EP233: Born Free: Rethinking Chronic Illness Through Systems Biology - Part 1 - Joshua Leisk
In a Nutshell
Joshua Leisk's Born Free model frames complex chronic illness as a self-reinforcing cycle of mitochondrial dysfunction, sympathetic overdrive, impaired glycogen storage, and progressive mineral depletion that leaves the system unable to restore homeostasis. Core drivers include lactic acidemia from prolyl hydroxylase inhibition, acetaldehyde-producing microbial overgrowth, barrier breakdown, and heavy metal accumulation that further impairs glutathione redox and NAD balance. Recovery requires a sequenced approach: restore resources (glycogen, minerals, glutathione), reduce burdens (microbial load, environmental toxins), and reestablish parasympathetic signaling before addressing downstream issues like aldehydes or biofilms.
These notes were generated by AI and may contain inaccuracies.
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Welcome to episode 233 of the Better Health Guy podcast. Today, we explore Born Free: Rethinking Chronic Illness Through the Lens of Systems Biology. My guest today is Joshua Leisk. Joshua is a biological engineer and independent researcher focused on complex chronic illness. He's the creator of Born Free, a patient-led community research project that develops models and potential interventions for conditions such as heart disease. His work takes a systems biology, reverse engineering approach, exploring how disruptions in metabolism, mitochondrial function, and cellular signaling may contribute to chronic disease. He is known for developing detailed, evolving models that aim to explain how illness begins, progresses, and may potentially be reversed. Joshua collaborates with a global community of patients, practitioners, and researchers. Joshua is a professor at the University of Michigan's Center for Sharing Pathway Diagrams, Hypotheses, and Research intended to advance the understanding of complex chronic conditions. He is a founder of the Collaborative Sciences Institute, which provides systems biology education for clinicians treating complex chronic disease. He's also involved with Renegade Research, a 501c3 nonprofit, bringing together patients, caregivers, scientists, and clinicians to drive innovation in healthcare.
In part one of our discussion here in episode 233, we talk about the many factors that drive these complex conditions. We talk about sympathetic overdrive, the microbiome, testing, and diet. In part two of our discussion in episode 234, we'll talk about the immune system, structural issues, hypoxia, oxidative stress, and inflammation, the mitochondria, cell activation syndrome, and the Born Free Protocol.
When I was diagnosed with chronic fatigue syndrome, before we even called it ME-CFS, very little was understood about the mechanisms that underlie the condition. Today's guest has deeply explored those mechanisms and put together a really detailed model for recovering from ME-CFS and many other complex chronic conditions. If you've looked into his work, you've probably seen his detailed pathway diagrams. Our goal today is really to try to explore the higher level concepts of his model and view chronic illness in a different way.
I had severe ME-CFS, not that it was called that back in my teens. I was bedbound. My worst rolling over in bed was enough to knock me out again for another day. People would carry me to the bathroom, that kind of thing. It was not a pleasant time. I recovered from that. That was a very slow grind and then ultimately had a successful career. I sold up the IT business back when I was 38. And at that point, I wasn't quite sure what to do with life. I'd put my feet up for a little while. I traveled a little. Focused on doing some metabolic coaching and fitness. And that was kind of a passion for a little while.
During that time, I had an interesting little moment where I noticed that there were different patterns between some of the clients that I was actually coaching. Some people would respond very directly to normal supplements. And then there was another group that was almost like aliens that would respond completely differently. And that was intriguing. And so I started scratching at that itch and exploring and pulling on that string. And the more it kept giving and giving and giving, and the patterns I noticed sort of started converging around certain pathway impairments and things. And I started looking into nitrogen metabolism and mitochondrial dysfunction. And at that point, I realized that I was looking at my old nemesis again. This was actually chronic fatigue syndrome. And I found that fascinating. I thought, well, I've got nothing better to do with my time. This seems like a valuable use of it. So let's focus on this for a while and see where this goes. That was six years ago.
The context for that was the idea that we're born into this world free of encumberments. And that's maybe perhaps not true, because we do inherit a number of things from both parents and the environment. But it's also suggestive that if we are able to shed those encumberments, that we can actually revert back to this original state.
