the University of Iowa (Iowa City) and now at Tufts University (Boston, Massachusetts), have performed novel work among patients having inflammatory bowel disease (IBD).17 Before the 20th century, IBD was unheard of. The incidence of IBD at the beginning of the 20th century is thought to have been about 1 case per 10 000, and the incidence is now 1 case per 250. Similar data exist for the incidences of asthma, hay fever, diabetes mellitus, multiple sclerosis (MS), and other diseases. Weinstock and colleagues conducted various investigations among patients with IBD and treated them with the therapeutic parasite Trichuris suis, a porcine whipworm, which was an ideal choice because it remains viable in the human GI tract for only a short time and must be continually administered. When introduced into patients with IBD, the organism had the following effects: (1) it induced changes in regulatory T-cell function, (2) it blocked T-cell proliferation, (3) it altered cytokine production and expression of innate immunity, (4) it changed the intestinal flora, and (5) it generally caused a lessening of symptoms and severity of disease. Pharmaceutical agents are now being developed along these lines to treat IBD.
(Leaky Gut Syndrome)
For much of the past 20 years, leaky gut syndrome seemed to be something that only naturopathic and functional medicine physicians talked about, but not any longer! Prestigious researchers (eg, Fasano and Shea-Donohue18 at the University of Maryland, Baltimore) have been researching the role of intestinal permeability in the pathogenesis of autoimmune disorders and bringing this concept full speed to the allopathic medical research community through publications in top-tier immunology and gastroenterology journals. In a 2009 article in Scientific American, Fasano19 eloquently brought the topic to the lay audience with his article “Surprises From Celiac Disease,” in which he described how his theory that leaky gut syndrome contributes to celiac disease and autoimmunity was initially greeted with skepticism by his colleagues. Fasano has proposed that 3 factors must be present for autoimmune disease to manifest. He equates these to a triangle (or a 3-legged stool), whereby the disease cannot exist if any one of the factors is absent. The factors are (1) an environmental trigger (ie, antigen), (2) genetic susceptibility (ie, an HLA pattern that is particularly efficient at presenting the antigen to the immune cells such as the presence of the HLA-DQ2 and HLA-DQ2 pattern in celiac disease), and (3) intestinal hyperpermeability (ie, leaky gut syndrome). He opines that by far the easiest of these 3 factors to alter clinically is intestinal permeability. Much of his work, and of others researching this topic,20 involves the study and future therapeutic manipulation of a protein that alters intestinal permeability known as zonulin.
Fasano and Shea-Donohue best summarize the role of intestinal mucosal health and hyperpermeability in autoimmunity in their 2005 article with the following statement: “Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur.”18(p416)
Naturopathic physicians and other nutritionally minded healthcare providers have been addressing the issue of leaky gut syndrome for a long time with effective natural agents, including L-glutamine, N-acetylglucosamine, anti-inflammatory botanicals and bioflavonoids, mucilaginous herbs, zinc-carnosine, omega-3 fatty acids, and more. A popular nutrient that is used frequently as an immune modulator in autoimmune conditions is vitamin D. However, most clinicians are unaware of the direct role that vitamin D has in intestinal permeability. In their 2008 article “Novel Role of the Vitamin D Receptor in Maintaining the Integrity of the Intestinal Mucosal Barrier,” Kong et al wrote: “In vitro experiments demonstrate that VDR mediates the activity of 1,25(OH)2D3 that induces junction protein expression and strengthens the tight junction complex. These data are consistent with, and explain at least in part, the observation reported in the literature that vitamin D deficiency is linked to increased incidence of IBD in human population.”21(pG215)
Another possible role for vitamin D in the treatment of autoimmune disease, including MS, involves antimicrobial action. In addition to the findings by Harkiolaki et al9 about molecular mimicry induced by various GI bacteria in MS, researchers such as Charles Stratton and colleagues at Vanderbilt University (Nashville, Tennessee) have identified clear associations between MS and Chlamydia pneumoniae.22 Others, including Donald Gilden23 at the University of Colorado Health Sciences Center, Denver, have implicated various viral triggers in MS. It has been shown that the human cathelicidin antimicrobial peptide gene is a direct target of the vitamin D receptor and is strongly upregulated in myeloid cells by 1,25 dihydroxyvitamin D3.24 This means that as vitamin D levels rise so does the production of this endogenous antimicrobial peptide in the body, which may explain some of the clinical benefit observed with vitamin D therapy in MS
and other autoimmune disorders.
Predictive Autoantibody Testing (A True Preventive Medicine Application?)
In a 2007 article in Scientific American entitled “New Predictors of Disease,” Abner Louis Notkins states in the subtitle: “Molecules called predictive autoantibodies appear in blood years before people show symptoms of various disorders: tests that detected these molecules could warn of the need to take preventive action.”25 Some of these tests have been used for many years in a selective manner, often simply to confirm the presence of a disease that is strongly suspected by clinical presentation and examination. However, the development and availability of low-cost autoantibody arrays have ushered in the possibility to use autoantibody testing in a much more proactive screening strategy to predict the future emergence of autoimmune disorders so that preventive action can be initiated early to short-circuit the disease process.26 Table 2 on the previous page summarizes some of the available predictive autoantibody tests, their positive predictive value, and the number of years before clinical diagnosis when they generally appear in the blood samples of patients with specific disorders.27-29 As inexpensive tests for predictive autoantibodies continue to be developed, they could become part of a routine checkup, particularly in the preventive setting of naturopathic and functional medicine physicians.30
This article should assist the physician in developing a comprehensive conceptual framework in which to view autoimmune disease and in instituting a new proactive clinical model in which to evaluate patients. Physicians should look for immune dysregulatory conditions, with a strong emphasis on the following: (1) very early detection with predictive autoantibodies, (2) a focus on optimizing GI mucosal immune function and the microbiome, (3) the eradication of infectious triggers with antimicrobial therapy, (4) the detection and elimination of food sensitivities, and (5) the promotion of an anti-inflammatory lifestyle.
