Background
Many patients present with illness that may be due to Lyme, other chronic infection, mold, or other toxicity. Primary symptoms include fatigue/low energy, musculoskeletal or nerve pain, and cognitive and/or depressive/anxiety issues. Related symptoms may be autonomic (palpitations, tachycardia, lightheadedness), mast cell/histaminic (congestion, itching, flushing, insomnia), or less commonly gastrointestinal (discomfort, bloating, heartburn, irregularity) or hormonal (thyroid, sexual). There may be a history of Lyme, tick bite, other infections, mold or toxin exposure, either recent or in the past. We generally do diagnostic assessment using standard (LabCorp or Quest) and where needed specialty lab and nonstandard testing, and based on that establish a tentative understanding of diagnosis and underlying causes, which is used to develop a treatment plan. In doing this we face a couple of significant challenges.
The first is that there are typically multiple contributing causes to such illness, and lab assessment of them is not straightforward. Some lab findings are pretty clear—low levels of nutrients or hormones, for example. But other findings are often either equivocal—a Lyme test that has several positives but does not meet conventional criteria for positivity—or are of unclear clinical significance—Epstein-Barr or herpesvirus antibody positivity, mold toxin excretion or elevated metal blood levels. Additionally, we don’t have testing available for issues that we’d like to better assess—healthy versus unhealthy immune system reactivity, mitochondrial dysfunction and causation, and immune or infectious activity in the brain.
The second challenge is that the treatment approach to such illness is often difficult to determine and implement successfully. There are several reasons for this. Most importantly, given that the causes of illness are multiple, treatment of one issue may not be helpful without treatment of others. Additionally, the treatments themselves are not often backed up by strong evidence of effect—patients who have failed or seek alternatives to conventional treatments often need interventions that have not been clinically trialed. Finally, some patients are quite ill or sensitive, and are only able to tolerate small, incremental treatment interventions.
Notwithstanding these challenges, our patients often improve through the course of our care. But for some the improvement is less than they or we would like, and we are always on the lookout for new ways of supporting more powerful healing.
With that in mind, we constantly re-examine our approach to patients with illness of this type. In this process we look at what is known about such illness, the evidence for various diagnostics and therapeutics, and what other practices are doing. A description of our evolving approach follows.
Current Understanding
Chronic illnesses that involve infection and/or toxicity result from the interaction between the infectious or toxic agent and the host response. Both sides of this interaction determine illness and resulting symptoms, and can be understood at a high level as follows:
- Infection/toxicity. We are part of broader ecology that includes micro-organisms and diverse plant and animal forms, many of whom predate and will likely outlive our species. Some of this ecology lives within us – we are born with viral DNA and a gut microbiome, and following birth and for the rest of our lives we are exposed to and acquire toxins, viruses, bacteria, fungi, and parasites. Some of these agents are beneficial to us—for example, the microbiome in our gut creates nutrients that we absorb and that affect our immune system and brain function in healthy ways. Sometimes, however, these agents are harmful. When a single agent produces acute illness, resolution may at times be achieved through conventional interventions to identify and eliminate it. In chronic illness, on the other hand, the cause of symptoms may not be attributable to a single agent but rather to an imbalance between toxic and healthy agents that disrupt healthy function or trigger adverse host response, with symptoms that increase over time. In such illnesses, treatment aims to restore balance among disruptive and healthy agents and host response.
- Host capacity for healing. We are also born with our own human set of genetic instructions. Over time these instructions are modified (epigenetically) by exposures to infectious agents, toxins, traumas, diet, metabolic intermediaries, etc. This results in an ever-changing capacity to respond to infection and toxicity through our detoxification and immune systems, and to produce energy at the cellular level. These systems are complex and intertwined, with subsystems that can be protective and beneficial in acute situations and when limited in scope but can be damaging to the host when they are uncontrolled or chronic. Host response depends both on host systems (genetics, hormonal, metabolic, energetic, etc.) and the type and amount of the agent provoking the response.
Infectious agents and toxins vary in their own biology and effect on the host. Lyme disease is classically an infection with borrelia burgdorferi, but may include infection by another strain of borrelia, by one or more coinfections, or by other infectious agents. Although as a consequence treatment of Lyme may need to vary depending on the organisms involved, for the most part we don’t know as much as we need to about the differences in biology and effects of these organisms. Here for example are some aspects of our understanding of the biology and effects of borrelia burgdorferi:
- The organism avoids oxygen-rich environments and is heat-sensitive, so may respond to oxidative and hyperthermic treatments
- Cell division cycle is long – 14-28 days – so treatment cycles likely need to be long
- The bacterium changes its structure to form cell wall-deficient forms that are resistant to some antibiotics, and antibiotic resistance also results from plasmid-mediated immunity, so treatment may require a combination of multiple antibiotics
- The infection is largely intracellular – in macrophages, epithelial cells, lymphocytes, fibroblasts – so treatment must include intracellular antibiotics
- When extracellular, the infection stimulates formation of biofilm that protects the organism from antibiotic treatment so biofilm disruption may be important
- The bacterium can successfully attack macrophages and lymphocytes including natural killer cells, compromising the immune response
- The infection promotes Inflammatory cytokine (IL-1, IL-6, IL-17, IL-22) chemokine, and toll-like receptor but not TNF alpha production, with short-term rise in CRP and inflammation in the central nervous system; the pattern of increase in these markers is variable across patients and may be responsible for damage to mitochondria, membranes, and myelin with resulting symptoms that may increase when antimicrobial treatment is undertaken
- The infection causes a shift in metabolism among immune cells away from mitochondrial oxidative phosphorylation toward glucose-based glycolysis (Warburg effect) and may be responsive to treatments that restrict glucose and shift metabolism from anabolic (mTOR) to catabolic (autophagy) states
As incomplete and complicated as this understanding is, it can be further complicated by the biology and effects of Lyme coinfections, or infectious agents, mold, and other toxins, about which we often know less. For example, patients with persistent Lyme are often positive for blood markers and mycotoxin excretion that may be indicative of mold toxicity. The clinical significance of this is variable, however. The healthy human gut microbiome has been shown to include many species of mold (including fusarium, aspergillus, and penicillium) and factors such as diet influence the presence and amount of such organisms. In some cases, these molds produce toxins that are associated with illness, but we don’t have an understanding of how and when this happens.
