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In part one of Clinical Consequences and Considerations of Chronic Candidiasis, I discussed various pathogenicity mechanisms of invasive candida, including increased intestinal permeability leading to a leaky gut phenomenon, arabinose toxicity and immune dysfunction. In this article (part 2 of 3) I will outline some laboratory test options for the detection of intestinal candida, as well as options for analyzing the invasive nature of these fungal organisms.

This article will profile three detection methods two of which are commonly used in functional and integrative medicine, namely stool analysis and organic acids test (OAT). The third method, serum testing, is more commonly associated with conventional medicine. We begin this discussion with serum testing for candida.

Serum Testing

Serum tests for candida antibodies, which may include immunoglobulins IgA, IgG and IgM, can be acquired from many commercial labs. In general, antibodies are blood proteins produced in response to a specific antigen for the purpose of immune recognition and neutralization of its activity. An antigen can be any substance which the body recognizes as foreign, including an allergen, bacteria, fungus, or viruses (1).

Many laboratories provide both IgM and IgG antibodies. IgM is the antibody that rises first before IgG is produced. IgG follows IgM production providing longer term immunity and stays elevated longer than IgM (2). IgA serum testing is available too, but since IgA circulates at lower concentrations in the blood compared to IgM and IgG, it is not a commonly analyzed serum immunoglobulin.

Being that many species of candida can normally inhabit the digestive system at low levels it has been debated if elevated antibodies carry any clinical significance. For example, reference material from a major laboratory in the United States mentions the following with regards to Candida IgG antibody testing:

A positive test does not necessarily indicate infection since antibodies to Candida species can be detected in uninfected individuals because of their exposure to commensal yeasts. This assay is unable to differentiate antibodies formed during mucosal colonization from those produced during deep infection. Consequentially, antibodies are found in many hospitalized patients who have no obvious Candida infection. A negative result does not rule out the possibility of deep-seated candidiasis in immunocompromised patients (3).

As discussed in part one of this article series, candida can move from a mucosal colonization phase to a more invasive form. Some labs have established reference ranges that correlate to higher concentrations of Candida-specific immunoglobulins indicating higher infectivity. For example, Great Plains Laboratory (CLIA certified 17D0919496) lists the following with regards to its IgG Candida antibody analysis (4):

The Candida albicans scale has been updated to account for the observation that Candida-specific immunoglobulins are present in the specimens of virtually all individuals tested. The new scale is intended to provide a clearer indication of clinical significance and was established according to population percentile ranks obtained from a random subset of 1,000 patients. Specifically, the range of insignificant and low IgG values correspond to the first and second quartiles of the distribution, while moderate values denote individuals in the 51st to 97.5th percentiles. Those with an IgG value greater than the 97.5th percentile are considered to have a high concentration of Candida-specific immunoglobulins.

Therefore, antibody testing, particularly of IgG can be an effective method for the detection of higher concentrations of Candida that may be adversely affecting an individual’s health. Like all testing, the data obtained from a laboratory analysis should be correlated with the clinical presentation of the individual.

Stool Testing

Stool analysis for the detection of Candida has been used by functional and integrative medicine practitioners for years. In this method, fecal samples are collected then analyzed for either visual appearance of yeast through microscopy or growth of the organism in a culture medium.

Being that Candida and other forms of yeast are common to the digestive system, it is not unusual to see a positive finding on microscopy. This is commonly listed as “moderate” or “many” yeasts detected, but the actual type of species is determined by stool culture analysis.

The culture component is more specific to isolating which type of yeast organisms are present. For example, Candida albicans is the most common type of candida found in the digestive system, but the culture method may detect others such as Candida glabrata or Candida tropicalis. One of the benefits of differentiating yeast strains through culture is the ability of the lab to provide sensitivity testing that may determine which botanical or medication is most effective in eradicating the organism. Unfortunately, however, stool analysis for Candidiasis through culture is not 100% accurate and can miss detection even though a patient may be symptomatic of candida overgrowth.

Polymerase chain reaction (PCR) has become a popular method of pathogen detection and this includes PCR analysis for candida in stool samples. PCR is a widely used method to help make billions of copies of DNA accessible for study (5).

The pros of PCR testing are that its more sensitive than conventional laboratory techniques for pathogens because it allows through a sample amplification process to detect organism at low numbers. Unfortunately, PCR testing does not differentiate between non-viable (non-living, not capable of reproducing) from viable (capable of reproduction) candida. Other considerations regarding PCR testing are that it can detect multiple pathogens but may not differentiate the causative organism and it may show false positives if the stool sample is collected too soon after previous treatments (antibiotics or antifungals).

Again, like positive serum antibody testing, any positive PCR detection should be correlated to the clinical presentation of the individual prior to a treatment decision.

Organic Acids Test (OAT)

Organic acids are metabolic compounds containing carbon, oxygen, and other atoms such as hydrogen, sulfur, and nitrogen. They are naturally occurring compounds linked to cellular metabolism or may be present because of problems in biochemical processing.

Some organic acids are produced by organisms in the digestive system, including bacteria, candida, and yeast species. These gut-produced organic acids get absorbed systemically then highly concentrate in the urine. Certain organic acids from yeast metabolism represent overgrowth within the digestive tract, while others are linked to invasive candida at the mucosal barrier within the small and large intestine. One such organic acid called Arabinose, which was discussed in part 1 of this article series, is reflective of invasive candida.

Arabinose

Arabinose, a sugar aldehyde, closely related to a sugar alcohol known as arabinitol (6), has been used for years as an indicator of invasive candidiasis. It is often high in those with autism (7) but has prevalence to various other health disorders such as Alzheimer’s disease.

The production of Arabinose (and other compounds) occurs secondary to oxidative reactions against hyaluronic acid which can be initiated by invasive candida and its production of hyaluronidase (8). Therefore, elevations of arabinose on organic acids tests reveals active invasion into the mucosal lining of the digestive system and a higher degree of candida severity.

Arabinose, as discussed previously, has various important pathogenicity mechanisms that are worth considering:

•  It can bind with the amino acid lysine forming a compound called Pentosidine (9). This complex can alter normal biological function, including neuronal structures through glycation end-product formation.
• Pentosidine is known to cause various adverse neurological reactions, including myelin damage, neurofibrillary tangle development and Alzheimer’s disease (10).
• The epsilon amino group of lysine is a functional component of many enzyme systems that also depend on cofactor binding from vitamin B6, lipoic acid and biotin (11). High amounts of pentosidine, which block these binding sites, may lead to functional deficiencies even when nutritional intake of these nutrients is adequate.

Conclusion

There are many testing options available for the detection of intestinal candida that can determine overgrowth and the degree of invasiveness. Candidiasis, defined as a fungal infection linked to any form of candida species that is detected via serum, stool or organic acid analysis does not necessarily indicate that a patient is suffering from Candidemia which is linked to actual fungal species found in the bloodstream. Unfortunately, blood cultures for candida are often unreliable (12) but understanding the clinical application of the aforementioned methods can provide specific data to help identify individuals clinically affected by candida overgrowth.

In short, the organic acids test is a preferred option because it shows mucosal reactivity to invasive candida even when a stool analysis reports no evidence of candida overgrowth. Often, a serum IgG test will report high levels of candida which may correlate with an elevated arabinose on the OAT. However, this is not always the case. Therefore, my preference is to use the OAT as a primary test for candida assessment and incorporate stool analysis and/or serum testing as complementary methods.

In part 3 of this article series we will explore various treatment options for chronic candidiasis, both from a conventional medicine and integrative medicine standpoint, as it is important to understand the pros and cons of each.

References:

1.  K. Abbas, Abul; Lichtman, Andrew; Pillai, Shiv (2018). Cellular and molecular immunology (Ninth ed.). Philadelphia: Elsevier. p. 97.
2. Pier GB, Lyczak JB, Wetzler LM (2004). Immunology, Infection, and Immunity. ASM Press.
3. LabCorp website - https://www.labcorp.com/tests/163135/i-candida-i-antibodies-iga-igg-igm-elisa
4. Great Plains Laboratory website https://www.greatplainslaboratory.com/igg-food-allergy-test
5. Saiki, R.; Gelfand, D.; Stoffel, S.; Scharf, S.; Higuchi, R.; Horn, G.; Mullis, K.; Erlich, H. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. 1988; Science. 239 (4839): 487–491.
6. Kiehn T, Bernard E, Gold J, Armstrong D. Candidiasis: detection by gas-liquid chromatography of D-arabinitol, a fungal metabolite, in human serum. Science. 1979; 206(4418): 577-580.
7. Shaw W, Kassen E, Chaves E. Increased excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clin Chem. 1995;41(8):1094-1104.
8. Jahn M, et al. Carbohydr Res. 1999, 321:228-34. 2. Shimizu MT et al. J Med Vet Mycol. 1995, 33:27-31
9. Sell D, Monnier V. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J Biol Chem. 1989;264(36): 21597-21602.
10. Smith MA, Taneda S, Richey PL, et al. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl. Acad. Sci U S A. 1994; 91(12): 5710-5714.
11. Mahler H, Cordes E. Biological Chemistry. 1966; Harper and Row, NY. Pgs 322-375.
12. Cornelius J. Clancy and M. Hong Nguyen. Finding the Missing 50%” of Invasive Candidiasis: How Nonculture Diagnostics Will Improve Understanding of Disease Spectrum and Transform Patient Care, 2013-04-04 Oxford Journals, Medicine & Health, Clinical Infectious Diseases, Volume 56, Issue 9 Pp. 1284-1292.

In part one and two of Clinical Consequences and Considerations of Chronic Candidiasis, I discussed various pathogenicity mechanisms of invasive candida and testing methods, respectively. In this final article I will outline various agents useful for chronic candidiasis, including medications, as well as a focus on certain botanicals and some of their known or suspected modes of action. There is an abundance of herbal remedies that have a long tradition of use as antimicrobials and to cover all aspects of all herbs would require more depth than we need here. Therefore, I have focused on five botanicals that are often found in combination herbal supplements and have been used successfully over many years in combating chronic candidiasis: bilberry extract, echinacea (angustifolia and purpurea), goldenseal, oregano, and tea tree oil.

This article will profile three distinct categories of chronic candidiasis intervention, namely Nystatin (non-systemic), Fluconazole (systemic) and botanicals. We begin this discussion with Nystatin in the non-systemic category.

Nystatin

Nystatin, a.k.a. Mycostatin, is an antifungal medication used for fungal infections of the mouth, intestines, skin, and vagina (1). It is not appreciably absorbed from the skin or mucus membranes, including the digestive tract. Available in various forms such as capsules, oral suspension, powder, and tablets, it has been a long-time favorite of many conventional and integrative doctors for the effective treatment of gastrointestinal candidiasis and oral thrush. A good safety profile for long-term use offers flexibility in usage for different age groups and provides good tolerance. Certain side effects of Nystatin include diarrhea, hives, nausea, hypersensitivity reactions and stomach pains (2). These are rarely encountered based on the author’s experience.

Nystatin, and a similar medication called Amphotericin B, act as an ionophore. These substances affect the cell membrane by either binding to an ion (e.g. sodium, potassium) and/or aiding in the transport of ions across the membrane (3).

Nystatin binds to a fungal cell membrane chemical called ergosterol (i.e. a chemical sterol) which disrupts cell wall integrity by forming pores and allowing for leakage of intracellular potassium. This process also causes acidification within the yeast cell leading to its death (4). Ergosterol is unique to fungi (e.g. yeast, mold), but is similar to the mammalian sterol called cholesterol. The main systemic toxic effects of Nystatin (and Amphotericin B) are linked to kidney damage via cholesterol disruption. However, this effect is primarily an issue with intravenous forms of these medications, not oral forms.

Systemic Antifungals

There are many systemic antifungals, e.g. Fluconazole (Diflucan), Itraconazole (Sporanox), Terbinafine (Lamisil) useful in the treatment of various fungal infections. A medication becoming “systemic” refers to its ability to be absorbed in high amounts from the digestive system into the bloodstream with wide distribution throughout the body. These highly absorbable medications are quite different from oral Nystatin which is considered to be a non-absorbable antifungal and has its effect locally. For the sake of simplicity, our focus will be on the medication Fluconazole.

Fluconazole, as an antifungal medication, is useful for a wide range of fungal infections, including candidiasis, blastomycosis, coccidiomycosis, cryptococcosis and others (5). The side effect profile of Fluconazole (and other systemic antifungals) is more extensive than oral Nystatin due to high systemic absorption and blood and tissue distribution. This tissue distribution includes the liver so it requires monitoring liver enzymes. In addition, QT prolongation reflective of cardiac electrical activity, vomiting, diarrhea, and seizures are known side effects too.

Fluconazole works by inhibiting a fungal cell cytochrome P450 enzyme called 14α-demethylase . This enzyme is involved in the formation of ergosterol, an essential component of the fungal cell membrane. Adversely affecting

14α-demethylase has fungistatic effects against fungal behavior, but at higher dosages fungicidal properties exist (6).

