EMILY STEIN, PhD INTERVIEW (September 2023)
Emily Stein’s unique scientific background spans molecular biology, microbiology, and molecular and cellular immunology with an emphasis on chronic infections and chronic inflammatory diseases. She completed her Post-doctorate Fellowship in the Department of Immunology and Rheumatology at Stanford University, where she studied the role of the neuro-endocrine axis in rheumatoid arthritis and other autoimmune diseases. Currently, she is the Chief Executive Officer and Clinical Director of Primal Therapies.
THE ORAL MICROBIOME – INFLAMMATORY ARTHRITIS CONNECTION
If you have an autoimmune disease, the oral microbiome seems to be a big player in triggering flares, exacerbating flares, or mitigating flares. We have known for quite a few years now, about the co-occurrence of rheumatoid arthritis and periodontitis based on the metadata of numerous international clinical studies. If you have rheumatoid arthritis, your risk of developing periodontal disease is significantly higher than the average person without that autoimmune disorder. Concomitantly, if you have periodontal disease you have an increased risk of developing reactive inflammatory arthritis. So, there seems to be this intimate relationship between these two states. If you think about inflamed joints, whether they be the phalanges of the fingers or the toes, or bigger joint spaces like the knees, hips, or the TM joints, they all involve inflamed ligaments. Additionally, there are ligaments around all of the teeth, which are often forgotten about by the medical community.
I began to study the relationship between all of these things when my grandmother who had Sjogren’s syndrome, rheumatoid arthritis, and periodontal disease that were exacerbated by her assisted living situation and the associated poor oral hygiene. Her advanced periodontal disease led to the need to extract a tooth which then led to her throwing a clot in her brain the next day and a stroke.
A retrograde analysis of hundreds of Medicaid cases in the United States led the realization that if you have a dental implant placed or a tooth extracted, you have a 50% higher risk of having a stroke or a heart attack four weeks following those procedures. I personally feel strongly, that if you have an autoimmune disease at the time of those procedures, your risk is significantly higher than is represented by that average.
My doctorate was in microbiology and when I started to study autoimmune diseases, particularly rheumatoid arthritis, and my grandmother had that event, I was in a unique position to bio-hack my grandmother’s oral microbiome and try to figure out a way to get her microbiome to stop causing inflammatory processes that would lead to even more problems.
Microbes don’t just stay put, they travel around; we are like walking petri dishes. During my Fellowships we looked at joints removed during joint replacement surgeries. In many cases, the patient had highly erosive osteoarthritis in their knee or shoulder, and the joints had a ton of microbial biofilm in that erosive lesion of the joint space. We discovered that the origin of the biofilm bacteria was often the mouth.
We are now finding similar things post-mortem in the brains of Alzheimer’s patients. Additionally, we are finding oral-origin bacteria in the pancreas of patients with pancreatic cancer. That led us to the question: Which came first, the chicken or the egg? A lot of studies in animals have suggested to a high degree that microbes are present at the time – or nearly the time – of the inflammatory event. And recently there have been two amazing published studies that show that microbes escaping from the mouth lead to a rheumatoid “flare,” especially if the tissue the microbes are inhabiting have been citrullinated. There’s this thing called “anti-citrulline autoimmunity,” wherein the body’s own immune system attacks its own cells, a condition enabled in predisposed subjects, by the reduction of immune system self-tolerance. Citrullination plays a role in inducing anti-citrullinated proteins/peptide antibodies (ACPA). Citrullination had been reported to be a process present in a wide range of inflammatory tissues including polymyositis, inflammatory bowel disease, and chronic tonsillitis.
WHAT IS COMING FROM WHERE?
What we see in dog’s mouths with arthritis is bacteria of gut origin. We essentially have a tube that runs through our body with two open ends, and you can think of it as a continuum. What we know now from 13 years of our research at Primal Health, is that if someone has oral dysbiosis it usually co-occurs in all sorts of patients with neuro-degenerative diseases, chronic pain syndrome, autoimmune diseases, cancers, and other things. What we have is a fundamental imbalance of the microbiota that inhabit these spaces. In the case of the mouth, its too many bacteria that are pro-inflammatory, namely, Porphyromonas species (but not all) with P. gingivalis being the biggest trouble-maker. We also see gut dysbiosis develop with patients who have oral dysbiosis. We also see patients with gut dysbiosis develop oral dysbiosis over time. So, it seems to be kind of a loop with one end influencing the other, whether it’s originating more on the “downstream” end or on the “upstream” end. Where it originates depends on the person, and it is mainly diet-driven. There is also in inheritability factor, as we inherit our mother’s microbiome (or if you are born by C-section you inherit the microbiome of that operating room).