Despite this complexity and the limited state of our knowledge, two conceptualizations of host response to infection and toxicity are emerging that bear on treatment approach.
The first is Robert Naviaux’s concept of the cell danger response (CDR). Naviaux proposes that there is a systematic, coordinated response to toxic and infectious threats to a host that aims to protect it by reducing energy production and energy-requiring activity but as a consequence results in chronic illnesses including chronic fatigue, autism and other neurologic/psychiatric conditions, autoimmune disease, and cancer. The response is led by mitochondria, which are primarily known as organelles where cellular energy is produced but as importantly are lookout points for cellular threats and communication units that interact with the cell nucleus and with surrounding cells. The response is triggered when a toxic “set point” is exceeded, can be amplified by subsequent toxic exposures, and does not abate until the threat is reduced or the system is reset. It involves a shift from healthy winter (autophagy) to unhealthy summer (mTOR) metabolic state with multiple consequences for the cell and for host healing capacity including:
- Energy production via less efficient glycolysis rather than more efficient oxidative phosphorylation in the electron transport chain with decreased energy
- Increases in intracellular oxygen and oxidative damage that consumes cellular antioxidants such as glutathione, causing cellular damage
- Stiffening of cell membranes that degrade neurologic and energy production functions
- Release of ATP and other nucleotides that signal to other cells to make similar metabolic changes and stimulation of host-wide inflammatory response, dysbiosis, gut leakage/autoimmunity
Naviaux proposes that it is possible to reverse the cell danger response and attendant chronic illness through a healing process that reduces exposure to toxic agents (either the specific precipitating one or the many that comprise the toxic background) and by increasing the host capacity to handle and eliminate toxins. He says that much of what must be done to accomplish such healing is still unknown, and that the healing process in chronic illness is requires months or more.
The second conceptualization is that of Thomas Seyfried, who is largely focused on a specific chronic illness – cancer. Like Naviaux, Seyfried highlights the importance of mitochondria, arguing that cancer is a metabolic disease in which toxic or infectious damage to mitochondria causes a switchover to glycolysis rather than electron transport- driven oxidative phosphorylation, with resulting changes in expression of genes that promote or suppress oncogenesis, such at the p53 (tumor suppressive) gene. His research rejects the prevailing view that cancer is caused primarily by somatic genetic mutations, which occur commonly, but instead depend on cytoplasmic metabolic changes.
Seyfried advocates for a ketogenic diet that restricts glucose in cancer patients while increasing the production of ketone bodies that can be used by non-cancer cells for energy. He also advocates for pulses of cancer cell killing via oxidative treatments that increase reactive oxygen species in cells, which may occur alongside of conventional killing by chemotherapy and radiation. Seyfried’s approach has been popularized by Nasha Winters who has explicated how it can be accomplished through diet and supplements, and Jane McLelland has expanded upon it with recommendations for use of supplements and repurposed prescription medications, including advocacy for an approach to oxidative killing that stimulates the Fenton reaction through ferroptosis.
Although the target of the Seyfried/Winters/McLelland conceptualization is cancer, it builds upon and addresses the Naviaux concept of mitochondrial injury and resulting metabolic and immune derangement. As such, it provides a relevant approach to metabolically-based and oxidative therapeutics that may be applicable to infectious/toxic disease. A challenge in all types of illness, however, is incorporate killing (cancer cells, microbes, toxin-damaged cells), without stimulating immune mediated damage to healthy host cells and resulting symptoms. Although much is known about innate and adaptive immune response, mediators (cytokines, chemokines, toll-like receptors), and helper cell Th1 and Th2 regulation, little is known about how to measure these aspects of host response in clinical practice and how to promote healthy response and repair or stimulate growth of damaged mitochondria.
Approach
Notwithstanding our incomplete understanding of the biology and effects of infections/toxins, there is need for a treatment approach that can be put into today’s practice. Based on the understanding summarized above, we advocate for a multimodal approach that seeks to engage the host healing capacity and to reduce the infectious and/or toxic load. Elements of this approach include:
- Enhance host healing capacity
- Encourage health-promoting lifestyle practices: sleep, exercise, and purposeful, spiritual, conscious living
- Address nutrient and hormonal deficiencies and imbalances identified through lab testing
- Promote healthy gut microbiome and reduce gut leakage through avoidance of food allergens and provision of pre- and pro- biotics, gut nutrients and immunoglobulins
- Optimize metabolism and encourage autophagy through increase in dietary protein and reduction in dietary carbohydrates, incorporation of periods of reduced dietary energy consumption, and use of autophagy-stimulating herbs and substances
- Promote a balanced immune response using low dose naltrexone, herbs, energetic treatments
- Promote mitochondrial health and healthy aging through herbs and other substances
- Promote detoxification and drainage systems through herbs and homeopathics
- Address dysautonomic and mast cell activation and toxic effects through vagal and brain training, acupuncture, herbs and substances
- Reduce microbial load
- Reduce environmental sources of toxicity – mold, radiation, etc
- Use antimicrobial and medication and herbal regimens to kill pathogens and reduce biofilm
- Use oxidative and energetic treatments to kill pathogens
References
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