Understanding Lyme Disease

Compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

  • Introduction
  • Antibiotic Treatment in Lyme Disease
  • Biomarkers Elevated in Lyme Disease
  • Carbon Dioxide, pH, Bicarbonate and Oxygen Levels in Lyme Disease
  • Co-Infections in Lyme Disease
  • Co-Infection with Chlamydia pneumoniae
  • Botanical and Nutritional Strategies for Lyme Disease Treatment
  • Natural Compounds that Target Biomarkers Involved in Lyme Disease
  • Reducing Inflammation with Natural Compounds
  • Examples of Natural Compounds that Regulate the Immune Response 
  • Examples of Natural Compounds with Antimicrobial Actions
  • Neurological, Hormonal and Immune Enhancing Properties of Natural Compounds
  • Blood Tests in Lyme Disease
  • Natural Strategies in Treating Lyme Disease

Introduction

Lyme disease, the most common vector-borne illness in the United States, is caused by infection with Borrelia burgdorferi, a spirochetal pathogen transmitted to humans and other mammals by Ixodes scapularis tick bites. The mouse model of borrelial infection has served as an invaluable tool for exploring immunopathogenic mechanisms in Lyme disease. B. burgdorferi-infected severe combined immunodeficient (SCID) mice, which lack functional B and T lymphocytes, exhibit persistent spirochetemia and progressive inflammation of the joints, heart, and liver. Adaptive immunity has a critical role in the control and resolution of disease, as underscored by the persistence of active carditis and the progressively destructive arthritis seen in SCID mice. Disease resolution correlates with the appearance of borreliacidal antibodies that, when passively transferred, protect naive animals against challenge with virulent organisms. (Tupin et al 2008)

Ticks engorge for several days on vertebrates, penetrating the skin, damaging vessels and obtaining blood from the ensuing hematoma. In response, neutrophils and other inflammatory cells are recruited to the bite site to disrupt tick feeding. Ticks counteract these forces with an assortment of immunomodulators, anticoagulants, and other biologically active proteins in saliva. (Narasimhan et al 2007)

Specific interactions between B. burgdorferi and tick salivary proteins may thus enable the spirochete to escape reactive oxygen-mediated damage during transmission. In addition, presumably, as spirochetes exit the tick, they are in the process of rapidly moving away from the feeding site and may escape the full brunt of the toxic environment. (Narasimhan et al 2007)Presentation and destructive effects of Lyme disease vary widely depending on the stage and magnitude of spirochete dissemination. Initial effects may include rashes or flu-like symptoms, while later stages may be characterized by arthritic, neurological, psychiatric and cardiac symptoms. (Vojdani et al 2007)

After introduction into the skin, the organism systemically disseminates and colonizes other tissues and organs ultimately resulting in arthritis, carditis, and/or neurological manifestations . The processes underlying the spirochete’s ability to spread and localize to host tissues leading to the pathology of Lyme disease are not fully defined. (Schmit et al 2011)

Immune System Activation by Borrelia:

The spirochete gets into contact with the complement system once transmitted to human skin, if not already in the midgut of the biting tick. It has been shown that B. burgdorferi effectively activates the alternative and even the classical complement pathway without requiring Borrelia-specific antibodies . Furthermore, B. burgdorferi has been shown to stimulate oxidative burst and to be susceptible to phagocytosis by neutrophils.  Oxidative burst is considered to be one of the main antimicrobial neutrophil functions. Nevertheless, because it has been shown earlier that neutrophils obtained from a patient with chronic granulomatous disease are able to kill borreliae associated with them, oxidative burst does not seem to be obligatory for the elimination of the spirochetes. In normal persons, however, oxidative burst most likely not only participates in the local killing of spirochetes but also plays a role in the further activation of the innate immune system. (Suhonen et al 2000)

Following a bite by a tick infected with Borrelia (B.) burgdorferi, the innate immune system is the first line of defense to encounter the spirochetes. This initial event is likely to determine the magnitude and quality of both the innate and the ensuing adaptive response. Erythema migrans (EM) (bull’s eye) is by far the most common symptom of Lyme borreliosis (LB) worldwide. In general, the prognosis of antibiotic-treated EM is good. However, some patients are troubled by persisting symptoms of various duration and character post-treatment. Follow-up studies on adult patients with disseminated infection, i.e. neuroborreliosis (NB), indicate that as many as 50% of the patients suffer from persisting complaints after antibiotic treatment. (Sjowall et al 2011)

The reasons for differences in the clinical outcome of LB are probably multi-factorial, albeit, largely unknown. To date, there is no convincing evidence that symptoms post-treatment would be caused by a persisting infection. On the contrary, the symptoms may be due to an improperly regulated immune response to B. burgdorferi, i.e. a weak initial inflammatory response, not generating proper down-regulatory feedback mechanisms. Indeed, previous investigations in both mice and humans have indicated that a successful clinical outcome requires an effective inflammatory T helper cell (Th) 1-type response that is adequately balanced by an anti-inflammatory and Th2-like response against B. burgdorferi. (Sjowall et al 2011)

