Last summer, two different boys, a ten-year-old and a seventeen-year-old, presented to my clinic with similar GI complaints. The families were unrelated and located in different areas, but both boys had symptoms of nausea, vomiting, and heartburn that were accompanied by poor reactions to certain foods.{class="lead"}

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## Case Histories

### Ten-Year-Old Boy

The ten-year-old boy experienced a two-year period of deteriorating health.  His hair was not growing well, and his nails had deep ridges that were almost deformed. His performance at school suffered so severely that he was pulled out of the regular classroom and instead received one-on-one education by tutors. While he’d once shined athletically, he was now so fatigued that running around the playground was difficult.

I performed a thorough patient history and discovered that his gastrointestinal symptoms had started immediately after a church picnic, where he’d eaten what may have been tainted potato salad. Other people who’d attended the picnic had also become sick, and his parents were able to date stamp his downward health spiral to the weekend of the picnic.

### Seventeen-Year-Old Boy

Before his illness, the seventeen-year-old boy was an active teenager who played quarterback for his high school’s football team. He presented with symptoms of reoccurring nausea, very painful heartburn, and occasional vomiting in the morning. His gastrointestinal complaints were so severe that he began avoiding food for fear that even his favorite foods would cause him pain.

He had become too ill to play football. That loss was catastrophic for him; he felt like the world was crashing down around him.

### GI-MAP Stool Testing Identified the Pathogen

I ordered a GI-MAP for both patients. In this instance and to my surprise, the test results showed that both boys were positive for the same pathogen - *H. pylori*.

When I shared the test results with the parents, both were amazed they finally had answers. They wanted to know why it had taken so long for a doctor to reach a diagnosis and why their regular pediatricians had not run a test like the GI-MAP.

## Personalized Treatment Protocols and Follow-Up Results

I personalized treatment for each patient. One boy’s parents opted for prescription treatment followed by GI repair protocols. The others chose to use the herbal treatment for *H. pylori* which I’ve recommended for years – Mastica, at a high dose for two months.

Both patients recovered dramatically within 60 days of treatment. The ten-year old’s mom was crying when she told me that he would return to his regular classroom in the Fall. His focus and concentration were back, and his hair and nails were growing normally. His stomach pain was gone entirely.

The seventeen-year-old quarterback had an even faster recovery - weeks not months. His only residual complaint was occasional heartburn after eating junk food or dairy.

## Final Thoughts

I find it particularly satisfying to resolve health complaints for children.  It’s been quite rewarding to get to know these two boys and their families. In both cases, other family members have come in for functional medicine testing.

The GI MAP’s ability to test using PCR technology gives me a clinical advantage when facing challenging cases. Practicing good quality functional medicine provides emotional rewards for me and my patients. Also, positive outcomes generate referrals, allowing me to grow my practice, and help those in need. To learn more about incorporating functional medicine in clinical practice, join me for my [1-Year Mentorship Program](https://courses.kalishinstitute.com/p/kalish-method-mentorship/?affcode=77790_pxsuunst) that educates clinicians about functional medicine and the value of functional testing.

The GI-MAP™ in Clinical Practice

The GI-MAP in Clinical Practice

Recent research indicates that T helper 17 (Th17) and regulatory T (Treg) cells are critical contributors to mucosal and systemic immune responses, especially within the gut.  Imbalances in Th17 and Treg responses are thought to contribute to autoimmune processes and chronic inflammation, as discussed in a recent review article.1 

Th17 cells normally function to promote inflammatory responses against extracellular bacteria and fungi. For example, in the normal, healthy gastrointestinal tract, Th17 cells not only help to protect against pathogens and opportunistic organisms, such as Candida, but also to help keep the normal resident (commensal) gut microbes in check. 

Treg cells have a critical role in restraining inflammatory responses and promoting immune tolerance to antigens from normally harmless sources such as food and commensal gut microbes. Th17 and Treg responses function together in a yin-yang-type manner to maintain homeostasis in the mucosal immune system.

Cytokines play a big role in the development of Th17 and Treg cells, as well as in their pro-inflammatory and anti-inflammatory roles, respectively.The presence of the pro-inflammatory cytokine IL-6, for example, promotes the production of Th17 cells, but its absence contributes to the production of Treg cells.