Joshua's work focuses on ME-CFS, but there's an extensive list of conditions on his website that the protocol may also apply to. These include long COVID, SIRS, fibromyalgia, Ehlers-Danlos, tinnitus, mast cell activation, POTS, other dysautonomias, STUDIO, MS, polycystic ovarian syndrome, Hashimoto's, Guillain-Barré, autism, Parkinson's, and others.
In Joshua's modeling, there is a common cascade and then there are individual variables that control the presentation. Mitochondrial dysfunction sits in many ways at one of the major intersections in all of this. There is a localized plus systemic set of impairments. The localized section is likely going to be a localized infection. There'll be particular pathogens involved in a particular tissue that's going to create a certain personality. The status of the minerals and the heavy metals are going to control a significant amount of the metabolism. And then essentially the presentation is going to relate to the affected metabolism in that tissue. And then ultimately the layers of compensation, trying to restore homeostasis, in a system that's basically digging a deeper hole every day.
The conditions and disorders and syndromes mentioned in the protocol are only ones that Joshua has seen data for. In each of those conditions or disorders, people have been putting the protocol or elements of the protocol into play and seeing a therapeutic benefit. Anecdotally, it appears to be the right direction. Clinical trials are being planned for a number of these things.
Alzheimer's was mentioned as a good example. There was an animal model recently. They found that if they restored the NAD Redox in that animal model, it reversed the entire trajectory. All of the memory deficits, everything was restored in the animal model. They used an exotic compound to do so. Figure 14 in Joshua's modeling work is a really good example of how he would explain a lot of the mitochondrial dysfunction at that core section. You see the layers of impact downstream and what that does to the glycogen homeostasis and parasympathetic metabolism. And then ultimately how that leads to a progressive sympathetic excess and overdrive, which then has deleterious function on the minerals and metals. But ultimately, it's where the gastroparesis, the swallowing, the immune dysregulation and potentially a lot of the microbiome maladaptive response comes from.
There is a link in some of the phobic section that talks about this. One of the things with the microbiome that's really interesting is that it can respond to shifts in the nervous system. There was a paper where they looked at a mouse model and they basically triggered some changes in the hypothalamus. And within hours, without any food being introduced, the microbiome was retiled and adapted around the signals being sent from the nervous system. Not fully understood how that signaling takes place. The hypothesis is that in the context of the fermentation syndrome that has been seen vastly across all of the data that's been collected, it appears to be a response to try to restore homeostasis to the sympathetic overdrive.
In the context of excessive adrenergic signaling and that moving downstream to CMPK, so that's cyclic AMP, protein kinase A, that is actually the intersection where the acetaldehyde excess ultimately triggers a downregulation of CMP via the endogenous opioid synthesis pathway. As the acetaldehyde ramps up, it's the same. Essentially, people self-medicating with alcohol, the body then produces the opioids, and then that downregulates CMPK and tries to restore the homeostasis. The problem is that the species that are often producing this fermentation product also happens to be opportunistic pathogens. So then in the context of a compromised system, they lead to ongoing barrier dysfunction, inflammation and immune response. This becomes part of the overall cycle of why there is this persistence.
If you look at a Parkinson's patient, an Alzheimer's patient, age related diseases, you'll see the same mechanism, the same dysbiosis and alterations, the same patterns in the mineral dysregulation, the same heavy metal accumulation, the same immune immunocompromised state. All of these are features across the board in all of these different conditions and disorders and diseases. We have a complex system that's always trying to heal. It's always trying to restore homeostasis, but it lacks the capacity to do so. If you've got a system that is always trying to heal and it can't, that's indicating that there's actually a number of things that could be impacting that. For example, resource shortages or there could be a range of different insults or toxins which are overloading the system, which once it's reached a certain threshold, it's just trying to keep its head above water and can't actually escape.
The process in the protocol is to restore the resources, reduce the burdens and then try to shift the direction of all of the metabolism and trajectory towards recovery rather than progressive decline.