Botanicals

Botanicals for the use of eradicating fungal infections have a long history of use in herbal medicine. Either the whole plant or components of a plant may contain various compounds, e.g. active substances, that provide antifungal properties, i.e. either inhibitory (fungistatic) or killing (fungicidal). As mentioned previously, we are going to focus on five common herbs known to be helpful in chronic candidiasis.

Bilberry Extract

Bilberry is an edible fruit from the plant species Vaccinium myrtillus. The berry has similarities to the American blueberry and goes by various names such as “wimberry”, “wortleberry”, and European blueberry (7). Much of the beneficial effects of bilberry extract focus on its antioxidant and circulatory properties for improved cardiovascular function. However, bilberry extract is known to contain cell-wall degrading enzymes that provide antimicrobial activity useful against opportunistic organisms (8).

Echinacea Angustifolia and Purpurea

Echinacea, as a group, are flowering plants found within the daisy family. There are ten known species referred to as coneflowers with some being used as herbal medicines, e.g. Echinacea purpurea (9). E. angustifolia has a long tradition as a folk remedy used by North American indigenous peoples as a remedy for cough, headache, pain, and sore throat (10).

Various studies have shown that polysaccharides from Echinacea provide protection against various bacteria, e.g. Listeria and Candida albicans. These polysaccharides likely stimulate immune cells such as macrophages (11). E. purpurea seems to specifically activate various leukocytes and natural killer cells too (12).

Goldenseal

Goldenseal, a.k.a. Hydratis canadensis, has extensive use amongst Native American tribes as both a medicine for digestive problems, but also an eyewash and diuretic. Various compounds within Goldenseal allow the herb to be used as a coloring agent too. Goldenseal is a perennial herb that flourishes in the eastern regions of the United States and Canada (southeastern).

Because of its various chemical properties as an astringent it can be helpful as an insect repellant (13). As an antimicrobial, an interesting characteristic is a proposed efflux pump inhibition effect (14). Efflux pumps are intracellular mechanisms of various organisms that allow it to excrete antimicrobial chemicals that are transported or diffuse into the cell.

Oregano

Oregano, a.k.a. Origanum vulgare, is in the mint family of plants. It too has been used in traditional folk medicine for centuries and as an oil extracted from the oregano plant it is used extensively in dietary herbal supplements with a good safety profile (16).

Its antimicrobial properties are diverse, but much of it comes down to two polyphenols called carvacrol and thymol (17). Other medicinal constituents of oregano oils are various terpenes which also contain antimicrobial properties.

Tea Tree Oil

The essential oil of tea tree, a.k.a. Melaleuca alternifolia, like oregano, contains various terpenes which appear to damage the cell membrane of various microorganisms, including Candida albicans, Staph aureus and Escherichia coli. Research has shown that the greatest mode of action of tea tree oil against candida is through cell membrane viability and cellular respiration disruption (18).

There are many other botanical remedies such as black walnut, garlic, gentian, grapeseed extract, lavender, raspberry and more that have their own unique antimicrobial properties and complementary affects when used along with other herbs. One of the greatest advantages of botanical remedies is their multi-use potential and cross-reactivity against various pathogens, e.g. bacterial, fungal, parasitic. In addition, botanical remedies often do not have the same side effect profiles seen with common prescription medications and are typically well tolerated by most children and adults alike.

BioBotanical Research (BBR)

BBR has a variety of botanical formulations that support digestive health and aide in the reduction and/or elimination of opportunistic pathogens, including candida.

Biocidin in its various forms (capsule, liquid, liposomal), combines bilberry extract, echinacea (both angustifolia and purpurea), goldenseal, oregano, tee tree oil and other complementary ingredients into a pleasant-tasting, well-tolerated, highly effective combination botanical supplement. Biocidin is often combined with additional BBR products such as Olivirex (combination of olive leaf extract, garlic, goldenseal and more) and Proflora 4R (soil-based organisms of Bacillus coagulans, Bacillus subtilis and Bacillus clausii) comprising a complementary trio offering excellent support for digestive health and maintenance.

For more information about Bio-Botanical Research and the clinical application of their products, contact a BBR representative at Bio-Botanical Research, Biocidin.com.

Conclusion

Chronic candidiasis can be a challenging condition for many individuals. Effective intervention requires reliable diagnostic testing, as well as understanding the various pathogenic mechanisms inherent to these sophisticated organisms.

The use of medications such as Nystatin at varying dosages, i.e. 250,000 units to 750,000 units three times daily for 30 to 90 days may be required for control of chronic candidiasis. Fluconazole is always and option too, but typically is used in shorter durations, e.g. 2 to 4 weeks, unless consistent blood liver enzyme levels can be monitored. Resistant candidiasis may require Fluconazole at 100mg to 200mg daily other interventions have failed.

Finally, Biocidin in varying dosages, i.e. 1 to 2 capsules two to three times daily can have positive outcomes for chronic candidiasis. The length of intervention is variable, but for most individuals dealing with long-standing problems, use of Biocidin for 60 to 90 is typical.

It is critical to understand that every individual dealing with a chronic candidiasis condition may require individualized dosing based on their unique health circumstances and tolerance. Therefore, tailoring a supplement program to each person is often helpful and BioBotanical Research, with its various botanical supplements, provides great flexibility in product usage.

References:

1. 1. Nystatin" . American Society of Health-System Pharmacists . Archived from the original on 2016-02-03. Retrieved 2016-01-27.
2. Hilal-Dandan, Randa; Knollmann, Bjorn; Brunton, Laurence (2017-12-05). Goodman & Gilman's the pharmacological basis of therapeutics. Brunton, Laurence L., Knollmann, Björn C., Hilal-Dandan, Randa (Thirteenth ed.).
3. P., Rang, H. (2015-01-21). Rang and Dale's pharmacology. Dale, M. Maureen, Flower, R. J. (Rod J.), 1945–, Henderson, G. (Graeme) (Eighth ed.). [United Kingdom].
4. Hammond, S.M. (1977). Biological activity of polyene antibiotics. Progress in Medicinal Chemistry. 14. pp. 105–79.
5. The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
6. Longley, Nicky; Muzoora, Conrad; Taseera, Kabanda; Mwesigye, James; Rwebembera, Joselyne; Chakera, Ali; Wall, Emma; Andia, Irene; Jaffar, Shabbar; Harrison, Thomas S. (2008). "Dose Response Effect of High-Dose Fluconazole for HIV-Associated Cryptococcal Meningitis in Southwestern Uganda" Clinical Infectious Diseases. 47 (12): 1556–1561.
7. Bilberry: Science and Safety | NCCIH" . Nccih.nih.gov. Retrieved 2018-03-19.
8. J. Agric. Food Chem. 2008, 56, 3, 681–688. Publication Date: January 23, 2008
9. Kelly K. "The Conservation Status of Echinacea Species" (PDF). USDA. Retrieved 29 October 2014.
10. Moerman DE (1998). Native American Ethnobotany . Timber Press. p. 205. ISBN 978-0-88192-453-4 .
11. Roesler J, Steinmüller C, Kiderlen A, Emmendörffer A, Wagner H, Lohmann-Matthes ML. Application of purified polysaccharides from cell cultures of the plant Echinacea purpurea to mice mediates protection against systemic infections with Listeria monocytogenes and Candida albicans. Int J Immunopharmacol. 1991;13:27–37.
12. Barnes J, Anderson LA, Gibbons S, Phillipson JD. Echinacea species (Echinacea angustifolia (DC.). Hell, Echinacea pallida (Nutt.) Nutt Echinacea purpurea (L.) Moench): A review of their chemistry, pharmacology, and clinical properties. J Pharm Pharmacol. 2005;57:929–54.
13. Niering, William A. ; Olmstead, Nancy C. (1985) [1979]. The Audubon Society Field Guide to North American Wildflowers, Eastern Region. Knopf. p. 737. ISBN 0-394-50432-1 .
14. Ettefagh K.A., Burns J.T., Junio H.A., Kaatz G.W., Cech N.B., "Goldenseal (Hydrastis canadensis L.) Extracts Synergistically Enhance the Antibacterial Activity of Berberine via Efflux Pump Inhibition", Planta Medica 2010.
15. Garlic" . National Center for Complementary and Integrative Health, US National Institutes ofHealth. April 2012. Retrieved May 4, 2016.
16. Oregano" . MedlinePlus, US National Library of Medicine. 2016. Retrieved 7 October 2016.
17. V Manohar 1 , C Ingram , J Gray , N A Talpur , B W Echard , D Bagchi , H G Preuss Mol Cell Biochem. 2001 Dec;228(1-2):111-7. Antifungal activities of origanum oil against Candida albicans.
18. Sean D. Cox , 1,* Cindy M. Mann , 1 Julie L. Markham , 1 John E. Gustafson , 2 John R. Warmington, 2 and S. Grant Wyllie 1 Molecules . 2001 Feb; 6(2): 87–91. Published online 2001 Jan 16. Determining the Antimicrobial Actions of Tea Tree Oil.

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Chronic Lyme disease has long caused debate throughout the medical community, from how to diagnose it to how to properly treat the illness. In the meantime, patients suffer from misdiagnosis, mismanagement, and are even told it is all in their heads. This article discusses some of the myths and misconceptions about the historic infection and touches on some of the clinical considerations and complications that must be understood when addressing each new Lyme case.

 Lyme Disease, An Umbrella Term

First, Lyme disease is an umbrella term that refers to the infection caused by the Borrelia species bacteria and its associated vector-borne pathogens, or coinfections. According to the CDC, it is the most common vector-borne disease in the United States with 300,000 new cases reported each year (1). 

In the 1970s, an unusual cluster of children in Lyme, CT were diagnosed with arthritis, later to be identified as Lyme disease. Although it was named in the ‘70s, the Borrelia spirochetes have been shown by genomic analysis to have split off as unique organisms at least 100 million years ago, with the earliest detections of the infection recorded in medical literature in the late 1880s (2). There is ongoing debate about where it comes from and how it is transmitted. 

Borrelia and its coinfections are said to not only be transmitted by the black-legged tick, but also, according to recent evidence, by other vectors such as spiders, fleas, mites, and mosquitos (3). Additionally, Lyme spirochetes have even been found in semen and vaginal secretions as well as in cord blood, which backs clinical claims of sexual and in-utero transmission (4). 

Originally thought to be found only in the United States in the New England territory, the Midwest states of Wisconsin and Minnesota, and the Northern Pacific states, Lyme disease has now been identified in all 50 states and across all continents, including the Arctic and Antarctica. Different strains of Borrelia can be seen throughout these different regions and are associated with their own unique set of symptoms (5).

Transmission

The rate at which Borellia is transmitted from vector to host is also under debate. It is said that transmission of Borrelia organisms occurs with a tick attachment of somewhere between 10 minutes and 72 hours. More commonly, transmission occurs in less than 16 hours. Ultimately, transmission rate depends on many factors including the type of tick (hard vs soft), species, location of spirochetes in the tick, if the tick is partially fed (most are), and the health or weakness of the host’s immune system. (6)

Acute vs. Chronic

There is not a very clear definition between acute and chronic Lyme disease, but clinically speaking acute Lyme refers to those who are infected and treated right away without residual symptoms. According to Dr. Joseph Burrascano, a board member of International Lyme and Associated Diseases Society (ILADS), chronic Lyme presents with three major criteria (7): 

1. Illness presents for at least one year.
2. Persistent major neurological involvement (such as encephalitis/encephalopathy)or arthritic involvement.
3. Continued active infection with Borellia regardless of prior antibiotic therapy.

Regardless of the definition, it is known that patients treated earlier in the illness fare better than those whose treatment is delayed (8).

The Great Imitator – Signs and Symptoms

Lyme disease, known as the “Great Imitator,” can easily be confused with other illnesses and infections. Its symptomology often overlaps common chronic conditions such as chronic fatigue syndrome, fibromyalgia, a number of autoimmune arthritic conditions, and MS to name a few. The most prevalent symptoms include fatigue, headaches, fever, joint pain, arrhythmia, parathesis and other neuropathies, and a pathognomonic skin rash called erythema migrans, or more commonly referred to as the “bulls-eye rash.” Although pathognomonic, the rash is not present in every Lyme case. In fact, the estimate for rash occurrence is a very wide range of 27% to 80% (9). In reality, the rash is probably only seen in about one-third of people who get Lyme disease, so this should not be used as a way to screen someone for Lyme, but rather can be used in lieu of testing to confirm a Lyme diagnosis. 

A Stealth Infection

Lyme is known as a stealth infection due to multiple factors such as its ability to morph between different spirochetal and atypical forms, to reside both extracellularly and intracellularly, and to change its outer protein surface markers.

Borrelia’s ability to morph between forms may require different treatment approaches. Besides the spirochetal form of Borrelia, there are also different atypical, cystic (round bodies) and granular forms (10) which it tends to morph into when under adverse conditions. These atypical and cystic forms can be much harder for our immune systems and antimicrobials to penetrate, creating a shield-like effect. 