David M. Brady, ND, DC, CCN, DACBN is a Connecticut-licensed naturopathic medical physician, a doctor of chiropractic, and a certified clinical nutritionist. At the University of Bridgeport, Bridgeport, Connecticut, he is vice provost of the division of health sciences, director of the Human Nutrition Institute, and associate professor of clinical sciences. He is also chief medical officer for Designs for Health, Inc and practices at Whole Body Medicine in Trumbull, Connecticut, specializing in functional and nutritional medicine.
Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002;347(12):911-920.
Inaba M, Ushijim S, Hirata N, et al. Methotrexate-related lyphomatoid granulomatosis in a patient with rheumatoid arthritis [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2011;49(8):597-601.
Mayes MD. Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect. 1999;107(suppl 5):743-748.
Pishak OV. The colonization resistance of the mucous membrane of the large intestine in patients with rheumatoid arthritis in a period of exacerbation [in Ukrainian]. Mikrobiol Z. 1999;61(5):41-47.
Tiwana H, Wilson C, Walmsley RS, et al. Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn’s disease and ulcerative colitis. Rheumatol Int. 1997;17:11-16.
Ebringer A, Rahid T. Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection. Clin Dev Immunol. 2006;13(1):41-48.
Ebringer A, Rahid T, Wilson C. Rheumatoid arthritis: proposal for the use of anti-microbial therapy in early cases. Scand J Rheumatol. 2003;32:2-11.
Liao F, Li Z, Wang Y, Shi B, Gong Z, Cheng X. Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis. Med Hypotheses. 2009;72:732-735.
Harkiolaki M, Holmes SL, Svendsen P, et al. T-cell–mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity. 2009;30:348-357.
Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453(7195):620-625.
Petru G, Stunzner D, Lind P, et al. Antibodies to Yersinia enterocolitica in immunogenic thyroid diseases [in German]. Acta Med Austriaca. 1987;14(1):11-14.
Anasaldi N, Palmas T, Corrias A, et al. Autoimmune thyroid disease and celiac disease in children. J Pediatr Gastroenterol Nutr. 2003;37(1):63-66.
Brady DM. Novel options in gastrointestinal diagnostics: DNA detection of gut microbiota. Nutr Perspect. 2008;31(3):5J-7J.
Weiss ST. Eat dirt: the hygiene hypothesis and allergic disease. N Engl J Med. 2002;347(12):930-931.
von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol. 2010;10(12):861-868.
Gutierrez D. Parasites in your gut actually help protect you from allergies. NaturalNews. February 11, 2010. http://www.naturalnews.com/028141_parasites_allergies.html. Accessed November 3, 2011.
Summers RW, Elliott DE, Weinstock JV, et al. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol. 2003;98(9):2034-2041.
Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005;2(9):416-422.
Fasano A. Surprises from celiac disease. Sci Am. 2009;301(2):54-61.
Sapone A, de Magistris L, Pietzak M. Zonulin upregulation is associated with increased gut permeability in subjects with type I diabetes and their relatives. Diabetes. 2006;55(5):1443-1449.
Kong J, Zhang Z, Musch MW, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastro Liver Physiol. 2008;294:G208-G216.
Yao SY, Stratton CW, Mitchell WM. CSF oligoclonal bands in MS include antibodies against Chlamydophilia antigens. Neurology. 2001;56:1168-1176.
Gilden DH. Infectious causes of multiple sclerosis [published correction appears in Lancet Neurol. 2005;4(5):269]. Lancet Neurol. 2005;4(3):195-202.
Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-hihydroxyvitamin D3. FASEB J. 2005;19(9):1067-1077.
Notkins AL. New predictors of disease: molecules called predictive autoantibodies appear in the blood years before people show symptoms of various disorders: tests that detected these molecules could warn of the need to take preventive action. Sci Am. 2007;296(3):72-79.
Leslie D, Lipsky P, Notkins AL. Autoantibodies as predictors of disease. J Clin Invest. 2001;108:1417-1422.
O’Bryan T. Antibody array for the detection of autoimmune disease disorder associated with gluten sensitivity and celiac disease. Paper presented at: American College for Advancement in Medicine 2009 Annual Symposium (Autoimmune Disease: 21st Century Approaches); November 6-8, 2009; Las Vegas, NV.
Shoenfeld Y, Blank M, Abu-Shakra M, et al. The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases: 2008. Isr Med Assoc J. 2008;10:13-19.
Lindberg B, Ivarsson SA, Landin-Olsson M, Sundkvist G, Svanberg L, Lernmark A. Islet autoantibodies in cord blood from children who developed type I (insulin-dependent) diabetes mellitus before 15 years of age. Diabetologia. 1999;42:181-187.
Vojdani A. Antibodies as predictors of complex autoimmune diseases and cancer. Int J Immunopathol Pharmacol. 2008;21(3):553-566.