The emphasis should be on immunoregulation and enhancement of cell-mediated immunity (macrophage function, NK cell function) and not enhancement of humoral immunity and antibody production, since induction of antibody production may actually worsen the autoimmune reaction or autoimmune disease exhibited in many patients with LD (Lyme borreliosis). (Vojdani et al 2007)

A striking feature of Borrelia is its ability to evade host immune response. One mechanism to evade host immune responses is the recombinant gene expression of the variable major protein-like sequence (vls) locus. This results in altered antigenicity of the lipoprotein VlsE and thus protection against anti-VlsE antibodies. Also, Borrelia can express complement regulator-acquiring surface proteins (CRASPs), preventing complement- mediated killing. Recently, another protein, Lmp1, was suggested to be important for evasion of the host adaptive immune responses. Yang et al. showed that the N-terminal region of the protein increased pathogen survival. Importantly, B. afzelii is associated with skin manifestations, B. garinii with neurological involvement and B. burgdorferi with infection of the large joints; however, there is a fair amount of overlap between the tropisms of the different genospecies.(Coumou et al 2011)

Acute Lyme Disease is one of the most important emerging diseases in the US. People with acute Lyme disease often develop swollen lymph nodes, or lymphadenopathy, but we do not know why this happens or what effect it has on the course of the disease. We show here that when mice are infected with live Borrelia burgdorferi spirochetes (the bacteria that cause Lyme disease), live spirochetes collect in the lymph nodes. These lymph nodes then swell up and start producing large numbers of antibody-producing cells. Although many of these antibodies can recognize the bacteria, they apparently lack the quality to clear the infection. We hypothesize that by moving into the lymph node, usually a site in which strong immune responses are induced, Borrelia evades the immune response: it goes to the lymph nodes and tricks the immune system into making a very strong but inadequate response. (Tunev et al 2011)

When the infection is untreated, the spirochete can disseminate and cause early neuroborreliosis (3-16% of Lyme manifestations), Lyme arthritis (5-7%), and seldom a (myo)carditits with (partial) atrioventricular block (<1%). Notably, since the late 1980s, increasing awareness for EM (erythema migrans or “bulls eye”) and better effective antibiotic regimes have probably made these clinical manifestations become even less common. Early neuroborreliosis can present with lymphocytic meningitis, which is more common in the United States, cranial nerve paresis, usually the facial nerve, painful radiculitis, which is more common in Europe, or all of the above, which is equivalent to the Bannwarth syndrome. In most patients, acute neurological symptoms improve or resolve in several weeks to months, even without antibiotic treatment. In the early disseminated phase of Lyme borreliosis, infection of the joints is oligoarticular and 50% occur in the knee. This manifestation is mostly observed in the United States, where 60% of untreated patients developed arthritis. Cardiac involvement in early Lyme borreliosis in adults is rare and symptoms are usually related to atrioventricular conduction abnormalities. (Coumou et al 2011)

Late neuroborreliosis is rare and includes encephalomyelitis, encephalopathy and axonal polyneuropathy, for a period of at least six months. Encephalomyelitis can present as a slowly progressive myelopathy beginning with an ataxic gait, a gradually worsening spastic paraparesis or tetraparesis or with hearing loss and is accompanied by relatively severe cerebrospinal fluid (CSF) pleocytosis or evident intrathecal anti-Borrelia antibody production. In contrast, symptoms of encephalopathy are mainly cognitive, in combination with aspecific symptoms, such as fatigue, malaise and myalgia. In most of these patients, there is no evidence of inflammation due to Borrelia in the central nervous system (CNS), and therefore, an encephalopathy might actually be an indirect effect of systemic (non-CNS) infection accompanying typical clinical findings of disseminated Lyme borreliosis. (Coumou et al 2011)

CNS involvement: is relatively uncommon, usually late, and occurs in either of two ways: an acute, disseminated encephalomyelitis and a more indolent, late, slowly progressive parenchymal neurologic disorder resembling multiple sclerosis. Patients with the acute form present with depressed mental status, cognitive deficits and multifocal abnormalities on neurologic examination. Magnetic resonance imaging (MRI) scans of the brain reveal predominantly white matter lesions, and the CSF examination can exhibit both lymphocytic pleocytosis and intrathecal anti-B. burgdorferi antibody production. These patients respond well to antibiotic therapy with little, if any, residual deficit. In contrast, patients with slowly progressive inflammatory CNS neuroborreliosis have often been misdiagnosed with multiple sclerosis and have received immunosuppressive treatment to stabilize their neurologic deficits. These patients have white matter lesions on brain MRI scans, which had led to the speculation that this form of neuroborreliosis is a demyelinating disorder. (Vojdani et al 2007)