Additionally, Borrelia can be found in fluid or tissue compartments, extracellular matrix, or intracellularly, creating more complexity and difficulty in delivering therapies effectively. There is not yet a single antibiotic that is effective in both compartments or extracellular and intracellular delivery, resulting in the need for combination therapy, conventionally seen as multiple antibiotic use (7)

Its ability to change its outer protein surface markers makes Borrelia not only challenging to identify on labs for diagnosis, but also difficult to be appropriately identified and addressed by our immune systems. This aspect of its pathophysiology is perhaps one of the main reasons why Lyme can be seen as a persistent infection and creates such systemic chaos.

Borrelia burgdorferi, one of the most common US strains of Borrelia, has been shown to evade host immunity through up- and down-regulation and molecular changes to various surface-expressed outer surface proteins (11), and to reduce the functionality of the innate immune response (12), including inhibition of complement activation and the adaptive immune response (13). What results are body-wide inflammation and cytokine storms that in essence create an autoimmune-like picture and immune dysfunction of the host.

Complications – Coinfections and Opportunistic Infections 

Treatment for Lyme disease is complicated by the fact that it takes much more than addressing bacterial load to resolve the infection once it becomes chronic. The other key areas to address are immune regulation, inflammation control, sleep disturbances, rebuilding a healthy gut barrier and brain barrier, reducing neuroinflammation, supporting cardiovascular integrity, and reestablishing appropriate autonomic control. On top of the body-wide systems affected by Lyme itself, careful consideration should be given to addressing coinfections and opportunistic infections.

Coinfections refer to a handful of infectious pathogens often transmitted at the same time as Borrelia. The most common ones include anaplasma, babesia, bartonella, chlamydia, ehrlichia, mycoplasma, and rickettsia (6). Their presence is so common that a diagnosis of Lyme disease almost always includes at least one coinfection, if not more. This can lead to complications of diagnosis and treatment. Each has its own set of symptomatology that often overlap, as well as require its own set of antimicrobials and treatment approaches and timelines. For example, babesia is a parasite. It is often required to be addressed first, or at the beginning of treatment, as it can be a more stubborn, immunosuppressive infection (7). Opportunistic infections are those that take advantage of a compromised immune system. Such infections may be viruses like EBV, CMV, and HHV6. For this reason, treatment protocols should make sure to target immune modulation to prevent opportunistic infections from thriving. 

As you can see, there are many complications and considerations when dealing with chronic Lyme disease. Understanding its pathophysiology is key to putting together a multifactorial approach for best treatment outcomes.

REFERENCES

1. “Lyme Disease.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 16 Dec. 2019, www.cdc.gov/lyme/index.html. 
2. Buhner, Stephen Harrod. Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses. 2nd ed., Raven Press, 2015, p.24.
3. Luger, S. “Lyme Disease Transmitted by a Biting Fly.” New England Journal of Medicine, vol. 322, no. 24, 1990, pp. 1752–1752., doi:10.1056/nejm199006143222415. 
4. Middelveen, Marianne J et al. “Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions.” F1000Research vol. 3 309. 18 Dec. 2014, doi:10.12688/f1000research.5778.3
5. Buhner, Stephen Harrod. Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses. 2nd ed., Raven Press, 2015, p.17.
6. Buhner, Stephen Harrod. Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses. 2nd ed., Raven Press, 2015, p.37.
7. Burrascano, Joseph. “Advanced Topics in Lyme Disease Diagnostic Hints and Treatment Guidelines for Lyme and Other Tick Borne Illnesses.” 16th ed., 2008. 
8. Bechtold, Kathleen T., et al. “Standardized Symptom Measurement of Individuals with Early Lyme Disease Over Time.” OUP Academic, Oxford University Press, 23 Nov. 2016, academic.oup.com/acn/article/32/2/129/2567082. 
9. Johnson, Lorraine. “LYMEPOLICYWONK: How Many of Those with Lyme Disease Have the Rash? Estimates Range from 27-80%.” LymeDisease.org, 10 Apr. 2014, www.lymedisease.org/lymepolicywonk-how-many-of-those-with-lyme-disease-have-the-rash-estimates-range-from-27-80-2/. 
10. Miklossy, Judith, et al. “Persisting Atypical and Cystic Forms of Borrelia Burgdorferi and Local Inflammation in Lyme Neuroborreliosis.” Journal of Neuroinflammation, vol. 5, no. 1, 2008, p. 40., doi:10.1186/1742-2094-5-40. 
11. Coutte, Loïc, et al. “Detailed Analysis of Sequence Changes Occurring during VlsE Antigenic Variation in the Mouse Model of Borrelia Burgdorferi Infection.” PLoS Pathogens, vol. 5, no. 2, 2009, doi:10.1371/journal.ppat.1000293. 
12. Miller, Jennifer C., et al. “Gene Expression Profiling Provides Insights into the Pathways Involved in Inflammatory Arthritis Development: Murine Model of Lyme Disease.” Experimental and Molecular Pathology, vol. 85, no. 1, 2008, pp. 20–27., doi:10.1016/j.yexmp.2008.03.004. 
13. Bernard, Quentin, et al. “Borrelia Burgdorferi Protein Interactions Critical for Microbial Persistence in Mammals.” Cellular Microbiology, vol. 21, no. 2, 2018, doi:10.1111/cmi.12885. 

One of the most challenging aspects of chronic Lyme disease is the ability to properly test for and diagnose the disease. There is controversy in the medical community about both testing and how to interpret the results. In this article, we will take a look at different testing options, their validity, and strategies for how best to interpret the results in light of clinical findings.

Chronic Lyme Diagnosis

Chronic Lyme disease is primarily a clinical diagnosis based on a person’s history, symptomatology, and physical examination (1). Laboratory testing is used to confirm clinical findings and presentations. Many, if not most, Lyme tests are not sensitive enough to detect all cases. Diagnosing Lyme – as well as convincing patients and other doctors that Lyme is present – can be difficult, especially when the patient is seronegative. The only definitive way to diagnose Lyme is from the presence of the pathognomonic erythema migrans, or bulls-eye rash. The problem is that up to two-thirds of people infected with Borrelia do not have a rash, or if they do form a rash it is often non-traditional or missed (2).

Timing

The time frame when someone gets tested for Lyme disease impacts the validity of lab results. Only half of people infected produce measurable antibodies to Lyme spirochetes in the first two to four weeks of being infected (2). This means if someone is tested too early after initial infection, they might not show positive results on labs even if they do have Lyme disease. The main antibodies tested, IgM and IgG, are also elevated at different times during the infection. IgM antibodies, which are the first responders and typically present during acute infections, “rise during the third week, peak after four to six weeks, then disappear by week eight,” according to authors Stephen Harrod Buhner and Neil Nathan (2). IgG antibodies, which play a role in long-term immunity, they note, “appear between six weeks and three months of infection and can persist for years or decades, even after successful treatment” (2). 

Other Reasons for Poor Testing Outcomes

False negatives refer to a negative test result even when the patient is clinically positive with Lyme disease. There are several reasons for this. Some individuals have a diminished response to antigens and therefore will not develop enough antibodies for testing to pick up (3). In addition, the bacteria dampens the immune response of the host, further depressing detectable markers. Some testing evaluates the presence of Borrelia DNA, however, spirochete levels may be too low for detection, even by the most sensitive testing (2). This is further complicated when antibiotic therapy is started before testing, lowering the number of spirochetes and further minimizing chances of detection. 

False-positive testing is also a possibility and is due to cross-reactivity of antibody responses to other microorganism proteins, such as the syphilis spirochete and viruses (4). 

There are many species of Borrelia known to cause Lyme disease and other illnesses. Limitations in the testing extend to the lack of specific species identification. Most ELISA and Western blot tests use assays for Borrelia burgdorferi. So if someone is tested for Lyme but has a different species of Borrelia than burgdorferi, a positive diagnosis may be missed. 

Center for Disease Control (CDC) Criteria

A two-tiered testing process is recommended for identifying Borrelia by the CDC (5). First, an ELISA (enzyme immunoassay) or IFA (Indirect immunofluorescence assay) is run. If it is negative, then no other testing is recommended. If found positive or undetermined, then the second-tier Western blot is used to confirm the diagnosis. The problem with this approach is that both types of tests have limitations.

Indirect Testing

Indirect tests, such as the ELISA, IFA, Western blot, and lymphocyte response assays, measure immune response to an infectious agent. When challenged, a healthy immune system reacts to the threat and creates specific antibodies and other immune markers. The problem with using indirect methods is that Lyme disease dampens the immune response. Therefore, results may be negative even in the presence of the disease (1). 

ELISA Testing

The ELISA test detects the presence of antibodies to Borrelia organisms. It is poorly specific as the assays are prepared from whole-cell cultured Borrelia, which lacks the reactive antigens that smaller, more specific antigens provide (6). Additionally, the assays express other antigens that can bind to non-Borrelia antibodies leading to cross-reactivity (7). Although claims are made that ELISA testing is adequate, it is not as sensitive as it should be to be considered a screening test (8). Studies have shown that only 65-70% of patients who tested positive for Lyme with culture showed an antibody response. This means 30-35% of these confirmed cases would have been missed with ELISA testing alone. There have been some advances in ELISA testing for Lyme. The C6 peptide ELISA test detects more specific proteins to B. burgdorferi. This test has been found to have high specificity with low cross-reactivity to other pathogens and has proven to be virtually equivalent to the two-tier protocol (15). It can detect early exposure to Borrelia and some studies suggest it can be used to track progression of the disease and treatment, as it has been seen to decrease with successful treatment (16).

Western Blot

The Western blot, although known to be more specific than the ELISA test, is only half as sensitive, especially in early onset of the disease (9). Western blot assays use outer protein fragments of the Borrelia bacteria and assess reactivity to these antigens by the immune system. Since proteins of the same molecular size cluster together in what are called bands, a blood specimen is tested to see how many bands the blood reacts with (2). The more bands, the more specific the diagnosis. 

According to the CDC standardized guidelines, two of three particular bands are required for a positive IgM blot result, and five out of 10 bands are required for a positive IgG blot result (6). There 

is disagreement, however, as to which bands are clinically significant as well as the number of bands needed to identify positive results. This dispute lies in the fact that the standardized guidelines were originally put in place for surveillance, not for clinical diagnosis (1). Other private and specialized lab companies consider not only IgM bands of 23-25 kDa, 39 kDa, and 41 kDa to be clinically significant, but also 31 kDA, 34 kDA, and 83-93 kDa. As for clinically relevant IgG bands, there are 10 bands tested, and of these, the CDC does not include bands 31 kDa or 34 kDa, which have both been seen to appear later in immune response and are highly Lyme specific (2). 

Cross-reactivity can also be a problem leading to false positives with the Western blot test. The 41 kDa band is often the first to react with blood but can also cross-react with other flagella-like organisms. So even though this band is considered significant, it should be considered in combination with other bands for greater reliability (1). 

There is also disparity in how the results are reported. Some labs will simply report positive or negative, while other, more specialized laboratory companies will report which bands were positive, negative, or indeterminate. Additionally, some labs quantify how strong the reaction is by indicating a single + up to multiple ++++. Having information about each band and the degree to which it was reactive is extremely helpful as it can aid Lyme-literate doctors in reading between the lines. Even in an overall “negative” Lyme result, there may be enough bands present and reactive to indicate there is some immune response to Borrelia. This type of result can be used in conjunction with the patient’s history and clinical presentation to determine if Lyme is present. Again, since the Borrelia bacteria hinders immune response, often the sickest patients with Lyme disease have negative or equivocal results (1). 

The Western blot test also has limitations in its ability to identify active versus past infection (6). Although it can provide information about the duration of infections over time, there are cases where seroconversion from IgM to IgG does not happen, even in chronic conditions. This is due to the ability of the bacteria to change its outer protein surface markers making it difficult to detect by testing and confusing the immune system into thinking it is confronting a new infection. The CDC specifies that IgM positive results alone on Western blot should only be used within the first month of infection (6). 

Some advances such as the Lyme ImmunoBlot offered by IGeneX, have increased specificity and sensitivity to 98.7% and 90.9% respectively (13). The ImmunoBlot is similar to the Western blot but rather than proteins separated by size, recombinant B. burgdorferi species antigens are sprayed at specific positions on the blot. It is designed to detect antibodies to B. burgdorferi variants, including the eight most common Borrelia strains found in North America and Europe (10).

According to a meta-analysis on test accuracy, the mean sensitivity for all tests and all samples was 59.5% and 53.7% when the two-tier methodology was used (14). All things considered – different degrees of sensitivity, specificity, criteria, and testing methods – these indirect tests have a wide range for interpretation making them unreliable for a clear diagnosis of Lyme disease. 