Some recent pregnant animal studies revealed that the leading route of microbiome inoculation of the placenta was via the mouth (bio-marked e. coli was introduced via the bloodstream vs. orally, vs. vaginally). It turned out that the oral inoculation route beat them all with regard to speed. So, there is a pathway we don’t yet fully understand which allow microbes from the mouth to gain access to the placenta during fetal development. We develop with the microbes from our mother. Hence, whatever the mother ingests influences the makeup and development of the microbiome of the fetus which has significant health implications for both mother and fetus. For example, if the mother has gingivitis, the chance of her having a pre-term birth skyrockets.
More on citrullination…
When we are diagnosed with seropositive rheumatoid arthritis there are two blood markers that go along with it: RF (Rheumatoid Factor) and ACPA (Anti-Citrullinated Protein Antibodies). These markers were thought to never change over time, so they were rarely tested-for again. However, there are some examples of their preponderance changing when a proper dietary treatment regimen was followed.
We mammals make antibodies against foreign and “domestic” (self and non-self) proteins. Our immune system goes through a training process as we grow up and become “tolerized.” Our immune system learns what “self” looks like, which includes the microbes we are born with. We have floating around in our bodies at all times, memory cells that recognize our own tissue. They don’t react to it, because they have learned to be non-reactive to that tissue. However, everything that’s not “self,” is identified as being foreign. A lot of that occurs on the “innate” level – the first level – the level of the microbiome. The ACP antibodies come into play a little later in the adaptive stage of immune defense where B-cells turn into plasma cells (plasma cells are like antibody factories that spew out antibodies specific to each perceived threat).
In our body, if we are RF+, we have plasma cells that are secreting RF, or if we are ACP+ we have plasma cells secreting antibodies which recognize citrulline indiscriminately or discriminately, based on context. I don’t want to get too far into the weeds here, but if we are positive for either of those conditions, we have B-cells and plasma cells floating around in our bloodstream spewing out antibodies whenever they see something they believe is foreign, or whenever the innate system activates them. An example of the latter is a rheumatoid arthritis flare due to an infection being present that had nothing to do with the rheumatoid disease state itself, yet it triggered the body to up-regulate and increase RF or ACPA, because of the co-occurrence of these events.
Where periodontal disease comes into play:
There are microbes in the mouth that can citrullinate our tissue. The outcome is “foreign” -looking tissue: the microbes fundamentally change the protein structure of gum tissue. We have evidence internally, that this is happening outside of the mouth as well. For instance, this is happening in women’s genital-urinary cavities, as well as in the gut because the foreign epitopes being created travel everywhere. Every time we swallow, we are ingesting more than a million microbes, and it’s a false assumption that all of them are killed by the stomach acid. So, “downstream” processes are affected as well. Porphyromonas species (there happen to be three species that we know of) secrete enzymes called PAD (peptidyl arginine deiminases) which take the basic amino acid arginine (which also has anti-caries properties) and converts it into citrulline by changing its shape and charge. Additionally, Porphyromonas species modify the surrounding bacteria. So, they are not only able to modify your tissue by making it appear to our immune system to be foreign, but they can also modify the surrounding microbiome by converting it from being identified as “self” to “non-self.” That’s a double-whammy of inflammation activation. In the mouth, this tends to be the entire microbiome, and this shift is also detectable in the bloodstream, so the implications may not be localized. Porphyromonas needs heme to survive. It not only has enzymes that change our amino acids through citrullination, but it also causes wounds in our tissue which supply the heme that allows it to thrive and influence the behavior of the entire microbiome. (Studies show that even at a low percentage of 1% bioburden presence in the microbiome Porphromonas is able to negatively influence the entire microbiome)
What we now know about autoimmune diseases is that our body can “see” a foreign molecule but not always react to it. What is often required is co-activation; something needs to be identified as being foreign in addition to the presence of an overabundance of what the immune system perceives to be a hazardous microbe: In this case, Activation of a toll-like receptor occurs PLUS antigen recognition through this ACPA triggers a super flare event.
How does P. gingivalis get in our mouth in the first place?