More of the same. What COVID has done is give us volumes of data from people that are now suffering and the COVID interventions were much the same. In Australia, there was a totally different experience with COVID because borders were shut down and there were roughly nine months of preparedness to get ready for this. Progressively what has been seen is issues where there is reactivation of the herpes viruses. That's one of the most common things seen. There is a mechanism in the protocol and the model which explains that as part of the mitochondrial dysfunction and a particular fault sensor. There is a fault sensor called hypoxia inducible factors, one alpha that's downstream of these enzymes called the pro hydroxylases. Those are the actual fault sensor. They're multipurpose. They're also involved in the collagen synthesis and degradation pathways. It appears to be that the collagen synthesis is supposed to be upregulated when there's certain types of mitochondrial dysfunction, but at the same time it's one of those things that fails under certain conditions.
There's been a significant uptake in chronic disease and health decline. It's sad to say, but we're not in anywhere near as good shape as we were pre-COVID. And that continues to be the case. It's a totally reversible situation up to a point where things get very difficult. There's been an uptick in cancers. The progressive health decline has accelerated. It looks like the background level of insult has gone up in the last number of years and people's capacity to deal with that insult has been reduced. In the context of resilience against threat and insult, we have a population that is less prepared for the increased level of insult. It used to be that we'd get a flu season once a year. And we'd get a flu. We'd have various things going around. And now we seem to get three to four cycles a year at least of various different respiratory infections.
During that time, every time the immune system is busy dealing with a new threat, it allows the microbial infections to basically increase the size of their biofilms. It allows them to increase the size of the reservoirs, which then contribute to the overall load. Normally if an elderly patient ends up or even an adult ends up in hospital with a respiratory infection, despite it being a viral infection, they'll be given typically azithromycin or some other antibiotic to prevent secondary bacterial pneumonia. And it's for this very reason. While the immune system is busy dealing with a particular class of pathogen, particularly the viral pathogens, it's less equipped, particularly the native immune response, to deal with the other classes of pathogens, so the microbes. The more we can do to reduce the microbial burden and or the viral burden, the less susceptible we are to new threats and ongoing insults.
There are a number of different things that all kind of have slightly different inputs into this. We could be talking about nervous system adaptations. We can then look at burdens and different burdens. Aging, one of the differences that would be looked at with aging versus what we see with long COVID or something else in somebody's teenage years is that we have at that point the proliferation of latent herpes virus infections. So varicella, various other herpes viruses that have been a slow, perhaps smoldering infection that's taken over all the various tissues progressively. Varicella is probably more pronounced in that context because its ability to replicate throughout the body seems to be a lot more enhanced than Epstein-Barr or some of the others. If you get a varicella reactivation or shingles, you're looking at rashes across large sections of tissue. There was a very interesting study where they were looking at cadavers and they were looking at the different viral infections in different tissues.
Nervous system dysregulation is a key piece because the autonomic nervous system is a big driver in the disease state in essentially dysregulating or unbalancing the homeostasis, essentially pushing the mitochondria beyond. And of course driving the sympathetic excess and overdrive and there's multiple loops. It's easy to think about things in straight lines when looking at causality in biochemistry. That's really not helpful because these are cycles that are all interconnected. And so throwing out one system and the homeostasis out of one cycle essentially affects the others. And all of these different cycles are trying to restore homeostasis. When we're looking at the ripple effect from one change in one cycle in one system, it then has layers of compensations and ripples throughout the others.
Going back to early childhood, we could look at how the nervous system might respond to different threats. The nervous system is an interesting one to look at because it's the bridge essentially between our consciousness and the biochemistry and the physiology. In that context, we have our layer of consciousness. We're kind of a consciousness, which is experiencing our body and the outside world through an evolved slash hybrid monkey. And then we have the nervous system, which is trained to do a whole range of different things. But essentially one of those things is to keep us safe from threats. The nervous system itself, its autonomic parts, has its own level of memory and its own ability to react and respond to things ahead of the prefrontal cortex and our actual conscious state. It's important to remember that if the amygdala, if essentially the nervous system is getting trained to perceive patterns, electrical signals as threats, it's going to learn to predict those as threats. And it's going to essentially, in some ways, potentially keep the consciousness hostage in this world that it creates, where essentially everything is a danger. Everything is a threat. And it can be a horrible experience when you're stuck in that state. It's like you don't want to be thinking and feeling that the world acts like a certain way, but ultimately that's the way it's being presented.