Other Indirect Tests

Immunofluorescence Assay (IFA) detects the combination of antibodies (IgM, IgG, and IgA) against B. burgdorferi. It is still looking at immune response, but the benefit is that it is not as dependent on the timing of testing. If the antibodies are present, the slides will fluoresce bright green when viewed with a fluorescent microscope (12). It may be used in conjunction with the Western blot but should not be used as a stand-alone test.

The ELISPOT (Enzyme-Linked ImmunoSpot) assay detects T cell activation to Borrelia-specific antigens. The benefits of this test are that it can detect this T cell reaction early on, before antibodies may be detected, or even later in the disease stage when antibodies are low (10). This makes this test especially helpful for those who are seronegative yet still suspicious of Lyme disease. Additionally, it can demonstrate quantitative aspects of the disease as it measures the amount of T cell reactivity, allowing us to assess the level of immune response, and predict disease severity (11).

Direct Tests

Direct tests are those such as microscopy, culture, and molecular methods of measurement such as Polymerase Chain Reaction (PCR), which detect the presence of the actual microbe (3). These tests can be much more definitive in identifying Lyme and other infections than indirect methods. Microbial culture is considered the “gold standard” of direct-testing methods, although not all organisms may effectively be cultured.

PCR

PCR evaluates the presence of bacterial DNA in serum or other body fluids (1). This test is very specific, although false positives are possible as DNA and mRNA can be detected in samples after spirochetes are no longer present (2). Additionally, Borrelia hide deep in the tissues and cells and are often not found in the bloodstream. PCR may be more helpful in early stages of the disease when spirochetes are prevalent in the blood (1).

Culture

Culturing refers to growing bacteria or organisms from a blood sample. The blood sample is placed on a special medium that promotes growth. If the microbe is present, it will reproduce. It can then be identified by cell formation and growth characteristics and further confirmed by immune-staining or PCR (1). This test is more reliable than the Western blot and more sensitive than PCR, however, it can take weeks or even months to produce bacterial growth. Some organisms do not grow well on the medium and spirochetes with a low concentration in the blood may be hard to find. If the sample being used does not have spirochetes present, then there will be no growth (2).

Direct Antigen Test

The Direct Antigen test looks for the Borrelia bacteria or antigens of the bacteria in urine (12). The antigens are combined with anti-B. burgdorferi-specific antibodies and treated with a stain that makes them change color for identification. This test is often done with antibiotic or antimicrobial provocation to enhance the presence of antigens in the urine (1). It can be helpful when a patient is seronegative and PCR negative, but Lyme is still suspected. 

Testing for Coinfections

Because coinfections are common in Lyme disease, it is important to test for them to understand the disease complex and guide treatment approaches. If coinfections are present, then appropriate antimicrobials must be used to address them. The clinical picture which includes history, symptoms, and physical exam should be taken into consideration when trying to identify coinfections. Like Lyme, testing can come back negative, even if a patient has the suspected infection. Some of the most common tests for coinfections include antibody testing, Fluorescent In-Situ Hybridization (FISH) tests, and PCR tests (1). The FISH test is a direct test that uses a blood smear with fluorescent dye to identify the microbe (12). If the organism is present it will fluoresce. The FISH test for Babesia and Bartonella can identify different strains of each infection and has a high level of specificity with very few false positives. It can be falsely negative, however, if there were no pathogens in that particular sample. 

Conclusion

Testing for Lyme disease is as complicated as the disease itself. Except for the presence of an erythema migrans rash, there is no guaranteed way to diagnose Lyme disease. Laboratory testing is used as a way to help clarify the possible diagnosis of infection and coinfections. Lab results should be viewed in light of their limitations and interpreted in combination with clinical presentations, physical exams, and response to treatment. 

REFERENCES

1. “Testing For Lyme .” The Beginner’s Guide to Lyme Disease: Diagnosis and Treatment Made Simple, by Nicola McFadzean, BioMed Publishing Group, 2013, pp. 79-99. 
2. “Lyme Disease and Other Borrelial Infections .” Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses, by Stephen Harrod Buhner and Neil Nathan, 2nd ed., Raven Press, 2015, p. 46-56. 
3. Info. “Lyme Disease and Detection.” Fry Laboratories, L.L.C, Fry Laboratories, L.L.C, 25 July 2019, frylabs.com/resources/lyme-disease-and-detection/. 
4. Naesens R, Vermeiren S, Van Schaeren J, Jeurissen A. False positive Lyme serology due to syphilis: report of 6 cases and review of the literature. Acta clinica Belgica. Jan-Feb 2011;66(1):58-59.
5. “Diagnosis and Testing.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 20 Nov. 2019, www.cdc.gov/lyme/diagnosistesting/index.html. 
6. Branda, John A, et al. “Advances in Serodiagnostic Testing for Lyme Disease Are at Hand.” OUP Academic, Oxford University Press, 7 Dec. 2017, academic.oup.com/cid/article/66/7/1133/4706288. 
7. “Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 15 Aug. 2019, www.cdc.gov/mmwr/volumes/68/wr/mm6832a4.htm?s_cid=mm6832a4_w. 
8. Bakken, L L, et al. “Interlaboratory Comparison of Test Results for Detection of Lyme Disease by 516 Participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Proficiency Testing Program.” Journal of Clinical Microbiology, vol. 35, no. 3, 1997, pp. 537–543., doi:10.1128/jcm.35.3.537-543.1997. 
9. VK;, Steere AC;McHugh G;Damle N;Sikand. “Prospective Study of Serologic Tests for Lyme Disease.” Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/18532885/. 
10. “IGeneX Inc. Introduces New Diagnostic Tests for Lyme Disease and Tick-Borne Relapsing Fever.” IGeneX, 29 July 2019, igenex.com/press-release/igenex-inc introduces-new-diagnostic-tests-for-lyme-disease-and-tick-borne-relapsing-fever/. 
11. Slota, Meredith, et al. “ELISpot for Measuring Human Immune Responses to Vaccines.” Expert Review of Vaccines, vol. 10, no. 3, 2011, pp. 299–306., doi:10.1586/erv.10.169. 
12. “Test Methodologies.” IGeneX, 23 Apr. 2020, igenex.com/test-methodologies/. 
13. Lyme Immunoblot IgM and IgG, IGeneX, igenex.com/wp-content/uploads/LymeImmunoBlot-DataSheet.pdf. 
14. Cook, Michael, and Basant Puri. “Commercial Test Kits for Detection of Lyme Borreliosis: a Meta-Analysis of Test Accuracy.” International Journal of General Medicine, Volume 9, 2016, pp. 427–440., doi:10.2147/ijgm.s122313. 
15. C6 Lyme ELISA, Oxford Immunotec, 2017, www.itk.nl/files/images/ITK%20-%20C6%20Lyme%20ELISA%20Brochure_v6.pdf. 
16. Philipp, M. T., et al. “C6 Test as an Indicator of Therapy Outcome for Patients with Localized or Disseminated Lyme Borreliosis.” Journal of Clinical Microbiology, vol. 41, no. 11, 2003, pp. 4955–4960., doi:10.1128/jcm.41.11.4955-4960.2003.

Chronic Lyme disease is an extremely complex illness. Once it has been diagnosed, the next challenge is understanding how to treat it. In this article, we will touch upon conventional antibiotic therapies used to treat Lyme borreliosis and its associated coinfections, as well as discuss general approaches for how best to support patients toward remission. Botanical therapies can also play a critical role in the treatment process. Understanding their advantages can assist in choosing the best therapeutic approach. Biocidin® has conducted in vitro research showing a pronounced effect against Borrelia in all of its forms.

Antibiotic Considerations

One of the main considerations when using antibiotics is the fact that Borrelia, based on the environment, has different pleomorphic forms it can select – spirochete, cell-wall deficient form, cyst form/round bodies. For this reason, multiple antibiotics are needed to appropriately treat each form and its location, intracellular and extracellular. Some of the major groups of medications that are used include macrolides (tetracyclines and erythromycin), which target bacterial ribosomes and are used for intracellular cell-wall deficient forms. Penicillins and cephalosporins that target cell walls are best for extracellular spirochetes. And some medications target cyst forms of Borrelia such as metronidazole, tinidazole, and Plaquenil (hydroxychloroquine) (1). The choice of medications and dosages used will differ from person to person based on duration and severity of the illness, as well as the presence of coinfections and opportunistic infections, immune deficiencies, gut health, weight, age, and tolerance (2).

Doxycycline

The most common antibiotic recommended for any Lyme presentation is the tetracycline Doxycycline, with its ability to address intracellular, cell-wall deficient forms of Lyme. The CDC recommends dosing at 100 mg twice daily for 10 to 14 days for early or acute Lyme borreliosis and up to 28 days for more disseminated Lyme (3). According to ILADS – the International Lyme and Associated Diseases Society made up of Lyme-literate experts – this dose and duration are not enough to eradicate Borrelia. This dose is bacteriostatic (4) rather than bactericidal, and large spikes in blood and tissue levels show more bactericidal activity. Thus Doxycycline prescribed at 200 mg 2x/day is more effective against Lyme borreliosis (2).

Doxycycline has side effects that should be monitored. First, it can create photosensitivity resulting in severe sunburns. Patients should be directed to stay out of the sun while on this medication. It also often leads to GI distress and the inability to tolerate the medication, especially at higher doses.

For initial treatment of early Lyme with erythema migrans (EM) presentation, ILADS recommends Doxycycline be used for at least four to six weeks, often alongside other first-line antibiotics and those that target cyst form (5). Treated immediately and aggressively, acute Lyme can be successfully resolved, and when an EM rash is present, waiting for laboratory confirmation to treat is not recommended (2).

In chronic Lyme, continuous treatment should be administered until the active infection has been cleared. This typically requires a minimum of four to six months and often much longer (2). Additional classes of antibiotics are strongly suggested to address the cyst and spirochete forms of Lyme and other possible coinfections. Doxycycline has been shown to be effective where Anaplasma or Ehrlichia are also possibilities.

For more information on antibiotic treatments for addressing Borrelia please visit Dr. Burrascano’s Treatment Guidelines For Lyme And Other Tick-Borne Illnesses.

General Principles in Addressing Chronic Lyme Disease

Chronic Lyme disease affects every system in the body. The biggest challenge is knowing where to start when it comes to treatment. Using a holistic and integrative approach is critical not only for reducing the bacterial load but also for strengthening and supporting each system. No one protocol fits all, and individual circumstances such as comorbidities, coinfections, and opportunistic infections, heavy metals, mold toxicity, methylation defects, and chronic inflammatory states must be taken into consideration when developing a treatment plan.

The sole purpose of antibiotics is to kill the infection. Although this is an important part of treating chronic Lyme disease, focusing on “killing” alone is not enough. These bugs are very good at evading our immune systems and antimicrobial agents, so focusing solely on killing the infection can be ineffective. The general principles in addressing chronic Lyme disease, which should be prioritized, include supporting detoxification pathways, reducing inflammation, immune modulation, and, of course, using antimicrobial agents.

Detoxification

Detoxification is key to help reduce Herxheimer (Herx) reactions that occur when using antimicrobials. As the Borrelia and coinfections are killed, they release toxins and neurotoxins that can make symptoms worse before they improve (6). Often, Herx reactions are so intense that patients cannot continue antimicrobial treatments. Therefore, it is key to start protocols with some sort of detoxification support. Many Lyme patients also suffer from already impaired detoxification pathways that may be affected by genetic SNPs, toxins, and heavy metals (even mycotoxins) from mold. Pushing ahead with protocols without properly supporting detox pathways will often set patients back. It is critical to allow enough time to work on detox and drainage before introducing antimicrobial protocols and to continue them through the entirety of their treatment. When addressing detoxification, make sure to consider all major emunctories including liver, kidneys, lungs, colon, lymph, and skin.

Glutathione

Glutathione is a potent antioxidant made up of the three amino acids: cysteine, glutamine, and glycine. It is produced in the liver and targets reactive oxygen species. It is known to be neuroprotective as it prevents neuronal death associated with amyloid plaque deposits (7). This is a useful nutrient for detoxification as well as for supporting brain function and can be valuable for those who also suffer from mycotoxin illness.

Smilax glabra

Smilax glabra is an excellent herb for supporting detoxification and inflammation. The polysaccharides contained in the rhizomes have been shown to reduce nitric oxide, TNF-alpha, and IL-6, thus modulating inflammatory response. Unlike the other species of Smilax, this form can cross the bloodbrain barrier, giving it the ability to neutralize neurotoxins and play a significant role in mitigating Herx reactions, particularly where they include the worsening of neurological symptoms (8).