Joint manifestations: can occur months to years after exposure, with intermittent recurrent attacks that persist for days, weeks, or months and are typically asymmetrical and pauciarticular in nature and involve one or two larger joints and almost invariably the knee. Most Lyme arthritis patients respond well to conventional antibiotic treatment strategies, such as doxycycline, but a small percentage will continue to have chronic joint inflammation, not due to persistence of the spirochete. This is called antibiotic-refractory Lyme arthritis. (Coumou et al 2011)

Cardiomyopathy: In dilated cardiomyopathy, a very rare manifestation of late Lyme borreliosis, spirochetes have rarely been isolated by culture. This might indicate that symptoms could be due to past infection and myocardial scarring rather than ongoing inflammation due to the presence of the spirochete. (Coumou et al 2011)

Biomarkers in Lyme Disease

Interferon gamma (IFN-gamma), IL-10, TNF-alpha, IL-1beta, IL-6 – Previous studies have shown a predominant Th1-type inflammatory response in the skin of EM lesions. Furthermore, analysis of cytokine mRNA in EM skin biopsies from patients without concomitant EM-associated symptoms, have shown expression of both IFN-γ and IL-10, whereas cytokine analysis in skin of EM-patients with such symptoms have additionally shown a large number of macrophage-derived pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6. This indicates that cytokine expression patterns in the skin may be of importance for the development of symptoms. However, very little is known about the clinical outcome of EM in relation to early cytokine expression in situ in infected skin, which constitutes the primary entrance route of the spirochetes. (Sjowall et al 2011)

IL-6, TNF-alpha, and PGE(2), NF-kappaB – Lyme disease has been associated with damaging inflammation within the central nervous system. In the present study, we demonstrate that Borrelia burgdorferi is a significant stimulus for the production of IL-6, TNF-alpha, and PGE(2) by microglia. This effect is associated with induction of NF-kappaB, and increased expression of Toll-like receptor 2 and CD14, receptors known to underlie spirochete activation of other immune cell types. These studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B. burgdorferi. Such production may play an important role during the development of Lyme neuroborreliosis. (Rasley 2002)

MAPK – Dysregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage. Mitogen-activated protein kinases (MAPK) play a key role in the regulation of neuronal development, growth, and survival, as well as that of pro-inflammatory cytokine production. Inhibition of both p38 and Erk1/2 significantly diminished TNF-alpha production, and totally abrogated production of this cytokine when both MAPK pathways were inhibited simultaneously. MAPK inhibition thus may be considered as a strategy to control inflammation and apoptosis in Lyme neuroborreliosis. (Ramesh & Phillipp 2005)

Interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon-γ, and transforming growth factor-β (TGF-beta) – Various cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon-γ, and transforming growth factor-β have been detected in the CSF of Lyme neuroborreliosis patients, indicating that they play a role in the pathogenesis of this form of Lyme disease. (Ramesh et al 2008)

Carbon Dioxide, pH, Bicarbonate and Oxygen Levels in Lyme Disease

Increase in dissolved CO2 levels benefits Borellia – also affected the synthesis of borrelial RpoS and BosR, an alternate sigma factor and redox regulatory protein, respectively. Specifically, RpoS and BosR were induced greatly when B. burgdorferi was grown anaerobically in the presence of 5% CO2 compared to the synthesis in cells grown anaerobically without CO2 or in micro-aerophilically grown B. burgdorferi. The overall trend (i.e., more RpoS as the level of CO2 increased) was consistent. These results suggest that CO2 levels modulate the production of borrelial proteins that are believed to be important for adaptation in the mammalian host environment. (Hyde et al 2006)

CO2 imposes a selective pressure that preserves genome stability and thus infectivity – Consistent with this contention, several of the borrelial genes (ospC, dbpA, and BBK32) and products of  previous work demonstrated that there is a correlation between higher atmospheric CO2 levels and the maintenance of infection-associated plasmids of B. burgdorferi during in vitro cultivation, suggesting that CO2 imposes a selective pressure that preserves genome stability and thus infectivity. The ability to sense CO2, either as CO2 or as bicarbonate, influences the expression of virulence determinants in other pathogenic organisms, suggesting a potential role for CO2 sensing in borrelial virulence gene expression. (Hyde et al 2006) Based on this study it is probably not a good idea to supplement with TriSalts or sodium bicarbonate in Lyme disease.