Cytokines produced by Th17 cells, including interleukin-17 (IL-17) causes other cells, such as macrophages, to release pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. In this way, Th17 cells contribute to a cascade of responses that characterize an inflammatory response.

Among the cytokines produced by Treg cells is IL-10, which inhibits the production of pro-inflammatory cytokines from several types of immune cells. It is thought that insufficient Treg responses, including IL-10 production, may enhance or prolong Th17 responses, contributing to a wide range of chronic inflammatory and autoimmune conditions, including Rheumatoid Arthritis, Inflammatory Bowel Disease, Multiple Sclerosis, and Psoriasis.

Assess pro-inflammatory and anti-inflammatory systemic immune balance, including TH17 and Treg cells, using the [CytoDx™ panel](/tests/cytodx-cytokine-response-profile).

The Role Th17 and Treg Cells Play in the Gut and Autoimmunity

As preventative health continues to be a primary focus, we continue to seek out ways to improve health through diet and lifestyle changes. At the same time, research continues to call our attention toward our gut and the microbes that reside within, as a primary influencer of our health.

Integrative and functional medicine clinicians are keenly aware of the importance of optimizing the microbiome of gut as a foundational step toward tackling nearly any health condition. With its immense contributions toward immunomodulation, inflammation, gene expression, neurotransmitter production, endocrine function, detoxification, and nutrient metabolism, the microbiome can easily become a tool in redirecting many biological processes toward homeostasis and health. We are also mindful of the fact that poor diet, chronic stress, age, disease, antibiotic use, and unhealthy lifestyle choices have wreaked havoc on the microbiome of many individuals. Therefore, dysbiosis, SIBO, and other microbiome disturbances seem to be the rule, rather than the exception.

While no two individuals will ever possess identical microbiomes, research has told us that healthy individuals possess greater amounts of specific types of bacteria that impart important health benefits. On the other hand, other species of microbes are associated with specific health problems as they alter our immunity, increase inflammation, and even turn on genes that may cause health problems in the future. If we can alter the balance of microbes in the gut to favor the health-promoting species, we can prevent chronic inflammatory and metabolic disorders that are common in developed nations. These conditions include cardiovascular disease, diabetes, cancer, gastrointestinal conditions, autoimmunity, mental health conditions, and chronic pain syndromes.

Short Chain Fatty Acids and Health
----------------------------------

More recent literature is focusing on the health benefits of bacterial phyla that produce short chain fatty acids (SCFAs) as byproducts of carbohydrate fermentation. SCFAs are common ligands to multiple receptors on a variety of cell and tissue types and are important signaling molecules between the gut microbiome and the host. They are also key regulators in human metabolism and more notably, vital contributors to maintaining healthy colonic epithelium and gut integrity. Formate, acetate, propionate, and butyrate are the chief SCFAs. Butyrate, particularly, is the preferred fuel of colonocytes, but all SCFAs help regulate the epithelial barrier by regulating tight junction proteins. Additionally, SCFAs play roles in glucose homeostasis, lipid metabolism, appetite regulation, immune function and inflammatory pathways.1

Microbiome diversity is key for maximizing the production of SCFAs. To date, most studies have focused on dietary interventions for reestablishing microbiome diversity and SCFA production. High-fiber diets are especially useful for rebuilding SCFA-producing microbes, but emerging studies have made yet another discovery. Diet may not be the only method of diversifying the microbiome to favor SCFA production. Exercise, alone, may alter the microbiome.

Exercise and the Microbiome
---------------------------

Exercise has long been recognized as an effective way to modulate human metabolism in various ways and improve health outcomes. The benefits of exercise are similar to those of altering the microbiome toward a more favorable composition of SCFA-producing microbes. So the question is raised, “Does exercise potentially exert its positive effects by altering the microbiome?”