Other Supportive Detoxification Botanicals and Practices

Other botanicals that can support detoxification include milk thistle, dandelion root, burdock root, and schisandra, as well as aloe for supporting the colon, juniper berry for the kidneys, and cleavers for the lymphatic system. In addition to botanicals and nutrients, patients can incorporate at-home practices such as dry brushing the skin for supporting the movement of lymph, castor oil packs over the liver, Epsom salt baths for supporting detoxification and relaxation of the muscles, and full-spectrum infrared sauna for those who have access. Many Lyme patients are particularly sensitive to detoxification. These patients can use homeopathic drainage remedies that focus on liver, kidney, and lymph drainage to open emunctories. Finally, binders such as Biocidin’s G.I. Detox™+, which includes activated charcoal, zeolite clay, and silica, help absorb and eliminate the toxins that are circulating. Because it is extremely important to mitigate Herx reactions, G.I. Detox™+, is often given to patients early in the protocol for optimal support.

Inflammation

Those with chronic Lyme disease suffer from immense amounts of systemic inflammation, with additional inflammation triggered by the Herx reactions. This inflammation causes many of the symptoms these patients experience including joint and muscle pain, nerve pain, cognitive dysfunction, GI distress, and even inflammation of the lining of the heart and brain (6).

Where does all this inflammation come from? Borrelia stimulates cytokine production through two mechanisms, directly by creating the cytokines and indirectly by stimulating the body’s cytokine responses to the infection (9). Borrelia morphs to and from different forms and changes its outer protein surface markers, confusing the immune system. As the spirochetes cause tissue breakdown, these tissue fragments, along with fragments of dead spirochetes, create an autoimmune-like reaction in which the immune system starts to attack similar structures in the body (9). Spirochetes are also extremely fast. They have two “motors” which increase their motile power and allow them to easily escape the body’s slower-moving white blood cells, enabling them to colonize throughout the body. This explains the hallmark migratory pain that many Lyme patients experience. To get ahead of the symptoms, the inflammatory response must be addressed to reduce the cytokine storms and support a more balanced response from the immune system.

Curcumin

Curcumin is a compound found in turmeric and is a useful anti-inflammatory agent. It also has strong antioxidant capabilities and is immune balancing. Curcumin is neuroprotective and promotes neuroregeneration by increasing neuron stem cell growth in the brain up to 80% (10).

Red Sage (Salvia miltiorrhiza)

Red sage can normalize cytokine responses to microbial infections, in particular regulating unhealthy NF-kB behavior which is one of the primary pathways activated by Borrelia (11). It is often used in combination with Chinese skullcap.

Chinese Skullcap (Scutellaria baicalensis)

Chinese skullcap is one of the strongest cytokine-modulating herbs and is useful against the entire Lyme group of stealth pathogens. It has wide systemic absorption, is protective of endothelial and epithelial cell damage caused by intracellular cytokines, and is indirectly antibacterial as it blocks the ability of the bacteria to scavenge nutrients from the host cells, making it hard for the bacteria to survive (11). These cytokine-modulating herbs can reduce the severity of infection and protect cellular and organ health, making them a critical part of Lyme and coinfection treatment.

Immune Modulation

Although resolving infection is the ultimate goal, we have come to understand that because Borrelia has been shown to lower immune responses, a more realistic approach is to reduce the bacterial load to a threshold the immune system can handle on its own. This requires supporting immune function so it can appropriately respond to fight the infection. Because the gut harbors 70-80% of our immune system, it is key to address gut health in supporting immune function. Many immune-modulating botanicals have the bonus activity of supporting gut health.

Cordyceps

Cordyceps is highly protective of sphingomyelin (lipids of the myelin sheath), the lungs, brain, and kidneys. It is a strong inhibitor of hydrogen-peroxide oxidation and LPS in microglia cells. It inhibits production of NO, PGE2, and proinflammatory cytokines and actively protects the mitochondria from ROS. Cordyceps modulates immune responses intracellularly which is key when addressing an intracellular infection. To be effective, it must be viewed as a medical food and dosed with a minimum of three grams daily, but six grams daily is ideal as a baseline (11).

Astragalus

Another potent immune modulator is astragalus. It works by supporting several facets of the immune system, including enhancing phagocytic activity of monocytes and macrophages, increasing interferon production and natural killer-cell activity, enhancing T-cell activity, and potentiating other antiviral mechanisms. It is particularly useful in endemic areas to help prevent Lyme disease as it counteracts immune suppression caused by saliva-inhibition factors of ticks. It should be noted that in patients with late-stage Lyme disease, astragalus may exacerbate autoimmune responses, while in others it alters Th1/Th2 balance and reduces autoimmune dynamics, so patients should be monitored when astragalus is used (12).

Treat the Gut with Biocidin® Liquid Formula

When it comes to the gut, factors such as diet and nutrition, increased permeability, overgrowth of yeast and bacteria, and microbial abundance and diversity must all be taken into account. Biocidin® Liquid is a proprietary blend of 17 botanical extracts and essential oils which give it broad-spectrum antimicrobial capabilities as well as immune-modulating properties. Biocidin capitalizes on the synergy of combining different herbs in a formula, as opposed to a single botanical, which results in a layering effect with a greater breadth of activity.

Along with Biocidin®, the probiotic formula Proflora®4R can be used to address the dysbiosis often seen in Lyme patients. Proflora®4R contains spored-based probiotics with quercetin for addressing tight junctions and lowering histamines. For additional support, L-glutamine or serum-derived immunoglobulins can be used. Once health has been restored in the GI tract, it is helpful to graduate to Biocidin®LSF, a liposomal formula, for enhanced intracellular and systemic delivery.

Antimicrobial Herbs

Herbal options provide a powerful way to address chronic Lyme and coinfections. They often have broad-acting mechanisms of action, fewer side effects, more support for overall vitality, and, due to their many constituents, less microbial resistance than conventionally used antibiotics.

Teasel Root (Dipsacus sylvestris)

Teasel root is considered a valuable antimicrobial and anti-inflammatory herb in the treatment of Lyme disease. Some sources believe that it helps to bring spirochetes into the bloodstream from the tissues, making them more vulnerable to antimicrobials. In particular, teasel root is very supportive in addressing Lyme arthritis. It can cause significant Herx reactions at the start of treatment but dropping the dose is typically all that is needed to reduce the reaction (10-30 drops daily) (6).

Cat’s Claw (Samento) (Uncaria tomentosa)

Cat’s claw has anti-inflammatory, antibacterial, antiviral, immune-modulating, and antioxidant properties. It contains quinovic acid glycosides, which are natural precursors to quinolones, a class of pharmaceutical antibiotics. It has been used as a stand-alone therapy and in conjunction with other antimicrobials (6).

Andrographis (Andrographis paniculata)

Andrographis is one of the best anti-spirochetal herbs for borrelial infections. This herb enhances immune function, protects the heart muscle, is anti-inflammatory, and crosses the blood-brain barrier. It is a systemic herb and helps correct inflammation-mediated neurodegeneration in the brain. It has been seen to prevent active infection when the tincture is applied topically and covered with bentonite clay for 24 hours to a bite site as soon as the tick is removed (12).

Japanese knotweed (Polygonum cuspidatum)

Red sage can normalize cytokine responses to microbial infections, in particular regulating unhealthy The most potent constituent in Japanese knotweed is resveratrol, a potent vasodilator, antiinflammatory, and inhibitor of platelet aggregation. Japanese knotweed modulates and enhances immune function, protects the body against endotoxin damage, and is highly protective of endothelial tissue. Japanese knotweed enhances blood flow and can cross the blood-brain barrier helping to reduce inflammation in the brain. It also helps other herbs and drugs enter difficult areas of the body to kill bacteria, making it a synergistic herb. It is a highly specific herb for Bartonella and Lyme infections (13).

Biocidin®LSF - Antimicrobial, Immunomodulatory, Anti-inflammatory Botanical Formulation

Biocidin®LSF has been a powerful tool in addressing Lyme disease in my patients, as it contains antimicrobial, anti-inflammatory, immune-modulating, and biofilm-breaking abilities. Additionally, its liposomal delivery is extremely helpful for enhancing intracellular absorption.

A year-long, in vitro study on the effect of Biocidin® Liquid and Biocidin®LSF liposomal formula on Borrelia, was completed with significant findings. The full, published article, which can be viewed here, looked at the Minimum Inhibitory Concentrations (MICs), Minimum Bacterial Death (MBD), and the time it took for these formulas to kill the Borrelia in vitro. Additionally, Dr. Leona Gilbert, one of the researchers who conducted the study, looked at all North American and European strains of Borrelia as well as the different pleomorphic forms (spirochete, blebs, round bodies, and biofilm) (14).

The MIC for the Liquid against all forms of the Lyme was 1:10, while the MIC for the LSF against all forms of the Lyme was 1:25. Using these dilutions, the formulas were exposed to 6 x 106 spirochetes in three ml of cultured media, and the cells were counted at 10, 20, 30, 60, and 120 minutes. In both scenarios, there was 97% cell death of the spirochetes in just 10 minutes after exposure to either Biocidin® delivery system. Even more impressive was the fact that the spirochetes did not morph into a cystic form, which will often happen when using potent antibiotic therapy.

Conclusion

Chronic Lyme disease is multifactorial, affecting every system of the body; thus, an integrative and systematic approach is the best way to successfully support recovery. Besides nutrient and botanical therapies that address the principles discussed in this article, lifestyle changes such as an antiinflammatory diet, addressing stress and hormone levels, and even managing PTSD should be focused on. Using a low-and-slow approach and implementing therapies strategically and simultaneously is the best way to achieve remission. There is no one protocol that will work for every person, so evaluating each individual’s presentation, labs, history, and symptoms will give the best insight into where to begin and how to build a successful treatment protocol.

REFERENCES

1. “Suggested Medication Protocols .” The Beginner’s Guide to Lyme Disease: Diagnosis and Treatment Made Simple, by Nicola McFadzean, BioMed Publishing Group, 2013, pp. 111-127.
2. Burrascano, Joseph J. “Advanced Topics In Lyme Disease: Diagnostic Hints And Treatment Guidelines For Lyme And Other Tick-Borne Illnesses.” ILADS. Sixteenth Edition. 2008.
3. “Treatment for Erythema Migrans.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 3 Nov. 2020, www.cdc.gov/lyme/treatment/index.html.
4. Peyriere, Hélène, et al. “Doxycycline in the Management of Sexually Transmitted Infections.” OUP Academic, Oxford University Press, 22 Nov. 2017, academic.oup.com/jac/article/73/3/553/4647739.
5. Daniel J Cameron, Lorraine B Johnson & Elizabeth L Maloney (2014) “Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease”, Expert Review of Anti-infective Therapy, 12:9, 1103-1135, DOI: 10.1586/14787210.2014.940900
6. “Fundamentals of Natural Medicine in Lyme Disease .” The Beginner’s Guide to Lyme Disease: Diagnosis and Treatment Made Simple, by Nicola McFadzean, BioMed Publishing Group, 2013, pp. 139-178.
7. Townsend, Danyelle M., Tew, Kenneth D., Tapiero, Haim. The importance of Glutathione in Human Disease. Biomedicine & Pharmacotherapy. Volume 57 issues 3-4 May 2003 Pg 145-155
8. Chuan-li, L., Wei, Z., Min, W., Meng-mei, H., Wen-long, C., Xiao-jie, X., & Chuan-jian, L. (2015). Polysaccharides from Smilax glabra inhibit the pro-inflammatory mediators via ERK1/2and JNK pathways in LPS-induced RAW264.7 cells. Carbohydrate Polymers, 122, 428–436. doi:10.1 016/j.carbpol.2014.11.035
9. “Initial Infection Dynamics, Cytokines, Encysted Forms and Biofilms .” Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses, by Stephen Harrod Buhner and Neil Nathan, 2nd ed., Raven Press, 2015, p. 114-165.
10. Hucklenbroich, J., Klein, R., Neumaier, B., Graf, R., Fink, G., Schroeter, M., & Rueger, M. (2014). Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo. Stem Cell Research & Therapy, 5(4), 100. doi:10.1186/scrt500
11. “Natural Healing of Chlamydia .” Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses, by Stephen Harrod Buhner and Neil Nathan, 2nd ed., Raven Press, 2015, p. 268-281.
12. “The Materia Medica .” Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses, by Stephen Harrod Buhner and Neil Nathan, 2nd ed., Raven Press, 2015, p. 333-424.
13. “Chlamydia .” Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses, by Stephen Harrod Buhner and Neil Nathan, 2nded., Raven Press, 2015, p. 240-255.
14. Karvonen, Kati, and Leona Gilbert. “Effective Killing of Borrelia Burgdorferi in Vitro with Novel Herbal Compounds.” General Medicine Open, vol. 2, no. 6, 2018, doi:10.15761/gmo.1000153.

Clostridia are a group of anaerobic bacteria that can inhabit the digestive system of humans. Many types of Clostridia bacteria are non-pathogenic and even normal inhabitants of the intestinal tract, but certain species can be very problematic leading to serious illness and even death. Well-recognized Clostridia bacteria are those that cause tetanus, botulism, and Clostridium difficile (C. diff) associated diarrhea and other illnesses resulting from inflammation of the colon. Pseudomembranous colitis (or C. diff colitis) is another type of inflammatory bowel illness triggered by C. diff. It is estimated that upwards of 29,000 people in the United States die yearly from a problem related to C. diff (1).