Carbon dioxide induces synthesis of pathogenic mechanisms in Lyme – This study demonstrated that dissolved CO2 functions as an additional environmental signal that modulates gene expression and protein production by B. burgdorferi. Although all of the molecules involved in responding to dissolved CO2 have yet to be characterized, it is conceivable that the PAS domain of BB0764 senses CO2, as well as several other environmental cues, and initiates an Rrp2-dependent cascade that interfaces with the RpoN-RpoS regulatory pathway to increase the transcription of lipoprotein genes (i.e., ospC and dbpA). Interestingly, several adhesin genes purported to be important for mammalian infection (i.e., dbpA and BBK32) were also induced in the presence of CO2. There was also increased synthesis of BosR, the borrelial oxidative stress regulatory protein, and NapA in the presence of CO2, suggesting that in addition to the RpoN/RpoS inducible system, an additional multifactorial adaptive response by B. burgdorferi is employed. Further studies are necessary to elucidate the responses of these regulatory pathways to different dissolved oxygen and CO2 levels within the context of the pathogenic mechanisms operative during B. burgdorferi infection. (Hyde et al 2006)

pH of 6.8 and 7.5 – 8.0 is preferential for gene expression of Borrelia – Another important variable that B. burgdorferi is exposed to during the various stages of its life cycle is pH. Carroll et al. determined that pH differences (6.0 to 8.0) altered the expression of 37 membrane proteins. pH and temperature were analyzed simultaneously, and a reciprocal pattern of regulation was observed, such that one set of genes were preferentially expressed at pH 6.8 and 37°C (98.6°F) (including ospC) and the other set were expressed at pHs between 7.5 and 8.0 independent of temperature (including ospA). This analysis also revealed that, in addition to ospC and ospA, several other genes also exhibited ospC-like (ospF, mlp-8 and rpoS) or ospA-like (lp6.6 and p22) expression that could be classified into group 1 and group 2 sets of genes, respectively. (Seshu et al 2004) (Normal blood pH is 7.35 – 7.45. Neutral is 7.0, so blood is very weakly basic.)

Increased concentrations of dissolved oxygen is damaging to Borrelia Borrelia membranes can be damaged simply by exposure to physiologically relevant concentrations of dissolved oxygen. (Boylan et al 2008)  Based on this study oxygen therapy, aerobic exercise, adaptogens, saffron and fresh green food which build up concentrations of dissolved oxygen in the blood should be damaging to Borrelia.

Co-Infections in Lyme Disease

Extensive evidence now shows that persistent symptoms of Lyme disease are due to chronic infection with the Lyme spirochete in conjunction with other tick-borne coinfections. The mechanisms of chronic infection appear to involve CWD (cell wall deficient) forms of the spirochete and biofilm formation. (Stricker & Johnson 2011)

Ticks may contain and transmit to the host a multitude of potential pathogens. The clinical presentation of Lyme therefore reflects which pathogens are present and in what proportion. Apparently, in early infections, before extensive damage to the immune system has occurred, if the germ load of the co-infectors is low, and the Lyme is treated, many of the other tick-transmitted microbes can be contained and eliminated by the immune system. However, in the chronic patient, because of the inhibited defenses, the individual components of the co-infection are now active enough so that they too add to features of the illness and must be treated. (Burrascano, Advanced Topics in Lyme Disease, 2008

)Although the transmission processes of Borellia burgdorferi and Babesia microti are similar, B. burgdorferi is acquired nearly twice as often as B. microti. This less efficient transmission of Babesia microti seemingly requires more tick bites to maintain similar zoonotic prevalence. In a previous study, we suggested that a threshold of >20 nymphal ticks collected per hour was necessary to maintain zoonotic endemicity of B. microti in white-footed mouse populations. (Rodgers & Mather 2007)

In Babesiosis, no single test is reliable enough to be used alone. Only in early infections (less than two weeks duration) can the standard blood smear be helpful. In later stages, one can use serology, PCR, and fluorescent in-situ hybridization (“FISH”) assay. Unfortunately, many other protozoans can be found in ticks, most likely representing species other than B. microti, yet commercial tests for only B. microti and B duncani (Formerly known as WA-1) are available at this time! In other words, the patient may have an infection that cannot be tested for. Here, as in Borrelia, clinical assessment is the primary diagnostic tool. (Burrascano, Advanced Topics in Lyme Disease, 2008)

In Bartonella, use both serology and PCR. PCR can be performed not only on blood and CSF, but as in LB, can be performed on biopsy specimens. Unfortunately, in my experience, these tests, even when both types are done, will presently miss over half the cases diagnosed clinically. (Burrascano, Advanced Topics in Lyme Disease, 2008)

Bartonella is perhaps the most challenging of all the co-infections to identify. Common strains of Bartonella, such as B. quintana and B. henselae, can usually be detected using antibody tests that are available at most medical laboratories. The PCR test can also be used to screen for Bartonella. See the resources section to learn of labs that perform Bartonella PCR testing. Antibody tests may fail to detect Bartonella even when it is present by PCR testing. Many times the diagnosis of Bartonella (or BLO as we discussed in chapter 2) is a clinical diagnosis, in that it is based on a patient’s symptoms, the doctor’s examination, and the elimination of other possible diagnoses. (Singleton, The Lyme Disease Solution, 2008)