Very few studies have sought to establish a direct link between exercise and the gut microbiome. One of the first of such studies looked at a group of Irish International rugby players during a pre-World Cup training camp in which dietary intake and physical activity were monitored. Researchers compared their activity level, body composition, creatine kinase, inflammatory cytokine markers, and composition of fecal microbiota with a control group of nonprofessional athletes of both high and low BMI. Professional rugby athletes had lower inflammatory cytokines, higher creatine kinase levels (corresponding to exercise intensity), and a significantly more diverse population of microbes in their gut. In fact, 22 different phyla of bacteria were identified in the professional athletes, but only 11 and 9 phyla were identified in average athletes with a low and high body mass index (BMI), respectively.2

Although it is possible to suggest that these differences could be due to the increased food intake of the professional athletes, researchers proposed many mechanisms by which intense physical activity could favorably alter the microbiome, independent of diet. Regular exercise suppresses pro-inflammatory cytokines and increases anti-inflammatory modulators. These effects have also been noted in intestinal lymphocytes of mice and may contribute to a reduction in oxidative insult in the gut, creating an environment that favors healthy microbes. Regular, moderate exercise also reduces stress-induced intestinal barrier dysfunction in the areas of permeability, mucous thickness, and bacterial translocation, all of which modulate the microbiome.

A similar study was conducted on rats who were divided into 3 activity groups: sedentary, forced exercise on a treadmill for 40 min/day, or voluntary access to a treadmill all day. After 6 weeks, fecal pellets and cecal content was evaluated using 16S rRNA gene sequencing for bacterial identification. Results showed that both forms of exercise altered the gut microbiome, but the changes were different based on activity level. Both groups altered the composition of bacterial phyla, but voluntary exercise yielded less bacterial richness compared to forced exercise, and yet, forced exercise produced greater clustering of bacterial colonies. This study gives evidence to the fact that exercise can alter the microbiome.3

Most data showing a relationship between exercise and gut microbiota have come from animal studies, but more recently, research is confirming these observations in humans, too. A recent study sought to observe the effect of exercise on composition, functional capacity, and metabolic output of the gut microbiota in lean and obese adults. Diet was controlled so the effects could not be associated with dietary changes that often accompany exercise. After 6 weeks of supervised, endurance-based exercise training (3 days/week) that progressed from 30 to 60 minutes/day and from moderate (60% of heart rate reserve) to vigorous intensity (75%), the diversity of gut bacteria had changed significantly. Further, the genetic expression of the bacteria changed so the bacteria produced more short-chain fatty acids, which reduces inflammation in the body and enhances metabolism. However, these changes were most notable among those who were lean, rather than the obese subjects, suggesting exercise can more favorably alter the microbiome in lean individuals. This study was unique in that the microbiome of all subjects was again evaluated 6 weeks after participants refrained from any exercise. The favorable changes originally induced by the exercise were completely obliterated. Favorable, exercise-induced changes in gut microbes appear to endure only as long as exercise continues.4

Obesity
-------

Exercise has long been recommended for losing weight, but burning calories and enhancing your metabolism may not be the only reason exercise promotes a better body composition. If we can validate the hypothesis that exercise, alone, can alter the gut microbiome to favor weight loss, it may be logical to infer that these changes are partially responsible for positive effects of exercise on obesity. In fact, fecal transplants from obese and lean rats have been used to change body composition in germ-free rats, further supporting this idea. It is already well-established that the microbiome of obese individuals contains a lesser variety of microbes compared to lean individuals and the microbes present do not positively impact metabolism, and instead, promote energy reservation and fat accumulation.

The ratio of _Bacteroidetes_ and _Firmicutes_, the two most common bacterial phyla in the gut microbiota, is directly associated with body composition. Obese individuals have significantly higher levels of _Firmicutes_ and lower levels of _Bacteroidetes_ compared to normal-weight and lean adults. Animal studies have confirmed that repeated exercise can increase _Bacteroidetes_ and decrease _Firmicutes_ which favorably alters the microbiome to support a healthier body composition.5 Furthermore, this change is independent of dietary patterns since it has been noted in both studies of rats consuming a standard diet, high-fat diet, or chow. Additionally, exercise (and high intensity interval training, specifically) induces genetic changes within the microbes to more efficiently use metabolic pathways such as the TCA cycle to help the microbes metabolize energy from food.[5](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935139/)