Some people don’t have P. gingivalis in their mouth. That same group of people tend to not have gingivitis and periodontitis. However, 4 out of 10 Americans have P. gingivalis in their mouth, and subsequently have various degrees of periodontal disease. The earliest stage is bleeding associated with inflammation with the immune system activated where the wounds are located. And then over time, with the generation of the ACPA we see degradation of the periodontal ligament and surrounding bone, which is what holds the tooth in place. And with every tooth loss, statistically speaking, lifespan is shortened.
WHAT CAN BE DONE TO ELIMINATE THIS SELF-DESTRUCTIVE CYCLE?
Vaccines against P. gingivalis have been unsuccessful. In the veterinary world, a vaccine was introduced which subsequently failed, because you can have periodontal disease without the presence of P. gingivalis. So, it’s not just this one bad actor, it seems to be a polymicrobial infection that leads to this state we call periodontal disease. And as stated earlier, there are several Porphyromonas species that can secrete the PAD enzyme. There are several non-P species that appear to be involved that we are currently doing research on as well. We also know that fungus plays a role. How many autoimmune disorder patients have concurrent mold allergies? Answer: Many of them do.
My company Primal Health specifically, is taking a different approach toward resolving these challeges. We are not trying to develop a vaccine, or an antibiotic, because microbes just adapt and redesign themselves around them. We are changing the ecosystem of the mouth through modulation of the food sources available to the pathogens that they need to thrive. A human can eat whatever they want, but we block bacterial uptake of sugar by the microbes, because part of what Porphyromonas species grow really well on is the waste products of sugar fermentation of other bacteria. That’s why Porphyromonas thrives in the mouth, it’s the location of a lot of primary sugar. That’s also true in the brain, pancreas, and cancer cells.
There exists a common link between Alzheimer’s Disease, dementias, pancreatic disease, cancers, and periodontal disease. These are high sugar fermentation areas that support the presence of Porphyromonas – which does not consume sugar itself (it’s a secondary feeder that depends on the presence of Streptococcus species to be present as well. The streptococcus species catabolize carbohydrates and as a metabolic biproduct create the organic acids Porphyromonas needs). When we swallow, within seconds microbes are working on breaking down sugars.
We don’t know how Porphyromonas gets established initially, it might be through our water, or through our food. Porphyromonsa is a commensal bacteria that is inherited, and often shared within a family, even between pets and humans. If we eat carbohydrates and are cohabitating with someone who has Porphyromonas, we are likely to become inoculated with it as well.
Our goal is to block global sugar fermentation in the mouth by streptococcus species, and by doing so, we are starving out the downstream pathogens like Porphyromonas by limiting the amount of organic acids available to them to allow arginine citrullination and the subsequent destructive autoimmune response.
Another way to think about this, is that we ask the whole microbiome to switch over to a “Keto” diet and use amino acids as their primary food source. When we do that, the pathogens (both pathogenic streptococcus species and Porphyromonas species*) are out-competed by the non-pathogenic bacteria (lactobacillus and others) and they’re subsequently unable to exist on a level that can cause dental decay, periodontal, or other systemic issues of oral bacteria origin.
*Porphyromonas is also a slower metabolizer than the more “global good” bacteria that live in the mouth, and by cutting them off from sugar byproducts, and the amino acids are being used up by faster catabolizers; Phorphyromonas is “starved out” via nutrient pressure.
THE EVOLUTION OF THE HIGHLY PROCESSED AND HIGH CARBOHYDRATE AND SUGAR-INFUSED WESTERN DIET HAS FUELED THIS PROBLEM
Additionally, a lot of people with Rheumatoid Arthritis have a history of major bouts of antibiotic treatment during childhood, which eradicated their good bacteria, and then they inherited pathological environmental microbes in their place. This transition was facilitated by the nature of their diet. For example, how many of us eat things that contain preservatives? Preservatives are not good for beneficial microbes. How many of us consume products that contain glyphosate? Conversely, how many of us eat fermented foods? Not very many of us – which is a big cultural shift over the past 50-75 years – that’s how we historically used to preserve food along with smoking and dehydrating. We no longer eat that way on a daily basis.
When you think about autoimmune diseases, there are very few recorded cases of these types of problems 100 years ago. You cannot explain the current epidemiologic occurrence rates any other way. Additionally, we live in an overly sanitized society wherein our natural microbiome is constantly being disrupted by disinfectant soaps, hand cleaners, shampoo, toothpastes, fluoride and so forth. We are no longer outside in the sun and around healthy environmental bacteria. If we are too clean we will probably have gut and anxiety issues (because of the gut brain axis). If we don’t grow up with a pet that goes outside regularly, we are much more likely to have an inflammatory-respiratory disease of an autoimmune nature. Microbes are a fundamental aspect of our human biology. They help keep our immune system in check.