There is one test that may be useful in screening patients suspected of being infected with Bartonella. This test may also be particularly useful in the follow-up of patients with Bartonella/ BLO. This blood test is called “vascular endothelial growth factor” (VEGF). This test measures a substance that is produced by the Bartonella microbe in order to facilitate its entry into the body tissues it likes to inhabit. Elevated levels of VEGF often (but not exclusively) mean that a patient is infected with Bartonella. By monitoring VEGF levels during the course of treatment, physicians can monitor the progress of treatment (antibiotics). When VEGF levels return to normal, it generally means that the antibiotics have been successful and can be discontinued. The VEGF test is available from standard commercial laboratories. (Singleton, The Lyme Disease Solution, 2008)

In Ehrlichiosis and Anaplasmosis, by definition you must test for both the monocytic and granulocytic forms. This may be accomplished by blood smear, PCR and serology. Many presently uncharacterized Ehrlichia-like organisms can be found in ticks and may not be picked up by currently available assays, so in this illness too, these tests are only an adjunct in making the diagnosis. Rarely, Rocky Mountain Spotted Fever can coexist, and even be chronic. Fortunately, treatment regimens are similar for all agents in this group. (Burrascano, Advanced Topics in Lyme Disease, 2008)

Ehrlichia and Anaplasma are in the family of bacteria known as Rickettsia. The diagnosis and treatment of these microorganisms should be prompt and based on clinical grounds. Treatment should not be based on test results alone, which results may be negative early in the course of the infections. As far as lab reliability, standard commercial lab tests generally do a good job of detecting antibodies (IgM and IgG) for both human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA), formerly known as human granulocytic ehrlichiosis. In some cases, however, blood smears or the PCR test may be considered, as well. (Singleton, The Lyme Disease Solution, 2008)

Co-Infection with Chlamydia pneumoniae

Chlamydia (Chlamydophila) pneumoniae is an obligate intracellular bacterium that causes acute and chronic respiratory disease in humans including; sinusitis, pharyngitis, bronchitis, and pneumonia. In addition, C. pneumoniae may be a risk factor for immuno-reactive disorders such as adult onset asthma, reactive airway disease in children, and reactive arthritis. C. pneumoniae infection has also been associated with an increased risk of cardiovascular disease. (Campbell et al 2010)

Clarithromycin – Inflammation may have a fundamental role in coronary heart disease, and infections may promote atherosclerosis or acute coronary syndrome. Chlamydia pneumoniae has been shown to be present in atherosclerotic tissue. Macrolide antibiotics (eg. clarithromycin) are anti-inflammatory and eradicate C pneumoniae from atherosclerotic plaques. Two small trials showed significant beneficial effects of macrolides on cardiovascular morbidity in patients with acute coronary syndrome, spurring several randomised trials. Short term clarithromycin in patients with stable coronary heart disease may cause significantly higher cardiovascular mortality. The long term safety of clarithromycin in patients with stable ischaemic heart disease should be examined. (Jespersen et al 2006)

Chlamydophila pneumoniae is recently confirmed to be a pathogen in bronchial asthma. Clarithromycin and telithromycin were thought to interfere with the signal pathways between ERK and NF-kappaB. These results suggest that airway mucus hypersecretion is one of the mechanisms of C. pneumoniae-induced bronchial asthma, and that macrolide and ketolide antibiotics represent a novel therapeutic intervention in these patients. (Morinaga et al 2009)

Evaluation of efficacy and safety of pristinamycin (PRI), compared with amoxicillin (AMX), both at 3 g daily for 7 to 10 days in adults with community-acquired pneumonia (CAP) (Chlamydia pneumoniae – 13.2%).  A satisfactory bacteriological response was observed in 82.3% (51/62) of PRI patients and 88.1% (59/67) of AMX patients. In this study, PRI 3 g daily was clinically as effective and well tolerated as AMX 3 g daily, for 7 to 10 days, in PPc, in the treatment of bacterial community-acquired pneumonia. (Tremolieres et al 2005)

The most common pathogen in community-acquired pneumonia (CAP) is still Streptococcus pneumoniae, followed by other pathogens such as Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella species. For the treatment in the elderly of low-risk pneumonia, an aminopenicillin such as amoxicillin with or without a β-lactamase inhibitor is frequently recommended. Treatment duration of more than 7 days is not generally recommended, except for proven infections with P. aeruginosa, for which 15 days of treatment appears to be appropriate. (Thiem et al 2011)

Botanical and Nutritional Strategies for Lyme Disease Treatment

Diagram from Vojdani et al 2007 which illustrates how using CAM (Complementary and Alternative Medicine) treatment could prevent different processes ranging from the attachment of the tick to the inflammatory process, CNS invasion, and the induction of neuroborreliosis. CAM can act through the enhancement of natural killer cell activity, macrophage function, inhibition of pro-inflammatory cytokine production, inactivation of the fibrinolytic system, and repair of blood brain barriers.