In another study, the gut microbiome of obese, hypertensive, and control rats were identified using 16S rRNA gene sequencing before and after a testing period during which the animals trained on a treadmill for 30 min per day, 5 days per week for 4 weeks. After the testing period, not only did the ratio of _Firmicutes_ to _Bacteroidetes_ improve as expected, but also the number of health-promoting microbes including _Streptococcus alactolyticus, Bifidobacterium animalis, Ruminococcus gnavus, Aggregatibacter pneumotropica and Bifidobacterium pseudolongum_ and other bacteria from the Pseudomonas and Lactobacillus families. Favorable microbial alterations were noted in all rat genotypes, though not all genotypes represented the same degree of microbial variations across all bacteria phyla.6 Overall, the changes in microbial diversity resulted in greater production of fermentation byproducts including butyrate, lactic acid, CO2, acetic acid and/or ethanol to maintain a more acidic environment conducive to digestion, gut epithelial health, and the exclusion of pathogens.

Establishing a healthy microbiome is vital for launching and maintaining good health. Emerging research is showing us that not only are dietary changes an effective means of altering the gut microbiome, but exercise also is an independent modifier. If exercise can help alter the diversity and the activity of health-promoting microbes in the gut, then it should be embraced as a critical aspect of a healthy lifestyle.

Altering the GI Microbiome with Exercise

#### Please Note: GI-MAP has been further enhanced since this post was published in 2018.

* Additional test information is available at: [GI-MAP™ Enhanced with New Bacterial Biomarkers](/webinars/new-gi-map-microbiome-markers-what-clinicians-need-know) (2019)
* Additional test information is available at: [The Industry's Leading Comprehensive Stool Test Just Got Better!](/webinars/gi-map-2022-update-test-overview) (2022)

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The Gastrointestinal Microbial Assay Plus (GI-MAP) is the first and only stool test in the world to be running full quantitative polymerase chain reaction (qPCR) on multiple GI targets, including pathogenic and opportunistic bacteria, worms, yeasts, parasites, and comprehensive antibiotic resistant genes, alongside intestinal health, digestive, and immune markers.

Not all pathogens cause disease if they are present. Knowing exactly how much of an organism is present, in combination with immune markers, gives the practitioner important information for better clinical decision-making.

The updated GI-MAP now includes 22 new markers:

* 5 additional *H. pylori* virulence factors (8 total)
* Epstein-Barr & Cytomegalovirus
* Phyla microbiota ratios
* 5 worm species
* Additional autoimmune and opportunistic bacteria

## Methodology Update: qPCR

Diagnostic Solutions Laboratory (DSL) uses a cutting-edge technology known as quantitative polymerase chain reaction (qPCR).

qPCR (or real-time polymerase chain reaction) combines amplification and detection into one step, and is one of the most powerful and sensitive gene analysis techniques available. It is used to quantify gene expression, analyze single nucleotide polymorphisms (SNPs), determine genotypes, detect pathogens, validate drug targets, and measure RNA interference.

The new GI-MAP gives practitioners quantitative information about *Giardia, Clostridium difficile, Salmonella*, and many more. The method measures the 16S and/or 23S ribosomal RNA (rRNA) regions and other target-specific genes to detect bacteria. It also measures virulence factors and viral targets (RNA).

### What is 16S and 23S?

The ribosome is an essential component of cellular organisms, with consistent form and function across species. A key aspect of ribosomes and ribosomal RNA is that their function is ‘highly conserved’ or maintained by natural selection between, and among, species. The exact sequences of DNA that encode these components are not identical between organisms, and so through variation in rRNA sequences we can distinguish organisms at the species level.

The 16S gene sequence is a highly conserved region of rRNA, which means it is not species, or strain specific, but it is a reliable genus marker.

Testing the 16S region for *H. pylori*, for example, will reliably pick up all *Helicobacter*, but only at the genus level. By targeting it both in the 16S and 23S region and testing for two other genes, ureA and ureB, the GI-MAP is able to accurately detect *H. pylori* present at the species, and strain level, as well as detect virulence factors. Similarly, Protozoa, as well as E. coli and C. difficile are very difficult to target in the 16S region, requiring other genes to be targeted in order to accurately detect them at the species and strain level.