So, back to our treatment strategy: what we are seeing, is that when we put microbes on a “keto diet” in the mouth, respective of what the host is consuming, we can completely knock down the inflammation and negative immune response. As a consequence, tissue health improves while the diversity of the microbiome improves as it moves away from pathogenicity. We see an increase in lactobacillus and other microbes we need present because they help us regulate and settle the immune system down. They also help with tissue function homeostasis: you regain healthy barrier function in both the mouth and in the gut. That is achieved by asking (and helping) the “good” bacteria to eat amino acids instead of carbohydrates. We added vitamin B6 because the enzymes that our “good” bacteria need to break down protein require it.
For cases when patients are in memory care (and their oral hygiene tends to be terrible) and in animals (who don’t get their teeth brushed) we added L-arginine to help the bacteria start the amino acid breakdown process more easily by creating an amine-friendly environment with a nitric oxide burst as a metabolic byproduct (reason: Porphyromonas is an obligate anaerobe that hates nitric oxide, so the nitric oxide functions as an additional Porphyromonas disrupter). In net, we are disrupting Porphyromonas’ access to its preferred nutrients in two ways plus we are hitting it with nitric oxide.
Acid Bad – Nitric oxide good
Patients who have periodontal disease have inflamed tissue which is a byproduct of the acidic environment created by the infection. Thus, avoiding acidic foods is a good strategy, because acid inflames (and that includes no vinegar on salad if you have an active oral infection). If you are inflamed, acid is the fastest way to upset your immune system, and create “leaky” gum tissue.
Sauerkraut = good
The souring effect in sauerkraut is the end product of sugar degradation, and it’s acidic, so that’s not a good thing for the mouth if you have P. gingivalis present, however, the abundance and activity of prebiotics created by the fermenting process may outweigh the negative impact of the acidity. The data on fermented foods is very strong with regard to immune system modulation, and gut health.
There is a mouse model for inducing autoimmune arthritis. It requires a foreign collagen (bovine) which is identified as a foreign protein by the mouse’s immune system, which has been prepped in acid in addition to containing a microbial component (usually heat-killed tuberculosis bacteria) injected into the mouse and suddenly you have autoimmune arthritis in the mouse. If you skip the acidification step, you do not get the immune system activation, because proteins lose shape in the presence of acid, which is why when we preserve something like eggs (an egg in vinegar for example which decalcifies the shell, or a quick pickle), you are hitting them with acid to kill bacteria and denature protein. Acid creates foreign epitopes (denatured proteins) that are harmful if you are immune reactive. So, acid isn’t a good thing for autoimmune situations -period.
Where you have inflammation, you have acid (arthritic joints have more acidic synovial fluid), and where you have acid you have inflammation.
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Gingival health is a “gateway tell” as to how the whole body is doing. Puffy, edematous, bleeding gingival tissue is a total red flag with systemic implications, including the health of the joints. The ‘quieter’ calmer, and healthier the gingival tissue (which is an indication of the health of the mucosa and its immune status) influences mucosal immunity in the lower gut. Fibroblasts are everywhere: in our mouth, gut, and joints, and inflamed synovial fibroblasts cause a lot of problems. If we can heal the oral mucosa and therefore prevent more microbes from escaping from the mouth into the bloodstream and then into those protected joint spaces and causing problems, that will reduce pain, swelling, slow down the erosion process and the joint deterioration process.
Right now: Don’t waste your money on any probiotics (because they cannot penetrate the biofilm of the mouth or gut), I would instead spend money on drinking clean water frequently throughout the day, because the more hydrated you are, the more waste you are going to remove (the pathogenic bacteria are secreting inflammatory waste products constantly). Avoid fruit because it is both high sugar and high in acid. And exercise, including stretching as you need to move those joints – it’s like a flushing mechanism, by forcing fluid exchange.
NSAID use over time causes gut dysbiosis: If possible do this instead:
Resveratrol (anti-inflammatory properties)
Curcumin (analgesic and anti-inflammatory properties)
Olive oil (anti-inflammatory due to omega-3 fats)
Fish – omega 3 fatty acid