Vitamin D – Studies have shown evidences of 1,25(OH)2D in inhibiting disease induction in autoimmune encephalomyelitis, thyroiditis, type-1 diabetes mellitus, inflammatory bowel disease (IBD), systemic lupus erythematosus, and collagen-induced arthritis and Lyme arthritis, as reported by Hayes et al and Adorini et al. (Ginanjar et al 2007)

Natural Compounds that Target Biomarkers Involved in Lyme Disease

MAPK (Mitogen-Activated Protein Kinase) – MAPK pathways are involved in many pathological conditions, including cancer and other diseases. The MAPK pathways are located downstream of many growth-factor receptors, including that for EGF.  MAPK – Dysregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage. Mitogen-activated protein kinases (MAPK) play a key role in the regulation of neuronal development, growth, and survival, as well as that of pro-inflammatory cytokine production. Inhibition of both p38 and Erk1/2 significantly diminished TNF-alpha production, and totally abrogated production of this cytokine when both MAPK pathways were inhibited simultaneously. MAPK inhibition thus may be considered as a strategy to control inflammation and apoptosis in Lyme neuroborreliosis. (Ramesh & Phillipp 2005)

Examples of Natural Compounds that Regulate MAPK
Andrographis – downregulates p38-MAPK. 
Betulinic acid activates the proapoptotic MAPK cascade in human melanoma cells. (Tan et al 2003)
Curcumin – downregulates MAPK. (Ajaikumar 2008) 

NF-kappaB

NF-kappaB is an important transcription factor that is up-regulated in practically all cancers.  It up regulates inflammation, angiogenesis, metastasis and tumor promotion. NF-kappaB – Lyme disease has been associated with damaging inflammation within the central nervous system. In the present study, we demonstrate that Borrelia burgdorferi is a significant stimulus for the production of IL-6, TNF-alpha, and PGE(2) by microglia. This effect is associated with induction of NF-kappaB, and increased expression of Toll-like receptor 2 and CD14, receptors known to underlie spirochete activation of other immune cell types. These studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B. burgdorferi. Such production may play an important role during the development of Lyme neuroborreliosis. (Rasley 2002)

Examples of Natural Compounds that Inhibit or Down-Regulate NF-kappaB:
N-acetyl cysteine (NAC) (Sailai et al 2010) NAC enhanced hypoxia-induced caspase-3 activation and apoptosis in part by way of inhibition of hypoxia-induced NF-kappaB. (Qanungo et al 2004)
Omega-3 fatty acids – Very recent and exciting work has uncovered a mechanistic link between the beneficial effects of omega-3 fatty acids and inhibition of the NF-κB pathway (Oh da et al 2010).  This work reveals new sites of potential intervention in the pathways between diet, NF-κB and insulin resistance. (Baker et al 2010) 
Panax ginseng (Jou et al 2009) and panax notoginseng (Son et al 2009) 
Pterostilbene (Pan et al 2009) and quercetin (Granado-Serrano et al 2010) 

TGFβ1
(Transforming Growth Factor Beta) is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis. Over-expression of the immunosuppressive cytokine TGFbeta1 stimulates IL-17 and is another strategy that tumors have developed to evade effective immune surveillance. (Cancer Res 2008) 
Transforming growth factor-β (TGF-beta) – Various cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon-γ, and transforming growth factor-β have been detected in the CSF of Lyme neuroborreliosis patients, indicating that they play a role in the pathogenesis of this form of Lyme disease. (Ramesh et al 2008)

Examples of Natural Compounds that Suppress TGF-β1 
Astragalus and Salvia extract suppressed cell invasion triggered by TGF-beta(1) in HepG2 cells. (Liu et al 2010)
Curcumin (Ajaikumar 2008)
Green tea extract (40% EGCG)
Reishi – brings TGF-beta1 down.

TNF-α – Tumor necrosis factor-alpha
is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.  The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, as well as cancer. 

TNF-alpha – Lyme disease has been associated with damaging inflammation within the central nervous system. In the present study, we demonstrate that Borrelia burgdorferi is a significant stimulus for the production of IL-6, TNF-alpha, and PGE(2) by microglia. This effect is associated with induction of NF-kappaB, and increased expression of Toll-like receptor 2 and CD14, receptors known to underlie spirochete activation of other immune cell types. These studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B. burgdorferi. Such production may play an important role during the development of Lyme neuroborreliosis. (Rasley 2002)

Examples of Natural Compounds that Suppress TNF-α
Andrographolide (J. Immunol 2004)
ITCs downregulate TNFα (Nitric Oxide 2007)
Resveratrol (Polygonum cuspidatum)
Scutellaria baicalensis extract – has strong anti-inflammatory properties by inhibition of iNOS, COX-2, PGE2, IL-1beta, IL-2, IL-6, IL-12 and TNF-alpha expression in animal cells. (Kim et al 2009) 
White Willow 


Reducing Inflammation with Natural Compounds

Lyme disease is a multisystemic, inflammatory disorder caused by the pathogenic spirochetal bacterium Borrelia burgdorferi. (Hyde et al 2006)