## What Is qPCR & Why Is It So Exciting?

The advent of Polymerase Chain Reaction (PCR) for the first time facilitated the specific detection and production of large amounts of DNA. This allowed scientists to diagnose disease, clone and sequence genes and detect pathogens (Garibyan, 2013). Dr Kary Mullis, who discovered the assay in 1986, and won the Nobel Prize for his work, stated “it lets you pick the piece of DNA you’re interested in and have as much of it as you want” (Mullis, 1990). This is the process of amplification. PCR can be performed using source DNA from a range of tissues and organisms, including peripheral blood, skin, hair, saliva and microbes. It needs only trace amounts of DNA and hence is a sensitive assay.

### What does PCR require?

1. Strand of double-stranded template DNA that includes the target sequence
2. Primers - short single stranded DNA sequences that are complementary to a specific part of the target sequence. They can be thought of as 'genetic bookmarks'
3. dNTPs - these are the building blocks for the new DNA strands
4. DNA polymerase - the enzyme that uses single stranded DNA as a template to synthesis a complementary DNA strand
5. Mg ions - the reaction runs in a buffer containing magnesium ions which are crucial for the activity of the enzyme

This process happens in a thermal cycler instrument which automates the cycling of three reaction steps through different temperatures. The first step is termed “denaturation” which separates the DNA strands through heat (96C) Once they are separated they are cooled to allow the primers to bind to the DNA segments. This is called hybridization or annealing. The temperature is raised again and then the DNA polymerase extends the primers by adding nucleotides the developing DNA strand. With every repetition of these three steps the number of copied DNA molecules doubles.

And so, the DNA replication by PCR is an exponential process.

1 cycle yields 2 copies, 2 cycles yields 4 copies, 3 cycles yields 8 copies, 4 cycles yields 16 copies, and so it continues. After 30 cycles we will have 2^30 or 1 billion identical DNA copies. This is enough DNA to detect a pathogen in stool and other powerful applications.

Amplification produces multiple copies of what DNA is there and hybridization matches the target gene to a complementary DNA sequence on a probe. Imagine forging keys that open very specific locks. This allows the test to be highly specific and accurate. It is this precision that allows the test to run on one stool sample.

But it gets even better…. qPCR provides information beyond simply the detection of DNA. It assesses *how much* of a specific DNA or gene is present in the sample. So, it allows for both *detection and quantification* of the PCR product in real-time while it is being synthesized.

This technique is unique to the GI-MAP, truly making it superior to other tests on the market because it of its sensitivity, specificity and ability to quantify actual numbers of micro-organisms.

For more information on the methodology and comparisons with other GI stool testing methods, please see the [fully-referenced white paper](/assets/documents/gi-map-white-paper.pdf).

## Clinical Advantages of the GI-MAP qPCR Technology

The GI-MAP only requires a single, small sample. This is helpful for all patients, but particularly for children or any patients struggling with constipation, diarrhea, or logistical complications for whom multiple samples may present additional complications.

The turn-around-time is only <s>5-7</s> [7–10 in 2026] working days, allowing for a more rapid receipt of results and implementation of clinical intervention.

To Summarize:

* The GI-MAP opens the door to find infections otherwise missed. Culture techniques are limited by what organisms can actually grow, and this technique is unable to accurately quantify numbers of organisms. Similarly, sequencing analyzes only one region of the genome. There are many examples of microbes that cannot be measured easily, or at all, by sequencing. For example, most pathogens, especially all of the *E. coli* strains and *C. difficile*.
* Additionally, this test addresses virulence factors for pathogens which can further elucidate treatment - to treat or not to treat, that is the question.
* Validated by 3rd parties. If results are positive, the same stool sample can be run in another lab that does PCR and find the same result.
* qPCR measures both the 16S and 23S regions ribosomal RNA. The gene sequence 16S has been proven to be a reliable genetic marker as it is present (conserved) in all bacteria and its function has not changed over time. Additionally, measuring the 23S region enables further detection capabilities - species and strain differentiation - within variable regions.
* Automation minimizes human error.