It gets particularly difficult if biological processes are being perceived as threats. If you then look at the nervous system and say, okay, well, it's both something that we have to look at from a biochemical angle, but then also something that we have to look at as patterns and programming. You may have a series of different threats and mitochondrial metabolism issues, which then lead to energy issues, which then create metabolic alarms in the central nervous system. Which then lead to an unfavorable state, then shaping the patterns, which are then set to program the autonomic nervous system. In that context, things that we would normally perceive as safe or low noise type threats, like a level one threat might then be perceived as a level 10 threat because the metabolism is basically biasing the nervous system to perceive it that way. And that becomes very tricky because essentially the autonomic nervous system is learning by repetition. The repetition of unsafe, unsafe, unsafe leads to a state of lack of safety. And I think that this is something that is prevalent that you'll see in the autism spectrum, OCD, ME, CFS, long COVID, everything else is essentially the nervous system being stuck in this state where it's reacting hyper arousal and hyper vigilance around essentially like low level noise and threats.
The cell danger response model from Naviaux's work explains how biochemistry sets up the nervous system for dysregulation. Extracellular ATP functions as an alarm signal outside the cell, binding to P2X and P2Y receptors to communicate threats to surrounding cells. Normally, this alarm is dampened by inosine, which is produced downstream of the oxidative pentose phosphate pathway and glycolysis. Data from Therion Aristotle reports shows that individuals in a pre-CFS state, typically those on the autism spectrum or with ADHD who have not yet reached metabolic collapse, exhibit inosine levels that may reach 400% above normal. Once deep metabolic collapse occurs, the metabolism can no longer support inosine production, resulting in low or very low levels that allow the cell danger response to treat level one threats as level 10 threats.
Loss of parasympathetic signaling and localized energy storage in the form of glycogen leads to progressive reliance on systemic energy sources including lipolysis, BCAAs, and beta oxidation, with sympathetic signaling scaling according to energy demands. In autism and related presentations, common findings include microbiome dysbiosis, elevated oxalates, histamine issues, muscle activation, and Ehlers-Danlos syndrome type metabolism, all of which illustrate mitochondrial dysfunction and neurotransmitter dysregulation.
Figure 14 on the Born Free website illustrates how the methylation cycle feeds glutathione synthesis, which is required for glutathione redox. Glutathione redox then controls NADPH redox, which partners with pathways including the oxidative pentose phosphate pathway. Poor methylation from MTHFR mutations or low zinc impairs transsulfuration, resulting in low glycine and cysteine output. This prevents adequate glutathione production in response to oxidative stress generated in the mitochondria. Glutathione synthesis and redox act as an automatic cooling system for mitochondrial metabolism. Excess reactive oxygen species inhibits complex I (NADH dehydrogenase), causing the NADH pool to build up and driving glutamate dehydrogenase and NADP transhydrogenase. This elevates intracellular glutamate and the NADPH pool, which should drive glutathione synthesis and redox, but problems with glycine and cysteine leave glutamate high and impair the cooling system.
Heavy metals accumulated due to prior low glutathione levels inhibit glutathione peroxidase and glutathione reductase activity, preventing maintenance of the redox pool. The combination of impaired mitochondrial cooling, heavy metal accumulation, and reduced ability to detox mycotoxins and environmental insults progressively impairs glycogen synthesis, inosine synthesis, NAD synthesis, and all key synthesis pathways required for energy and immune function. This cascade leads to progressive sympathetic overdrive, an immunocompromised state, and accumulation of passenger pathogens. Nervous system cells become primed at a biochemical level toward progressive threat perception or misperception.