PGE(2) Lyme disease has been associated with damaging inflammation within the central nervous system. In the present study, we demonstrate that Borrelia burgdorferi is a significant stimulus for the production of IL-6, TNF-alpha, and PGE(2) by microglia. This effect is associated with induction of NF-kappaB, and increased expression of Toll-like receptor 2 and CD14, receptors known to underlie spirochete activation of other immune cell types. These studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B. burgdorferi. Such production may play an important role during the development of Lyme neuroborreliosis. (Rasley 2002)

The following is a list of some of the natural compounds that are effective at reducing inflammation:
Curcumin – targets PGE2 – Curcumin is a polyphenol present in the spice turmeric, which can directly scavenge free radicals such as superoxide anion and nitric oxide and modulate important signaling pathways mediated via NF-kappaB and mitogen-activated protein kinase pathways. Polyphenols also down-regulate expression of pro-inflammatory mediators, matrix metalloproteinases, adhesion molecules, and growth factor receptor genes and they up-regulate HDAC2 in the lung. Thus, curcumin may be a potential antioxidant and anti-inflammatory therapeutic agent against chronic inflammatory lung diseases. (Biswas & Rahman 2008) 
Ginger – targets PGE2.  Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8 in ovarian cancer cells. (Rhode et al 2007) 

Omega-3 fatty acids
– Very recent and exciting work has uncovered a mechanistic link between the beneficial effects of omega-3 fatty acids and inhibition of the NF-κB pathway (Oh da et al 2010).  This work reveals new sites of potential intervention in the pathways between diet, NF-κB and insulin resistance. (Baker et al 2010)

Zinc –
inhibits NF-kappa B. And NF-kappaB is constitutively activated in many cancer cells, resulting in activation of antiapoptotic genes, VEGF, cyclin D1, EGFR, MMP-9 and inflammatory cytokines. (Prasad et al 2009) 


Examples of Natural Compounds that Regulate the Immune Response

To date, there is no convincing evidence that symptoms post-treatment would be caused by a persisting infection. On the contrary, the symptoms may be due to an improperly regulated immune response to B. burgdorferi. (Sjowall et al 2011)

The emphasis should be on immunoregulation and enhancement of cell-mediated immunity (macrophage function, NK cell function) and not enhancement of humoral immunity and antibody production, since induction of antibody production may actually worsen the autoimmune reaction or autoimmune disease exhibited in many patients with LD (Lyme borreliosis). (Vojdani et al 2007)

Indeed, previous investigations in both mice and humans have indicated that a successful clinical outcome requires an effective inflammatory T helper cell (Th) 1-type response that is adequately balanced by an anti-inflammatory and Th2-like response against B. burgdorferi. (Sjowall et al 2011) 

Echinacea – We found many functional immune assays were affected by Echinacea preparations, suggesting that Echinacea not only stimulates innate immunity, but also enhances adaptive immunity. (Zhai et al 2007) The results demonstrate that Echinacea, Astragalus and Glycyrrhiza herbal tinctures stimulated immune cells as quantified by CD69 expression on CD4 and CD8 T cells. This activation took place within 24 h of ingestion, and continued for at least 7 days. In addition, these three herbs had an additive effect on CD69 expression when used in combination. (Brush et al 2006)

Ganoderma lucidum – polysaccharides (especially beta glucans) are immune enhancing. The beta glucans attract Natural Killer cells to attack tumors and they work very well with monoclonal antibodies.  Together they puncture tumor cells.  There is good data on beta glucans working synergistically with Rituxan and monoclonal antibodies. (Hong et al 2003)  

Glutamine – is necessary for the production of Interferon gamma and Natural Killer cells. A precursor of glutathione.  Protects the structural and functional integdrity of intestinal mucosa.  GALT (Gut Associated Lymphoid Tissue) requires glutamine for optimal immune response.  GALT is the tissue that B and T cells are primed against intestinal antigens, thus forming a healthy immune defense of memory cells. 

Lactoferrin – is a natural forming iron-binding glycoprotein with antibacterial, antioxidant and anti-carcinogenic effects. Lactoferrin also has the capacity to induce apoptosis and inhibit proliferation in cancer cells as well as restore white and red blood cell levels after chemotherapy. (Gibbons et al 2011) Colostrum is the richest source of lactoferrin. Lactoferrin stimulates IL-18, IL-α & IL-γ which stimulates NK cells.


