Autoimmune conditions are the conventional practitioner’s burden and the integrative and functional medicine practitioner’s gift. I say this because conventional medicine effectively addresses the symptoms, but has little to offer in the way of reversing autoimmune disease. On the other hand, autoimmune diseases are a challenge, but a surmountable challenge, given the number of tools available to integrative and functional medicine practitioners. Common areas of analysis and treatment in autoimmune conditions are: the gut microbiome, intestinal permeability, celiac disease and food sensitivities, nutrition, stealth infections, and toxicity, to name a few.
The GI-MAP is a go-to test for your patients with autoimmune disease. Unlike other stool tests, the GI-MAP provides a unique view of gut microorganisms (or “bugs”) that could initiate autoimmune conditions. An autoimmune bug by itself may not be a serious threat to immune function if your patient has a strong gut barrier. That’s why you want information about the state of the intestinal barrier. Fecal zonulin* is an add-on test when ordering the GI-MAP and can be used as an adjunctive measure of intestinal permeability. Between microbes that can prompt autoimmune processes and a marker of intestinal permeability, this stool test helps you identify some of the top gut-related triggers of autoimmunity.
Begin with the Gut
You’ve heard it a million times, so why not one more time? “All disease begins in the gut,” a wise man named Hippocrates once said. In integrative and functional medicine, we also look to the gut first, especially when there is immune dysfunction. Stool testing is therefore a first step in trying to assess patients with autoimmune conditions such as Hashimoto’s thyroiditis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, multiple sclerosis, Parkinson’s disease, or lupus. If a patient with one or more of these conditions has a gut pathogen, microbial imbalance, poor digestion, gluten reactivity, or inflammation, then treatment is advisable. It can turn their health around and give them hope for the first time in years, or even decades.
The GI-MAP helps you zoom in on specific microbes that might be “confusing” the immune system. The stool test specifically measures potential autoimmune triggers, including Klebsiella pneumoniae, Mycobacterium avium subsp. paratuberculosis (MAP), cytomegalovirus (CMV), and Epstein-Barr Virus (EBV), among others (see Table 1 for a complete list). While the evidence supporting the role of these bugs in autoimmunity is not conclusive, it is suggestive. And since integrative and functional medicine practitioners would rather not wait 20 years until it is finally incorporated into routine medical practice, it is worth knowing about right now and it might be worth addressing in your patients suffering with autoimmunity.
Generally, the detection of these microbes in the stool is not by itself reason for alarm. Conventional medical sources would say they are normal in stool and don’t require treatment. They are thought to be harmless to the immunocompetent host and “contained” in the gut. However, we have a different viewpoint in integrative and functional medicine. In susceptible individuals who have moderate to high levels of these microbes, and certainly in a patient with an ongoing autoimmune process, these microbes might be a contributing factor. If the patient also has leaky gut, this adds to the potential for these microbes to cause extraintestinal infections or to kickstart an aberrant systemic immune response. Treatments to directly shift dysbiosis of autoimmune bugs include antimicrobial herbal formulas, high dose probiotics, and a diet that is conducive to a healthy microbiome (low-sugar, plant-based, and high-fiber diet, if tolerated by the patient). See more treatment recommendations in the GI-MAP interpretive guide.
A Perfect Storm
Dysbiosis of potentially autoimmune microbes together with high fecal zonulin* is a telltale pattern for an autoimmune process. When zonulin is high, it’s a sign that the tight junctions in the gut epithelium are wide open.2 If a patient has microbial dysbiosis with a high zonulin, it takes gut dysbiosis to a whole other level- a systemic level. Without that healthy gut barrier, microbes from the gut can get into the bloodstream where they don’t belong. Now you have a situation where dysbiotic microbes, large food molecules, and inflammatory signals can penetrate the intestinal lining and gain access to the whole body. It’s bad news for the patient and could be the beginning of an autoimmune downward spiral.
This conjures up the theory of autoimmune pathogenesis that was so elegantly described by Alessio Fasano in his publications on zonulin, celiac disease, and intestinal permeability. Genetically susceptible people encounter an environmental trigger (wheat in his example, or an autoimmune microbe in my example) and if they develop intestinal permeability (or “leaky gut”), it sets off a domino effect which leads to immune dysregulation and even mistaken attack of self proteins.3 It is humbling to see the litany of autoimmune diseases that follow in the wake of celiac disease, which is the textbook case example of this phenomenon.2,4,5
Microbes as a Trigger of Autoimmunity
It has long been known that microbes from the gut or genito-urinary tract can initiate autoimmune disease. One example is reactive arthritis which can be brought on by genito-urinary infections with Proteus miribalis or Chlamydia6,7 or gastrointestinal infections with Salmonella, Shigella, Campylobacter, Yersinia,8,9 and Clostridium difficile. Parasites such as Strongyloides stercoralis, Giardia lamblia, Ascaris lumbricoides, and Cryptosporidium species can also lead to reactive arthritis.10,11 Reactive arthritis patients may display noninfectious urethritis, arthritis, and conjunctivitis a few weeks after a gastrointestinal infection. But symptoms affecting other systems are also common: musculoskeletal, skin and nails, eyes, genitourinary, gastrointestinal, and more.12
MAP has been implicated as a possible cause of Crohn’s disease and causes a similar condition in cattle (Johne’s disease). MAP has been detected both in blood and intestinal tissue of Crohn’s disease patients13 and it has been cultured from peripheral mononuclear cells in 50-100% of Crohn’s patients.14
A large body of evidence points to Klebsiella pneumoniae as the main microbial agent triggering or perpetuating ankylosing spondylitis, a chronic inflammatory arthritis affecting the sacroiliac joints and axial skeleton.15 Klebsiella pneumoniae antibodies are significantly elevated in patients with ankylosing spondylitis and Klebsiella bacteria have been isolated from the bowel of patients with active disease.16 25% of patients with Crohn’s disease were positive for Klebsiella in the large bowel and relapses of Crohn’s disease were associated with Klebsiella colitis.16
CMV has been implicated in the development of autoimmune diseases: systemic lupus erythematosus, systemic sclerosis, diabetes mellitus type 1, and rheumatoid arthritis. In some autoimmune conditions, such as lupus and systemic sclerosis, patients have far higher antibodies against CMV than healthy controls.17
EBV has a central role in the pathogenesis of systemic autoimmune diseases, specifically rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome.18 EBV has been suggested to increase the risk of developing multiple sclerosis17 and it might be a contributory factor in autoimmune thyroid disorders.19
Don’t Leave Home Without It
When you are confronting a challenging autoimmune condition, you want to be armed with a stool test that is not only sensitive and specific, but one that targets clinically relevant microbes. The GI-MAP helps you zoom in on microbes that may trigger or perpetuate autoimmune diseases. Since the gut is a strategic first place to look for immune dysregulation, a stool test that measures microbes that can trigger autoimmunity, together with gut permeability markers, is an essential in your clinical tool bag.