However, there are other aspects of C. diff that can be problematic. Various chemicals produced by these bacteria have toxic effects beyond those that trigger C. diff colitis and the intestinal problems often associated with it. Many of these toxins, e.g. HPHPA, 4-Cresol, can adversely affect the brain and nervous system.

This series discusses various aspects of specific Clostridia bacterial infections as they relate to not only influences on digestive system illnesses but also neurological consequences. I will discuss: 

1. Certain toxins of Clostridia
2. Mechanisms of pathogenicity
3. Laboratory testing
4. Treatment intervention options

In Part 1, we begin with examples of certain Clostridia bacterial toxins and their mechanisms of pathogenicity:

• Toxins A & B
• HPHPA (3-(3-hydroxyphenyl)-3-hydroxypropionic acid)
• 4-Cresol (aka p-Cresol, 4-methylphenol).

Toxins A & B

In 1977, it was established that pseudomembranous colitis was caused by toxins produced from Clostridium difficile. These toxins referred to as toxin A and toxin B are enterotoxins produced by various types of C. diff that cause damage to the intestinal mucosa and initiate other detrimental processes within the digestive system (2).

Toxin A, known specifically as an enterotoxin (a toxin released by microorganisms that target the intestines), functions by changing host cell metabolism, as well as disrupting actin and tight junction function leading to mucosal damage and leaky gut.

Toxin B, known as a cytotoxin (a chemical or antibody that is toxic to other cells, the brain, digestive system), causes major cellular disruption by interfering with signaling pathways, tight junction formation, and derangement of overall gut epithelial cell structure.

These reactions and others like Tumor Necrosis Factor-α and various pro-inflammatory cytokines can also have local gastrointestinal and systemic effects within the body.

HPHPA and 4-Cresol

In 2010, William Shaw, Ph.D., from Great Plains Laboratory in Lenexa, Kansas published an important paper in Nutritional Neuroscience discussing how a toxic compound called HPHPA was found in very high concentrations in urine samples of children with autism compared to age- and sex-appropriate controls, and in adults with recurrent diarrhea due to C. diff infections (3). In fact, the highest value was 7500 mmol/ml creatinine – a value 300 times the median normal value for an adult. It was found in an individual with acute schizophrenia whose psychosis remitted after an antibiotic treatment course of oral vancomycin.

For years, through my private patient consultations and health-professional educational programs, I have been recommending that parents and caregivers of individuals with autism, as well as adults themselves with chronic digestive illnesses and/or brain, neurological, and mental health concerns, perform Organic Acid Testing (OAT) from Dr. Shaw’s Great Plains Laboratory for the evaluation of HPHPA (see image 1 below) and other metabolic toxins.

Image 1:This image is from the Clostridia Bacterial Markers section of the OAT. The elevation of HPHPA is quite high. Notice that one of the strains of Clostridia known to produce this toxin is Clostridium botulinum, the bacteria known to cause botulism.

The role of Clostridial infections in neurological health had been poorly understood until Dr. Shaw’s paper in 2010, but the clinical experience of many integrative medicine doctors working with special needs individuals who recognized digestive pathogens and their role in negative health outcomes dates back many years. The major impact I personally see clinically in patients with elevated HPHPA (and 4-Cresol), particularly in individuals on the autism spectrum, is erratic, aggressive, and self-injurious behavior. Sometimes these behaviors are so severe the person is heavily medicated in attempts to control the problems. In some others without autism, anxiety, depression, poor memory, and sleep disturbances can occur.

In Part 2 of this series, I will cover laboratory testing for Clostridia bacterial infections. More will be discussed with regard to HPHPA, 4-Cresol, and the Organic Acids Test. However, for now I want to focus on another important pathogenicity mechanism of these toxins linked to neurotransmitter imbalances and associated problems.

HPHPA and 4-Cresol Inhibition of Dopamine-Beta Hydroxylase (DBH)

Biochemically, HPHPA and 4-Cresol specifically interfere with a converting dopamine enzyme called Dopamine Beta-Hydroxylase (4). This enzyme is responsible for converting dopamine into the neurotransmitter norepinephrine. Norepinephrine is the neurochemical most responsible for vigilant concentration, whereas one of the roles of dopamine is alertness (5). Image 2 below details the complex biochemical reaction between these two Clostridia bacterial toxins and their relationship in the metabolism of dopamine to norepinephrine.

Image 2: Clostridium difficile and multiple species of Clostridia produce various compounds, including HPHPA and 4-Cresol. These organic acid toxins can inhibit Dopamine Beta-Hydroxylase which interferes with the conversion of dopamine to norepinephrine.

When DBH is inhibited there can be a build-up of dopamine within the nervous system leading to cellular toxicity. A major problem recognized with the accumulation of dopamine and the negative effects it has on brain function has to do with neurodegeneration associated with oxidative stress.

A 2008 research article published in the Journal of Neuroscience (6) discusses the biochemical consequences of excess dopamine: •

• Dopamine is a reactive molecule compared with other neurotransmitters and dopamine degradation naturally produces oxidative species.
• More than 90% of dopamine in dopamine neurons is stored in terminal vesicles and is protected from degradation.
• A small fraction of dopamine is cytosolic, and it is the major source of dopamine metabolism and presumed toxicity.
• Cytosolic dopamine undergoes degradation to form a compound called 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as well as hydrogen peroxide via the monoamine oxidase pathway. The HVA and DOPAC are markers measured on the Organic Acids Test (see image 3 below).

Image 3: The elevated HVA is often seen with high HPHPA and/or 4-Cresol. The Dopamine Beta-Hydroxylase enzyme can be inhibited causing excess dopamine to build up leading to the production of HVA and DOPAC.

• Dopamine also undergoes oxidation to form superoxide, hydrogen peroxide, and o-quinone and reacts with cysteine residues on glutathione, thus rendering glutathione ineffective.
• Dopamine oxidation can also form cysteinyl-dopamine and cysteinyl-DOPAC conjugates which are neurotoxic.
• These biochemical abnormalities caused by excess dopamine may cause severe neurodegeneration of neural pathways that utilize dopamine as a neurotransmitter.

Prior to the 2008 article, a research paper published in 2000 in the Journal of Child Neurology discussed various benefits of short-term treatment with oral vancomycin to a group of autistic children (7). The authors summarized: “...although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.”

Although it was not specifically stated that these children had C. diff infections or elevated markers of HPHPA and/or 4-Cresol, it is known that vancomycin is often an effective antibiotic against these pathogens. I will discuss more about this research and its findings, along with other therapeutic information and intervention options for certain Clostridia bacterial infections in Part 3 of this series.

Conclusion

There are other pathogenicity mechanisms linked to Clostridia bacterial infections such as propionic acid interference with mitochondrial function (8) and spore degradation linked to poor digestive-system calcium absorption (9). However, the toxins listed in this article highlight some of the more common testable problems linked to these pathogens.

In Part 2 of this series I will go into more detail regarding different test options, i.e., stool analysis, Organic Acids Test for Clostridia bacterial toxins of A, B, HPHPA, and others.

REFERENCES

1. Leesa FC, Mu Y, Bamberg WM, et al. “Burden of Clostridium difficile infection in the United States.” N Engl J Med. 2015; 372: 825-834.
2. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP; October 2010. “The role of toxin A and toxin B in Clostridium difficile infection.” Nature 467 (7316): 711–3).
3. Shaw, W. “Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia.” Nutr. Neurosci. 2010. 13(3):135-43.
4. Goodhart, PJ, et al. “Mechanism-based inactivation of dopamine beta-hydroxylase by p-cresol and related alkylphenols.” Biochemistry. 1983 Jun 21; 22(13):3091-6.
5. Robert D. Hunt. “Functional Roles of Norepinephrine and Dopamine in ADHD: Dopamine in ADHD.” Medscape Psychiatry. 2006;11(1).
6. Linan Chen, et al. “Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice.” J. Neurosci. 2008 28, 425–433
7. Sandler RH et al. “Short-term benefit from oral vancomycin treatment of regressive-onset autism” J Child Neurol. 2000. 15(7):429-35.
8. Richard E. Frye, Shannon Rose, John Slattery, and Derrick F. MacFabe. “Gastrointestinal dysfunction in autism spectrum disorders - the role of the mitochondria and the enteric microbiome.” Microb Ecol Health Dis. 2015.
9. Travis J Kochan, et al., “Intestinal calcium and bile salts facilitate germination of Clostridium difficile spores.” PLoS Pathog. 2017 Jul 13;13(7).

The importance of oral health as required for systemic health is well-accepted in the functional world. However, with up to 47% of American adults over 30 years of age suffering from periodontitis, there is an urgent need to actively address oral health as a routine part of clinical practice.¹ It is important to identify causative factors and effective treatments. Diets high in refined carbohydrates, smoking, pregnancy, and immune suppression are well-established risk factors for periodontal disease. Additionally, a healthy mouth requires balance in the oral microbiome. In the mouth, there is a complex interplay between microorganisms, the immune system, and a variety of habitats in the body. The microbiome shifts between different body sites, due to prevailing properties of the local area (termed “ecological niche”), where a number of different habitats are present even within the oral cavity. The oral and the gastrointestinal communities exhibit the greatest diversity and are innately linked to one another. A flourishing, heterogeneous microbial community is essential both for oral and systemic health. ²

We now understand that there are 700+ species of bacteria in the mouth, with a mean of 296. In one milliliter of saliva, there are 10⁸ microorganisms, and as we swallow one liter or more of saliva each day, it is important to maintain optimal health in the oral microbiome.² Microbial diversity in the mouth includes bacteria, archaea, viruses, fungus, and protozoans.³

Biofilms Play a Significant Role in the Oral Microbiome

Bacteria commonly live in biofilm communities that can sense each other using chemical signaling molecules, a mechanism known as quorum sensing. Biofilms are responsible for 80% of all infections and most chronic infections. In the oral cavity, biofilm is plaque. Biofilms are complex, dynamic structures that react to stimulus in a coordinated behavior via intracellular communication. Biofilms are ten to 1,000 times less susceptible to antimicrobials than a single bacterium. Teeth provide a non-shedding surface, ideal for biofilms (plaque) development, whereas the epithelial tissue of the oral mucosa is in a constant state of turnover. ²

Neutrophils are the primary immune defense in the mouth but are not effective against biofilm-associated bacteria. As they attack biofilms, they set off an inflammatory cascade that develops into a gingivitis lesion and increased infiltration of T cells and macrophages. Gingivitis progresses into periodontitis, the characteristic periodontal pocket, and the destruction of surrounding tissue. Due to the anatomical proximity of the periodontal biofilm to the gingival bloodstream, pockets may act as reservoirs for pathogens and their metabolites, as well as inflammatory mediators and immunocomplexes that can disseminate systemically.⁵ In fact, “less than one minute after an oral procedure, organisms from the infected site may have reached the heart, lungs, and peripheral blood capillary system.”⁶

Oral health requires balance in the immune-inflammatory state. When there is a dysregulation in the complex interplay between salivary components, immune activity, and existing microbes, dysbiosis occurs, causing negative health implications such as caries, periodontitis, endodontic infection, alveolar bone loss, and tonsillitis.⁵ Systemically, the effects of oral dysbiosis are far-reaching:

Diseases Related to Oral Pathogens 2, 5, 7, 8, 9

• Cardiovascular Disease – release of mediators that have a systemic effect (e.g.: cytokines and prothrombin). Individuals with untreated tooth infections are 2.7 times more likely to have cardiovascular problems, such as coronary artery disease.
• Autoimmunity – 1,676 subjects aged 30–40 years old were randomly selected from the registry file of the Stockholm region (Sweden) to participate in a 30-year study starting in 1985. The result showed that subjects with a higher plaque index, a marker of poor oral hygiene, were more likely to develop autoimmune diseases.
• Adverse Pregnancy Outcomes - Analysis of the placenta and fetal gastrointestinal tract show transient occupation by microbes most closely aligned with the maternal oral commensal organisms and may assist in fetal development of the immune system. Conversely, periodontal disease, and oral infection during pregnancy are a hallmark of preterm delivery.
• Other Systemic Illnesses - Inflammatory bowel disease, cancer (oropharyngeal, esophageal, colorectal), respiratory tract infection (bronchitis, pneumonia), meningitis, abscess (brain, lung, liver, spleen), appendicitis, obesity, and diabetes mellitus.

<h3style="text-align: center;"="">Clinicians Can be a Key Influencer on their Patients’ Oral Health

<h3style="text-align: center;"="">Modifiable factors that drive oral dysbiosis include poor oral hygiene, changes in saliva (flow or composition), diet, smoking, alcohol consumption, and stress. Clinicians are in the unique position to influence most of these areas with patients. Counseling about oral hygiene practices and lifestyle choices can go a long way toward improving and ultimately maintaining health. Encouraging regular brushing and flossing helps with the mechanical reduction of biofilm.² Also, there are proven natural and gentle therapeutics that have a positive impact on the oral microbiome.