And so we are excited to bring you this latest version of the GI-MAP: ***intelligently designed, for best patient outcomes*.**

Sincerely,

Tony Hoffman
*President & CEO*

Technology Update: Advances to the GI-MAP

Autoimmune diseases have become increasingly more common. Medical doctors are taught that our health is the result of our genes, and that health is preprogrammed and predetermined. This view rejects the possibility that health reflects an accumulation of choices that we make and the environmental impact around us. The reality is our health and well-being are the result of how our environment interacts with our genes.

There are different autoimmune diseases within all specialties, and all of these are looked at individually, yet they all share common triggers. Therefore, in knowing what causes the immune system to attack itself and knowing some of the triggers for what causes a malfunction in the immune system (which we do) we can achieve greater success in helping patients with these conditions. 

Autoimmunity occurs a few different ways. With the first way, there can be a mistaken identity and the body attacks itself. This can occur with a virus where there is tissue destruction with the virus appearing to be foreign to the body. In addition, this can happen with heavy metal toxicities such as mercury. The second way autoimmunity occurs is through molecular mimicry which happens when the body makes an antibody (a protein that attacks objects in the body that appear to be foreign) to a specific antigen. These antigens, including proteins expressed by opportunistic bacteria overgrowing in the GI tract, can resemble certain proteins in the body and the antibodies attack our body’s own tissues. The third way is the development of T cells (of the immune system). This occurrence can be affected by genetics, stress, and environmental triggers. Environmental triggers are what integrative doctors mainly work with in functional medicine. These can be food triggers such as gluten or other food sensitivities that can trigger inflammation, as well as anything coming in with the food such as toxins or molds. Other factors include a person’s nutrient status and their gut health, which includes conditions such as “leaky gut” and dysbiosis. Finally, there are toxins that can affect the status of the immune system such as heavy metals and xenobiotics, as well as the total toxic burden in the body.

Many autoimmune conditions need to be addressed by optimizing gut health. Dietary approaches provide the most effective means to returning balance and dysfunction with the gastrointestinal system. Patients may need antimicrobials, botanicals, enzymes, prebiotics, and probiotics to optimize the gastrointestinal environment. Integrative health care practitioners can offer hope to these patients. Diagnostic considerations include stool testing, organic acid testing, food antibody testing, as well as gluten sensitivity testing or elimination of gluten from the diet. 

## Gastrointestinal Support Following the 4-R Approach

### Remove

This focuses on eliminating pathogenic bacteria, fungi, viruses, and parasites. Botanical extracts have a long history as natural antimicrobials. They offer a broad spectrum of activity against common pathogens in conditions of dysbiosis and are relatively sparing of normal flora. These may include tribulus extract, berberine sulfate, sweet wormwood, black walnut, grapefruit extract, bearberry extract, and caprylic acid. These botanical extracts are commonly represented on sensitivity testing stool profiles by major functional laboratories. 

### Replace

It is important to use digestive enzymes to support optimal digestion of food. Individuals who do not secrete enough proteases suffer from multiple food allergies and cause problems such as food allergies, leaky gut, colitis, and autoimmune diseases. 

### Reinoculate

Proper probiotic supplementation helps to assist with food and nutrient assimilation, inhibits harmful bacteria, and replaces beneficial bacteria lost to antibiotic use, disease, poor diets, and stress.

### Repair

Glutamine is the most important nutritional substance for healthy intestinal cells and main fuel of the colonocytes of the large intestine. Glutamine is essential in maintaining proper gastrointestinal function and helping to prevent "leaky gut." N-acetyl glucosamine also supports proper mucosal health and reduces intestinal permeability. In addition, it inhibits the growth and functional of abnormal T-cells that incorrectly direct the immune system to attack specific tissues of the body, such as in autoimmune disease. Combining L-glutamine, N-acetyl glucosamine with mucilaginous relaxing herbs (such as DGL, slippery elm, marshmallow, chamomile, okra, and cat's claw) will help soothe and coat the intestinal lining and promote healing of inflamed tissue.

What appears to happen with most autoimmune diseases is that there are multiple triggers chronically stimulating the immune system over a long period of time in multiple ways. As a result, our immune system gets into an overloaded, overwhelmed state and loses its ability to function. Lifestyle choices and environmental exposures filtered through genetic predisposition are fundamental factors in the expression of disease, and a successful treatment approach must address these factors.