Table 1. Bacteria and Viruses as Potential Autoimmune Triggers.
|Citrobacter spp. and Citrobacter freundii||Rheumatoid arthritis|
|Klebsiella spp. and Klebsiella pneumoniae||Crohn’s disease, ulcerative colitis, ankylosing spondylitis, and other spondyloarthropathies (which include ankylosing spondylitis, arthritis associated with Crohn’s or ulcerative colitis, psoriatic arthritis, and reactive arthritis)|
|Mycobacterium avium subsp. paratuberculosis (MAP)||Rheumatoid arthritis, Crohn’s disease|
|Prevotella copri||Rheumatoid arthritis|
|Proteus spp.||Rheumatoid arthritis|
|Proteus mirabilis||Rheumatoid arthritis and spondyloarthropathies (listed above)|
|Yersinia enterocolitica||Grave’s disease, Hashimoto’s thyroiditis, reactive arthritis|
|Cytomegalovirus (CMV)||Systemic lupus erythematosus, systemic sclerosis, type 1 diabetes, rheumatoid arthritis|
|Epstein-Barr Virus (EBV)||Rheumatoid arthritis, lupus, Sjogren’s, multiple sclerosis, autoimmune thyroid disorders|
*A recent publication1 has called into question the specificity of a commercially available assay for zonulin (or pre-haptoglobulin2). Instead, the Immunodiagnostik ELISA assay could be detecting related proteins from the “zonulin family.” Research findings showing increased zonulin by way of this assay should therefore be interpreted accordingly. Further studies are needed.
- Scheffler L, Crane A, Heyne H, et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Frontiers in endocrinology. 2018;9:22.
- Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25-33.
- Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nature clinical practice. 2005;2(9):416-422.
- Fasano A. Systemic autoimmune disorders in celiac disease. Current opinion in gastroenterology. 2006;22(6):674-679.
- Fasano A. Leaky gut and autoimmune diseases. Clinical reviews in allergy & immunology. 2012;42(1):71-78.
- Ebringer A, Rashid T. Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection. Clinical & developmental immunology. 2006;13(1):41-48.
- Ebringer A, Rashid T, Wilson C. Rheumatoid arthritis: proposal for the use of anti-microbial therapy in early cases. Scandinavian journal of rheumatology. 2003;32(1):2-11.
- Palazzi C, Olivieri I, D’Amico E, Pennese E, Petricca A. Management of reactive arthritis. Expert opinion on pharmacotherapy. 2004;5(1):61-70.
- Leirisalo-Repo M, Hannu T, Mattila L. Microbial factors in spondyloarthropathies: insights from population studies. Current opinion in rheumatology. 2003;15(4):408-412.
- Minerva P, Diamond HS. Enteropathic arthropathies. Drugs & Diseases 2014; http://emedicine.medscape.com/article/334746-overview#a0101. Accessed May 14, 2015.
- Ebringer A, Wilson C. HLA molecules, bacteria and autoimmunity. Journal of medical microbiology. 2000;49(4):305-311.
- Lozada CJ, Diamond HS. Reactive arthritis. Drugs & Diseases 2018; http://emedicine.medscape.com/article/331347-overview#aw2aab6b2b2. Accessed Oct 31, 2018.
- Qasem A, Naser SA. TNFalpha inhibitors exacerbate Mycobacterium paratuberculosis infection in tissue culture: a rationale for poor response of patients with Crohn’s disease to current approved therapy. BMJ Open Gastroenterol. 2018;5(1):e000216.
- McNees AL, Markesich D, Zayyani NR, Graham DY. Mycobacterium paratuberculosis as a cause of Crohn’s disease. Expert review of gastroenterology & hepatology. 2015;9(12):1523-1534.
- Puccetti A, Dolcino M, Tinazzi E, et al. Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are Present in Ankylosing Spondylitis. PLoS ONE. 2017;12(1):e0171073.
- Rashid T, Wilson C, Ebringer A. The link between ankylosing spondylitis, Crohn’s disease, Klebsiella, and starch consumption. Clinical & developmental immunology. 2013;2013:872632.
- Halenius A, Hengel H. Human cytomegalovirus and autoimmune disease. BioMed research international. 2014;2014:472978.
- Draborg AH, Duus K, Houen G. Epstein-Barr virus in systemic autoimmune diseases. Clinical & developmental immunology. 2013;2013:535738.
- Dittfeld A, Gwizdek K, Michalski M, Wojnicz R. A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders. Cent Eur J Immunol. 2016;41(3):297-301.