<h3style="text-align: center;"="">Effective Botanicals in Dental Hygiene

<h3style="text-align: center;"="">Botanicals have a long history of use in oral health with excellent research on their ability to disrupt pathogenic biofilms and function as broad-acting antimicrobials. A recent study by Dr. John Rothchild, DDS, illustrated the potential of a liposomal botanical formula to significantly reduce pathogen load. He used phase-contrast microscopy and examined nine participants that exhibited elevations in pathogenic microorganisms (gram-negative rods and spirochetes) in gingival crevicular fluid derived from the periodontal tissues. Seven out of nine participants had a significant reduction or elimination of pathogens when using liposomal Biocidin LSF for one month. This pilot study helped inform the creation of Dentalcidin LS.

<h3style="text-align: center;"="">The oral health protocol prescribed by Dr. Rothchild included swishing with 2 pumps of Biocidin LSF for three minutes, and spitting, three times/day. You can learn more about the liposomal oral care solution here. The Dentalcidin™ Toothpaste can be used daily along with the oral care solution for additional support.

The human microbiome plays a pivotal role in human biology through its influence on many physiological functions such as human development, physiology, immunity, and nutrition. Botanical therapies in the form of toothpaste and/or an oral rinse, represent a low intervention, effective, and easy-to-implement method for supporting overall health.⁵ To learn more about the curated line of 10 products Bio-Botanical Research offers, including the oral care line, please visit: http://www.biocidin.com/

Healthcare Practitioner Support

Bio-Botanical Research prides itself on a level of customer service that reflects the high standards of its products. The company offers ongoing educational resources, including free personalized training on products and protocols, to assist practitioners in clinical practice. If you are a practitioner working with a case of microbial dysbiosis anywhere in the body, consider the Biocidin® suite of products along with the four support formulas from Bio-Botanical Research Inc. For more information, visit Biocidin.com or call 800.775.4140.

*This article was written by Dr. Jocelyn Strand and may not be reproduced without consent from Bio-Botanical  Research, Inc. Originally produced for Dr. Kara Fitzgerald’s site.

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057715/ 
2. https://www.nature.com/articles/sj.bdj.2016.865 
3.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274568/ 
4.  https://www.jstage.jst.go.jp/article/internalmedicine/advpub/0/advpub_2908-19/_article-HPV 
5. https://www.mdpi.com/2304-6767/6/2/10/htm
6. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0757.1994.tb00019.x?sid=nlm%3Apubmed
7. https://www.ncbi.nlm.nih.gov/pubmed/29563402 
8. https://www.tandfonline.com/doi/full/10.1080/20002297.2019.1650597 
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797574/

Human cells make up only 43% of the body’s total cell count, while microorganisms comprise the remaining 57% (1). Considering that over half of the body is made up of microscopic organisms, it is important to maintain the delicate balance between harmful, beneficial, and probiotic species in the microbiome. Alterations in the intestinal microbial composition have long been associated with chronic inflammation (2). By first defining the microbiome and how a healthy gut benefits its host, the major phyla of the microbiome can be examined, along with the role they play in human health. Of particular importance for this discussion is the production of short-chain fatty acids (SCFAs), which help prevent lipopolysaccharides from damaging the epithelial barrier, jeopardizing its integrity, causing systemic inflammation, and ultimately resulting in autoimmunity.

The human microbiome represents the entirety of microorganisms, including their genes, functional gene products, and metabolites, found in and on the human body at a given point in time. A healthy gut microbiome provides absorption of NaCl and water, nutrient synthesis, control of epithelial cell proliferation, and protection against pathogens by a barrier effect. In addition, fermentation of undigested dietary residue and endogenous mucous in the gut produce SCFAs, which are “the key mediators for communication between the host and gut microbes and are metabolites produced by microbes that have the ability to influence host immunity and metabolism” (3).

The intestinal microbiome is dominated by phyla Bacteroidetes and Firmicutes and together they produce three of the most abundant SCFAs. Bacteroidetes is a gram-negative bacteria and the main producer of the SCFAs acetate and propionate (4). These two SCFAs can travel across the epithelium to the liver, where they are involved in lipid biosynthesis (4). Firmicutes is a gram-positive bacteria and the primary contributor of butyrate, a SCFA that is metabolized in the epithelial mucosa and responsible for gluconeogenesis (4). In addition to lipid biosynthesis and gluconeogenesis, SCFAs affect gut integrity by decreasing the luminal pH and enhancing absorption of some nutrients, all while directly impacting gut microbiota composition (4). As noted in 2019 research by Holota et al. published in PLOS One, “SCFAs have long been known to exert beneficial effects against intestinal inflammation and protect intestinal epithelial integrity. However, the molecular targets for these bacterial metabolites have been identified only recently” (2). SCFAs can decrease inflammation and oxidative stress by two mechanisms. In the first mechanism, SCFAs activate G-protein receptors (GPCRs). In the Holota et al. study, loss of Gprotein coupled receptors FFA2 and FFA3 were associated with inflammatory responses, suggesting they are critical regulators of intestinal inflammation and epithelial barrier function (2). In the second mechanism, SCFAs inhibit nuclear class I histone deacetylases (HDACs), decreasing pro-inflammatory cytokines (IL-3, IL-6, tumor necrosis factor-α), and thereby reducing NF-κβ (4).

The intestinal microbiome is dominated by phyla Bacteroidetes and Firmicutes and together they produce three of the most abundant SCFAs. Bacteroidetes is a gram-negative bacteria and the main producer of the SCFAs acetate and propionate (4). These two SCFAs can travel across the epithelium to the liver, where they are involved in lipid biosynthesis (4). Firmicutes is a gram-positive bacteria and the primary contributor of butyrate, a SCFA that is metabolized in the epithelial mucosa and responsible for gluconeogenesis (4). In addition to lipid biosynthesis and gluconeogenesis, SCFAs affect gut integrity by decreasing the luminal pH and enhancing absorption of some nutrients, all while directly impacting gut microbiota composition (4). As noted in 2019 research by Holota et al. published in PLOS One, “SCFAs have long been known to exert beneficial effects against intestinal inflammation and protect intestinal epithelial integrity. However, the molecular targets for these bacterial metabolites have been identified only recently” (2). SCFAs can decrease inflammation and oxidative stress by two mechanisms. In the first mechanism, SCFAs activate G-protein receptors (GPCRs). In the Holota et al. study, loss of Gprotein coupled receptors FFA2 and FFA3 were associated with inflammatory responses, suggesting they are critical regulators of intestinal inflammation and epithelial barrier function (2). In the second mechanism, SCFAs inhibit nuclear class I histone deacetylases (HDACs), decreasing pro-inflammatory cytokines (IL-3, IL-6, tumor necrosis factor-α), and thereby reducing NF-κβ (4).

The balance of the microbiome is important in maintaining the health of an individual because the ratio of SCFAs in the colon is influenced by strain and quantity of gut micr obiota (4). SCFAs have many roles, but in the interest of this article, they decrease pro-inflammatory cytokines and help to offset the damage that LPS causes. A study done by Wang et al. set out to investigate the effects of SCFAs on septic shock and found butyrate significantly decreased the mortality of septic mice. Pretreatment with butyrate led to significant attenuation of the LPS-induced elevation of inflammatory TNF-α, IL-6, and IL- 1β levels while significantly increasing upregulation of anti-inflammatory cytokine IL-10 (6).

Although many gut microbial populations have been characterized as either “good” or “bad,” they only play a part in a larger and more complex biological system (3). In a population study done in Denmark, “Individuals whose guts contained a low diversity of bacteria were found to have higher levels of body fat and inflammation than those with high gut-microbial richness” (7). Human health is impacted by the diversity of our microbiome, and resulting metabolites like SCFAs decrease inflammation and repair LPS damage. We have only begun to understand the importance of microbiome diversity and how it impacts overall inflammation levels and ultimately, human health.

In our next installment in this series, we will look at inflammatory diseases associated with LPS, followed by how botanicals have shown promise in balancing the microbiome and favorably impacting inflammatory conditions commonly seen in clinical practice.

REFERENCES

1. Gallagher, James. “More Than Half of Your Body is not Human.” BBC News, 10 Apr. 2018, https://www.bbc.com/news/health-43674270

2. Holota Y, Dovbynchuk T, Kaji I, Vareniuk I, Dzyubenko N, Chervinska T, et al. (2019) The long-term consequences of antibiotic therapy: Role of colonic short-chain fatty acids (SCFA) system and intestinal barrier integrity. PLoS ONE 14(8): e0220642. https://doi.org/10.1371/ journal.pone.0220642

3. Kagele, Dominique. “The ‘Skinny’ on Gut Microbes and Your Health.” The Jackson Laboratory, 26 May 2015, https://www.jax.org/news-and-insights/jax-blog/2015/may/theskinny-on-gut-microbes-and-your-health#. Accessed 23 Dec. 2020.

4. Feng W, Ao H and Peng C (2018) Gut Microbiota, Short-Chain Fatty Acids, and Herbal Medicines. Front. Pharmacol. 9:1354. doi: 10.3389/fphar.2018.01354

5. “TLR4 (Toll like receptor 4) - Receptor of LPS of Bacteria”. Cloud-Clone Corp., 17 Feb 2015, http://www.cloud-clone.com/topic/201502170821230035.html. Accessed 15 Dec 2020.

6. Wang F, Liu J, Weng T, Shen K, Chen Z, Yu Y, Huang Q, Wang G, Liu Z, Jin S. The Inflammation Induced by Lipopolysaccharide can be Mitigated by Short-chain Fatty Acid, Butyrate, through Upregulation of IL-10 in Septic Shock. Scand J Immunol. 2017 Apr;85(4):258-263. doi: 10.1111/sji.12515. PMID: 27943364.

7. Le Chatelier, E., Nielsen, T., Qin, J. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013). https://doi.org/10.1038/nature12506

Part 1 and 2 Review

Part 1 of this series discussed the importance of short-chain fatty acids (SCFAs) in regulating intestinal inflammation and epithelial barrier function. SCFAs also decrease pro-inflammatory cytokines (IL-3, IL-6, tumor necrosis factor-α), and reduce NF-κβ. Additionally, lipopolysaccharides (LPS) found throughout the cell wall of gram-negative bacteria cause damage to epithelial cells and tight junctions. This begins the cascade of inflammation by binding to TLR4 and activating NF-κβ and inflammatory cytokines (1).

Part 2 discussed diseases associated with gut dysbiosis, decreased diversity of beneficial gut microbes, and LPS translocation. From a clinical standpoint, we addressed adding microbiome and LPS-based inflammation to the differential diagnosis for a patient presenting with chronic fatigue, aching joints, and dementia.

Now that we understand the role of the microbiome and its ability to predispose towards good health or systemic illness, let’s apply this information in our clinical practices.

Botanicals and the Gut Microbiome

Botanicals have long been used for a variety of health reasons, and a review of the literature by Feng et al. found, “Herbal medicines are an important resource provider for production of SCFAs and have been demonstrated to be able to modulate gut microbiota composition and regulate SCFAs production” (1). The way that botanicals accomplish this is by providing nutrients to the gut microbiota that secrete enzymes to metabolize carbohydrates into SCFAs (1). SCFAs help maintain epithelial integrity in the gastrointestinal (GI) tract. They prevent gram-negative bacteria (including LPS) from passing through and entering the bloodstream, blocking inflammatory systemic disease.

Botanicals and the Oral Microbiome

Not only are botanicals effective in the gut microbiome, but also in the oral microbiome. A biocidal formula containing 17 herbs and essential oils was used by John Rothchild, DDS, in a dental pilot study. Dr. Rothchild used phase-contrast microscopy and examined nine participants that exhibited elevations in pathogenic microorganisms (gram-negative rods and spirochetes) in gingival crevicular fluid derived from the periodontal tissues.

Seven out of nine participants had a significant reduction or elimination of pathogens when using Biocidin® formula for one month (2).

Botanicals and Biofilms

Hashioka et al. showed that periodontal gram-negative bacteria like Porphyromonas gingivalis and its component LPS are found in the periodontal pocket (3). These harmful bacteria form biofilms and enter the pocket epithelium where they gain access to systemic circulation and release pro-inflammatory cytokines (3). Incredibly, botanicals have the power to break down biofilms, thus decreasing the likelihood of chronic oral microbial dysbiosis. A pilot study done by Binghamton University looked at Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli) biofilms and exposed them to a 50% concentration of Biocidin®(4). At 24 hours, most of the biofilms were eradicated in both species (see diagram). Of note is both of these species are gram negative.