Autoimmune Disease – What Lies Beneath

There is simply no doubt that the incidence of autoimmune disorders has been rising sharply over the past several decades in the Western industrialized countries, particularly the United States (See figure 1).1 A broad array of disorders considered immune-dysregulatory and autoimmune in nature, encompassing both those classically categorized as Th1 and Th2-dominant, are included in this phenomenon. The question is why has there been such a sharp rise in the incidence of these disorders? The answers may very well be found in the current medical research, but you would probably never know it by visiting a doctor. This may be because this situation serves as an example of the giant chasm that often exists between Western medical research, which is often outstanding, and the practice of clinical medicine, which often leaves quite a bit to be desired when it comes to the management of chronic disorders with high morbidity but low mortality.

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 nasty potential side-effects like leukemia and lymphoma.2 While these approaches admittedly can provide substantial symptomatic relief to the patient, they do not really get to the cause of these conditions and some research suggests that these approaches may result in a furthering of the pathological process. However, modern research into autoimmune phenomenon suggest radically different approaches may be required to reverse the above cited trends, including a strong emphasis on very early detection with predictive auto-antibodies, a focus on optimizing gastrointestinal 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 hot areas of emphasis in mainstream medical research journals and investigative communities in immunology.

Molecular Mimicry
-----------------

The concept of molecular mimicry is really a simple one, and it is an area 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), can in genetically susceptible individuals induce cross-reactions with structurally similar amino acid motifs associated with specific host tissues. There are now multitudes of associations that have been firmly established between immune incompatibility with specific dietary-derived antigens, as well as the overgrowth of certain opportunistic and pathogenic gastrointestinal bacteria, and the presence of specific autoimmune disorders (See table 1).3 While some of these associations have been known for quite some time, mechanisms of causality are rapidly being established in the research. However, patients suffering from disorders like rheumatoid arthritis (RA), ankylosing spondylitis (AS), and autoimmune thyroiditis (i.e., Hashimoto’s or Grave’s disease) who visit a rheumatologist or 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, as the conventional medical paradigm typically assumes an infectious cause, doesn’t it? Perhaps this is just another example of resistance to significant change in clinical approach within medicine, even in the face of compelling evidence to do so, as it would then require a least a passive admission that something so seemingly simple was missed for so long.

Pishak et al have demonstrated that the mucous membrane of healthy people is colonized by Bifidobacteria, Lactobacilli, Bacteroides, Escherichia and Enterococci; as contrasted with the mucous membrane in RA subjects which is mainly colonized by aerobic opportunistic conventionally pathogenic enterobacteria (i.e., enteropathogenic Escherichia, Citrobacter, Enterobacter, Klebsiella, etc.), Staphylococci, Enterococci and other anaerobic bacteria (Bacteroides, Peptococci, Peptostreptococci, etc.).4 They have also reported the observed phenomenon that as RA exacerbates and then enters remission, which is a common occurrence across the spectrum of autoimmune disorders, the composition of the subject’s GI microbiota correspondingly also changes between the aberrant pattern detailed above and the one typical of normal subjects. The data of Tiwana et al suggests an increased immune response to Klebsiella in patients with AS, ulcerative colitis (UC), and Crohn’s disease (CD) and to Proteus in patients with RA.5 Alan Ebringer and his group in the United Kingdom have established over the course of many years that a substantial percentage of patients diagnosed with RA have chronic stealth infection with Proteus mirabilis in the upper urinary tract.6 His group has also established the specific amino acid motifs of cross-reaction between the Proteus hemolysin and the RA-associated HLA-DR molecules, as well as those between the Proteus urease enzyme and hyaline cartilage, containing type XI collagen, the type only found in the small joints affected in RA. His successful treatment protocol includes antibiotic therapy, such as ciprofloxacin (sometimes in combination with NSAIDs, DMARDS, and immunosuppressive agents as needed), with the added use of natural blocking agents such as cranberry juice, vitamin C for urine acidification, and plenty of fluids.7     

Oral bacterial infection with Porphyromonas gingivalis, the primary cause of periodontal disease, may also play a role in peptide citrullination, theorized to be involved in the loss of self-tolerance and development of autoimmunity in RA, according to Liao et al.8 Clearly one of the challenges to the acceptance of bacterial agents as the cause of these autoimmune diseases has been that there is no universally observed association or one specific universally-causative agent. This issue is addressed head-on in research by Harkiolaki et al using a mouse model of multiple sclerosis (MS) when he states: “We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by cross-reacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS auto-antigen. Structural analysis demonstrates this cross-reactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to a degenerate TCR recognition. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS.”9 This phenomenon is also likely in play across a multitude of autoimmune disorders, and not something unique to MS.