Examples of Natural Compounds with Antimicrobial Actions

Artemisia – An exhaustive survey of literature revealed that the different species of Artemisia have a vast range of biological activities including antimalarial, cytotoxic, antihepatotoxic, antibacterial, antifungal and antioxidant activity. Some very important drug leads have been discovered from this genus, notably artemisinin, the well known antimalarial drug isolated from the Chinese herb Artemisia annua. Terpenoids, flavonoids, coumarins, caffeoylquinic acids, sterols and acetylenes constitute major classes of phytoconstituents of the genus.Various species of Artemisia seems to hold great potential for in-depth investigation for various biological activities, especially their effects on the central nervous and cardiovascular systems. (Bora & Sharma 2011)

Echinacea purpura – Along with evidence of enhanced macrophage function, we found that oral EP reduces bacterial burden during infection by Listeria monocytogenes, demonstrating its efficacy in vivo. (Sullivan et al 2008)

Garlic – In terms of antibiotic potency against Gram-positive and Gram-negative bacteria, authentic allicin (an antibacterial principle of garlic) had roughly 1-2% of the potency of streptomycin (vs. S. aureus), 8% of that of vancomycin (vs. S. aureus), and only 0.2% of that of colistin (vs. E. coli). (Fujisawa et al 2009)

Goldenseal – Crude extracts and isolated compounds from goldenseal have demonstrated antibacterial activity in vitro and in clinical trials. The antibacterial activity of goldenseal has typically been attributed to alkaloids, especially berberine, which has shown activity against various Gram-positive bacteria, including MRSA. (Ettafagh et al 2011) 


Examples of Neurological, Hormonal and Immune Enhancing Properties of Natural Compounds

American ginseng is a neurological protectant; it improves memory and learning, and has been shown to improve ADHD.  American ginseng extract has also been shown to improve brainstem neuronal activities, insulintrophic effects, free radical quenching activity and cerebral circulation, which contribute to its neuro-protective and anti-aging effects.

Rhodiola rosea has profound protective effects on the nervous and endocrine system as well as being anti-fatigue, Rhodiola rosea extract enhances immunity, increases capacity for exercise, increases the activity of superoxide dismutase, decreases serum lipids and modulates the ratio of cAMP and cGMP.  It also has antimutagenic and antioxidant properties, enhances memory and is an antidepressive agent.           

Epigallocatechin-3-gallate
(EGCG) is a major antioxidant in green tea.  EGCG decreases production of the protein beta-amyloid, which is related to Alzheimer’s disease and can accumulate abnormally in the brain, leading to nerve damage and memory loss.  EGCG’s ability to prevent beta-amyloid buildup requires much higher amounts than what would normally be consumed, so drinking green tea alone may be insufficient.  In addition, the amount of EGCG a patient needs to fight Alzheimer’s disease is much higher than that found in green tea.

Green tea also inhibits Alzheimer’s disease by inhibiting NF-kappa beta, a pro-inflammatory protein, by reducing oxidative neuron damage, reducing heavy metals and by enhancing oxygen uptake.

Eleuthero demonstrates favorable effects on various human functions, including visual acuity, color differentiation, hearing, fatigability, thinking association with motor activity.  It also possesses a capacity of displaying a normalizing effect regardless of the physiological abnormalities caused by damaging influences, e.g. normalization of blood pressure in patients with both elevated or lowered blood pressure; normalization of blood sugar levels in hyper-or hypoglycemia.

Blood Tests in Lyme Disease

Besides the standard diagnostic tests discussed earlier the following blood tests are helpful:

Assessment of Inflammatory Levels
1. CRP 
2. Homocysteine
3. ESR

Assessment of CO2 Blood Levels
1. CMP – fasting

Other useful blood tests
CBC
Vitamin D 25(OH)
Vitamin B12


Natural Strategies in Treating Lyme Disease

Following a diagnosis of Lyme Disease there is a need for nourishing and building (adaptogenic and anabolic) herbs and nutrients – in order to nourish and rebuild the damaged liver cells and tissues.  Lyme Disease is a destructive condition, so the concept of anabolic restoration is essential.  We also need to look at anti-microbial protection and immune modulation with botanicals and nutrients. We need to establish a good foundational therapy. We can also target any blood work abnormalities that may be revealed in the blood work such as CRP, Homocysteine, ESR, etc.

The following are some natural strategies that are helpful in treating Lyme Disease:
Immune System Regulation
Adaptogens.
Also see list of examples of immune regulating botanicals.

Anti-inflammatory Botanicals
Boswellia
Bromelain
See list of examples of anti-inflammatory botanicals 

Energy Enhancement and Mitochondrial Support
Adaptogens
ENADA

Cardiovascular Support
Anti-Microbials
As these have anti-microbial activity they can greatly increase the effectiveness of antibiotics.
Colloidal Silver,
Vitamin C,
See list of Examples of Anti-Microbial Botanicals.

To Oxygenate Tissues – Triquench with saffron

To Restore Beneficial Gut Flora after Course of Antibiotics. 
These are also important for immune system response and for resistance to secondary infections.
Sacromyces bourlardii
High potency acidophilus
Synbiotics
Candibactin

For Improving Memory and Enhancing Central Nervous System Activity
See list of examples of botanicals with neurological, hormonal and immune enhancing properties.

Pathways Activated in Lyme Disease that can be Downregulated with Natural Compounds: MAPK  NFkappaB  TGFbeta  TNFalpha 


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Compassionate Acupuncture and Healing Arts, providing craniosacral acupuncture, herbal and nutritional medicine in Durham, North Carolina. Phone number 919-309-7753.

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