Endotoxemia and Spore Probiotics

Final Thoughts

Respiratory conditions, both chronic and acute, are some of the most common issues seen in clinical practice. In 2016, chronic obstructive pulmonary disease (COPD) alone accounted for around three million deaths and was the third leading cause of death worldwide.¹ Asthma is one of the most common chronic diseases, globally affecting nearly eight percent of people (over 24 million) in the US alone. Childhood onset of asthma can impair airway development, and persist into adulthood. Adult asthma may accelerate the decline of pulmonary function, and increase susceptibility to infection. Both children and adults with severe asthma have impaired innate antiviral immunity with altered cytokine responses, and increased risk of hospitalization—an issue of particular concern currently. Comorbid conditions are common, with almost two-thirds of
those with asthma having at least one comorbidity. The most common comorbidities are diabetes, osteoporosis, metabolic syndrome, cardiovascular disease, and mental illnesses.² Lower respiratory infections were the fifth leading cause of death and the leading cause of infectious death globally in 2015.³

With the prevalence of both chronic and acute respiratory illnesses, it is in the best interest of our patients to identify and address root cause and practice prevention. A growing body of evidence has highlighted the influence of the gut microbiota on lung immunity—the Gut-Lung Axis—and current research has drawn a strong correlation between dysbiosis of several anatomical areas and pulmonary health or disease. Here is a synopsis of current research focusing on the microbiome, the Gut-Lung Axis, and their roles in pulmonary health.

The Role of Microorganisms in Cardiovascular Health and the Application of Botanicals

Cardiovascular disease (CVD) now affects 48% of adults in the US and is the leading cause of death. Within that category, coronary artery disease resulting in myocardial infarction is most prevalent, while stroke comes in second, and is the 5th leading cause of death overall.

The good news is that 90% of stroke risk is due to modifiable risk factors. As providers, we can work alongside our patients to alter factors that increase risk of CVD. Hypertension (HTN), the most common form of CVD, is a major modifiable risk factor for many other CVDs, including acute coronary syndrome, cardiomyopathy, congestive heart failure, pulmonary hypertension, and stroke.^1,2

Considering the prevalence of CVD and our ability to manage its risk, it is vital that we identify root causes and direct therapeutics accordingly. 

One potential target lies in the microbiome. The term microbiome describes the microbial composition of a given area on the body and varies depending on habitat. It is diverse, consisting of bacteria, archaea, fungi, protozoa, viruses, and their trillions of genomes collectively.³

Alterations in the balance (increased pathogen load, reduced commensals, or reduced diversity) of these microorganisms and their functions can result in microbial dysbiosis and have been linked to a host of local and systemic conditions, including cardiovascular disease.^3,4,7

Dysbiosis Creates Inflammation 

A healthy gut epithelium provides a barrier for microorganisms and metabolites. When dysbiosis occurs, pathogens release mediators that disrupt the GI mucosa and its ability to function as a barrier to systemic circulation. One of these metabolites is lipopolysaccharide (LPS). LPS is generated in the cell wall of both commensal and pathological gram-negative bacteria. It binds to LPS binding protein, which is then recognized by innate immune cells (macrophages, neutrophils, and dendritic cells). This initiates activation of toll-like receptor 4 (TLR4) and consequently nuclear factor kappa B (NF-kB). NF-kB is a transcription factor that activates a cascade of events including the release of pro-inflammatory cytokines, chemokines, and adhesion molecules. These chemical messengers result in a chronic inflammatory response mediated by both the innate (macrophage activation) and adaptive (T cell activation) immune systems. The downstream effect is chronic inflammation, platelet aggregation, foam cell formation, and ultimately the production of atherosclerotic plaque.^3,4

A two-to-three-fold increase in LPS is called metabolic endotoxemia (ME), which is commonly found in CVD patients. However, even modest increases in LPS have been shown to cause fat deposition, insulin resistance, chronic inflammation, damage to mitochondrial DNA in the heart, and increases in pro-atherogenic endothelial adhesion molecules.⁴

“Microbiota and their metabolites profoundly modulate the progression of atherosclerosis, the most common cause of ACS, stroke, and peripheral vascular disease.”³

The host-microbiome interaction influences the production of other metabolites including trimethylamine-N-oxidase (TMAO). In one study, higher levels of TMAO resulted from increases in Prevotella and decreased Bacteroides. TMAO is a bacterial metabolite that exerts harmful effects on the circulatory system, resulting in endothelial dysfunction. It increases chronic inflammation via increased expression of pro-inflammatory cytokines. There is mounting evidence that TMAO influences the progression of CVD, including a direct link to major adverse cardiovascular events. Its effects are so consistent and remarkable that TMAO is now considered a prognostic tool in patients with cardiomyopathy and possibly a marker for gut barrier permeability.^3,4

Oral Health and Cardiovascular Disease 

The role of the microbiota is not limited to the GI tract. In the mouth, there is a complex interplay between microorganisms, the immune system, and “ecological niche” (prevailing properties of the local area) that require balance. We now understand that there are 700+ species of bacteria in the mouth, with a mean of 296. In one milliliter of saliva, there are 108 microorganisms, and as we swallow one liter or more of saliva each day, it is critical to maintain optimal health in the oral microbiome.⁸

Oral health requires balance in the immune-inflammatory state. When there is a dysregulation in the complex interplay between salivary components, immune activity, and existing microbes, dysbiosis occurs causing negative health implications, such as caries, periodontitis, endodontic infection, alveolar bone loss, and tonsillitis.5 Release of mediators from oral pathogens has a systemic effect (e.g. cytokines and prothrombin). People with untreated tooth infections are 2.7 times more likely to have cardiovascular problems—such as coronary artery disease—than patients who have had treatment of dental infections.⁷

Proper oral hygiene has been shown to reduce risk of CVD, including HTN, and stool levels of opportunistic pathogens.¹³ Periodontal disease, which affects up to 77% of American adults over 30, promotes the release of pro-inflammatory cytokines and is well established as a risk factor for AS and other CVD. Furthermore, numerous bacteria associated with pathology in the gut are present in the mouth and can create pathology therein or translocate to the gut and contribute to GI dysbiosis.^7,13 Prevotella, which populates the mouth, is one example of a pathogen that is associated with the production of TMAO, a contributing factor in endothelial dysfunction.⁴

Biofilms Play a Significant Role in the Oral Microbiome and Cardiovascular Health

The teeth provide a non-shedding surface for organisms to establish biofilm in the form of plaque. Neutrophils are the primary immune defense in the mouth but are not effective against biofilm-associated bacteria. As they attack biofilms, they set off an inflammatory cascade that develops into a gingivitis lesion and increased infiltration of T cells and macrophages. Gingivitis progresses into periodontitis, the characteristic periodontal pocket, and the destruction of surrounding tissue. Due to the anatomical proximity of the periodontal biofilm to the gingival bloodstream, pockets may act as reservoirs for pathogens and their metabolites, as well as inflammatory mediators and immunocomplexes that can disseminate systemically.¹¹

“Less than 1 minute after an oral procedure, organisms from the infected site may have reached the heart, lungs, and peripheral blood capillary system”.¹²

Bacteria commonly live in biofilm communities that can sense each other using chemical signaling molecules, a mechanism known as quorum sensing. Biofilms are responsible for 80% of all infections and for most chronic infections. They are complex, dynamic structures that react to stimulus in coordinated behavior via intracellular communication. Biofilms are 10-5,000 times less susceptible to antimicrobials than a single bacterium.⁸

Botanicals Provide a Solution for Infection

Herbal medicines have been utilized by humans in the treatment of infection for thousands of years, and provide a safe and effective option for addressing biofilms and dysbiosis. A study with nearly 400 people found that herbal remedies were as effective as Rifaximin (the most studied antibiotic related to SIBO) at treating symptoms. An array of herbals and essential oils were used in that trial. The conclusion reads “Herbal therapies are at least as effective as Rifaximin for resolution of SIBO by LBT (lactulose breath test). Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for Rifaximin non-responders. Further prospective studies are needed to validate these findings and explore additional alternative therapies in patients with refractory SIBO.”¹⁴

Using the anti-pathogenic properties of more than one botanical in a combination or formula provides a broader spectrum of activity against pathogens. The resulting formulations, or “biocidal combinations,” are powerful allies that may be used to address infection. Testing has illustrated remarkable broad-spectrum antimicrobial activity (in vitro) with a combination containing Bilberry extract, Noni extract, Milk Thistle, Echinacea (Purpurea extract and Angustifolia), Goldenseal, Shiitake extract, White Willow Bark, Garlic, Grapeseed extract, Black Walnut (hull and leaf), Raspberry, Fumitory extract, Gentian, Tea Tree oil, Galbanum oil, Lavender oil, and Oregano oil. A & L Analytical Laboratories, performed USP Effectiveness Tests, in which this botanical combination was injected with large numbers of disease-causing organisms and then cultured for 28 days. The results demonstrated the bacteria and yeast pathogens are completely eliminated in a matter of hours and do not recur over a 28-day period of being cultured.

Botanicals are Effective Against Biofilms

Botanicals accomplish control of biofilms through several methods. One method is by the inhibition of quorum sensing. Quorum sensing is cell signaling by bacteria and other organisms using autoinducers to determine gene expression, virulence, resistance, and development of biofilms. Botanicals shown to inhibit quorum sensing such as Garlic and Oregano are well known for their antimicrobial ability. This understanding of how they can combat biofilms highlights their clinical and historical significance.¹⁵

Another method of biofilm control is the inhibition of efflux pumps within cells, called multi-drug resistance pumps. Plants containing tannins, berberine, and certain phenolics have useful effects as efflux pump inhibitors, demonstrating marked synergy when combined with conventional antibiotics against a variety of both Gram-positive and Gram-negative organisms. Goldenseal, Black Walnut, White Willow, Raspberry Leaf, and Garlic are a few that have been studied.^15,16

Bacteriostatic agents inhibit the reproduction of biofilm organisms and so help to control the spread of infection. Berberine has been proven bacteriostatic for Staphylococcus epidermidis. One study showed that sub minimal inhibitory concentrations blocked the formation of S. epidermidis biofilms. Both Gentian and Goldenseal contain Berberine and are useful additions to the biocidal combination for biofilm control. Grapeseed and Bilberry contain condensed tannins, which prevent adherence of biofilms and may inhibit swarming.^17,18,19,20 One study performed at the University of Binghamton shows the complete eradication of biofilms with exposure to a biocidal formula.

Use of Botanicals in Oral Infections

Botanicals have a long history of use in oral health with excellent research on their ability to disrupt pathogenic biofilms and function as broad-acting antimicrobials. A recent pilot study by Dr. John Rothchild, DDS, illustrated the potential of a liposomal botanical formula to significantly reduce pathogen load. He used phase-contrast microscopy and examined nine participants that exhibited elevations in pathogenic microorganisms (gram-negative rods and spirochetes) in gingival crevicular fluid derived from the periodontal tissues. Seven out of nine participants had a significant reduction or elimination of pathogens when using liposomal Biocidin LSF for one month. This pilot study helped inform the creation of Dentalcidin LS.

The oral health protocol prescribed by Dr. Rothchild included swishing with 2 pumps of Biocidin LSF for three minutes, and spitting, three times/day. You can learn more about the liposomal oral care solution here. The Dentalcidin™ Toothpaste can be used daily along with the oral care solution for additional support.

A Novel Approach

The wealth of data available on botanicals demonstrates the usefulness of herbals and nutrients as a safe and effective strategy addressing bacterial, viral, and fungal infections. Furthermore, there is ample evidence to suggest that many biofilm-encapsulated infections will also respond to use of these antimicrobial botanicals. Used correctly, the wealth of the planet kingdom is one of our greatest allies in optimizing our health and provides a strong defense against infectious diseases. Botanicals offer a novel approach and deserve consideration where CVD is concerned.

References 

1. https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2019/02/15/14/39/aha-2019-heart disease-and-stroke-statistics
2. https://www.heart.org/en/news/2019/01/31/cardiovascular-diseases-affect-nearly-half-of-american adults-statistics-show
3. https://www.ncbi.nlm.nih.gov/pubmed/31469291
4. https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13250
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746314/pdf/nihms929622.pdf
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057715/ (1)
7. https://www.nature.com/articles/sj.bdj.2016.865 (2)
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274568/(3)
9. https://www.jstage.jst.go.jp/article/internalmedicine/advpub/0/advpub_2908-19/_article – HPV
10. https://www.mdpi.com/2304-6767/6/2/10/htm
11. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0757.1994.tb00019.x?sid=nlm%3Apubmed(6)
12. https://www.ncbi.nlm.nih.gov/pubmed/29563402
13. https://www.nature.com/articles/s41440-019-0260-4.pdf?draft=collection
14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030608/
15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119553/
16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486105/
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840435/
18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101405/pdf/zac3043.pdf
19. https://www.sciencedirect.com/science/article/abs/pii/S0956713514006586
20. https://www.researchgate.net/profile/Mengfei_Peng/publication/307156613_Bioactive_extracts_from_berry_byproducts_on_the_pathogenicity_of_Salmonella_Typhimurium/links/5a295fd1aca2728e05dab087/Bioactive-extracts-from-berry-byproducts-on-the-pathogenicity-of-Salmonella Typhimurium.pdf