Researchers have now gone beyond establishing mere associations between the presence of various microbes and autoimmune disorders. Some have actually experimentally induced autoimmune disease by infecting animals with specific pathogens. Mazmanian et al inoculated a wild-type mouse with the bacterium Helicobacter hepaticus to create an experimental mouse version of the autoimmune disorder inflammatory bowel disease (IBD).10 H. hepaticus activates Th17 cells which release cytokines associated with inflammation, such as IL-17, which cause symptoms of the disease. They then introduced Bacteroides fragilis expressing the polysaccharide A (PSA) to the gut of the animals where the PSA molecule was taken up by dentritic cells and presented on their surface, activating CD4 T cells and regulatory T cells (Tregs). The Tregs release IL-10 which suppresses the inflammatory action of IL-17, alleviating the IBD in mice. In summary, the researches induced autoimmune disease by introducing specific bacteria to the gut, and resolved it by introducing another, making a compelling argument for a causal relationship between the GI microbiota and autoimmune activity.

Autoimmune thyroid disorders also have been linked to bacterial infections, mainly GI overgrowth of the opportunistic organism Yersinia enterocolitica. Petru et al state; “Yersinia shows on its surface saturable binding sites for TSH. TSH receptor antibodies could be produced in selected individuals having been infected with bacteria showing TSH receptors. It may, therefore, be assumed that the gram-negative bacterium Yersinia enterocolitica may have an active part in triggering immunogenic thyroid diseases.”11 Other researchers have shown a much higher prevalence of Yesinia serum antibodies in patients with thyroid disease versus controls. However, once again, there is no universal causality established, as autoimmune phenomena is a complex issue and seems to be potentially fueled by a multitude of potential antecedents, triggers, and mediators. For example, dietary antigens have also been linked to autoimmune thyroid disease. Celiac patients have approximately 10 times the rate of auto-immune thyroid diseases (such as Hashimoto’s thyroiditis and Grave’s disease) as non-celiac individuals, reflective of the affinity of gluten-gliadin antigen-antibody complexes for thyroid tissue.12  It may be no coincidence that the emergence of an apparent epidemic of autoimmune diseases has corresponded with the ever-increasing consumption of poor-quality modern processed foods known to both negatively alter the GI microbiome and to contain a constant (often hidden) stream of offending dietary antigens, including gluten-containing grains.

While all of these associations may be interesting to researchers, what does this really mean to a clinician? Some critics would argue that there is a lack of interventional data to suggest eradication of these associated organisms and/or avoidance of these dietary antigens positively affects patient outcomes. This may be true in some instances, but it has been well established, for instance, by Ebringer that successful treatment of Proteus clinically helps those with RA,7 and dietary elimination of gluten-containing grains is entirely accepted as the most viable intervention in Celiac disease. One potential issue in play is that by the time a patient is diagnosed with autoimmune disease there is often already substantial host-tissue damage. Perhaps the horse has already left the barn? However, what if potential triggers were routinely screened for and removed by health care providers, particularly in those with a family history of autoimmune disorders? The entire course of the disorder might be favorably altered, and many of these disorders might potentially never emerge clinically. In the naturopathic and functional medicine models, there is a strong emphasis on both early detection and interventions that target the underlying pathophysiologic basis and 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 also seems to intuitively make sense even in those who already have established disease; even though you may not be able to undo the damage already done, you can likely - if nothing else- slow down the train. This is particularly true since the interventions required pose little or no risk and are also relatively 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, utilizing PCR-DNA analysis, are also now available to clinicians at relatively low cost with rapid turn-around time.13

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From: Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. Sep 2002;347(12):911-920.

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