Dr. Neil Nathan notes that individuals do not necessarily need to feel safe in their world and bodies but need to feel safer to begin regaining homeostasis. Viral reactivation, including chronic herpes viruses, EBV, and CMV, is triggered by mitochondrial dysfunction. When prolyl hydroxylases are inhibited in an infected cell, this triggers reactivation of latent lytic viruses. Chronic viral outbreaks correlate with chronic prolyl hydroxylase inhibition and a bias toward mitochondrial dysfunction. Without the virus, the fault sensor still triggers anaerobic glycolysis and lactic acid metabolism, allowing the cell to survive despite inhibited mitochondrial function. Prolyl hydroxylases detect faults and, when inhibited, stop breakdown of hypoxia inducible factor 1 alpha, altering transcription factors to promote lactate dehydrogenase and pyruvate dehydrogenase kinase. Pyruvate is diverted toward lactate rather than acetyl-CoA and the citric acid cycle, enabling muscles and brain to produce lactate that is sent to the liver for Cori cycle processing and return of glucose. This keeps NAD redox balanced while glycolysis handles ATP production, magnesium, and phosphate uptake while mitochondria are offline.
Lactate dehydrogenase elevation biases glyoxylate metabolism toward oxalate instead of glycine. This feeds into the same glutathione synthesis and redox cooling system problems. Oxalate elevation in chronic conditions often stems more from endogenous production than diet. The analogy given is that if someone is already treading water and drowning, throwing a bucket of water on their head is not helpful. However, completely restricting dietary oxalates causes loss of Oxalobacter formigenes species, interrupting signaling to dump and metabolize oxalates through the gut. This progresses toward kidney stones because urinary excretion, enhanced by acidemia, is altered by the lack of these species, allowing dysbiosis to worsen. Dietary oxalates should not be completely eliminated.
Most people experience years of healthy life before disease develops, indicating the cellular programming initially performs well. Epigenetics represents long-term adaptations to maintain homeostasis rather than threats. Examples include athletic adaptations toward fitness or environmental toxin resilience. The host system is not attempting to harm itself and is always working to restore homeostasis and adapt to the best possible state under given conditions. The environment has become more toxic with microplastics and degraded food systems. The environment humans evolved in no longer matches current living conditions, with convenience measures disconnecting people from natural cycles that support health. A Finnish study replaced rubber playground flooring with dirt, resulting in children's immune systems blooming, demonstrating that dirt supports microbiome diversity. The microbiome functions as software updates and biomass that performs like the liver but produces potentially a thousand times more compounds. It is interchangeable, responding to host signaling and demand. Modern processed and cooked food, combined with distance from dirt, makes maintaining microbiome diversity more difficult. Pathogens exist in dirt but balance is maintained; exposure during hypothetical field surgery would involve better microbial balance than hospital superbugs.
Modern agricultural systems grow crops rapidly with fertilizers, depleting minerals from soil. Studies from the 1950s show mineral content in soil has dropped 50 to 60 percent. Micronutrient quality in vegetables, plants, and downstream animal products has declined. Aquatic plants have benefited from fertilizer runoff into seas. Reclaiming sea minerals and using them to cultivate and repair soil represents a potential direction forward.
Assessment involves microbiome testing across different body sites including the sinu biome, oral biome, and gut biome. Key patterns in chronic illness include overgrowth of fermenting species that produce acetaldehyde, including Candida, E. coli, most strep species, staph species, Klebsiella, and other fermenting species. These often work in clusters where one species produces alcohol and another produces acetaldehyde. Alcohol rarely enters systemic circulation in detectable amounts via ETG strips. When knocking out six of fourteen overgrown species, remaining species typically bloom to fill the gap, either due to real estate availability or ongoing host signaling. Butyrate-producing species, including Akkermansia, are often lost; these maintain mucin and barrier function. Acidemia from mitochondrial issues and lactic acid elevation can drop pH enough to kill pH-sensitive butyrate producers, allowing fermenting species to overgrow. Lactobacillus and Bifidobacterium are typically completely or almost completely lost. Simply supplementing these organisms fails if the terrain does not support colonization. Addressing keystone issues upstream is required before these beneficial species can reestablish.
Restoring butyrate-producing species becomes progressively harder when the system remains in lactic acidemia or acidosis. A shortcut exists through a pH-tolerant Clostridium species originally discovered in Japan and sold by Pendulum and other companies. This species produces butyrate even in acidic conditions, allowing butyrate production to be restored earlier while host metabolism is still being addressed. In the protocol, this becomes one of the early microbiome interventions, focusing on restoring Akkermansia and butyrate production as keystones before moving to the rest of the microbiome.
Once mucin and butyrate production are restored, barrier function improves, which reduces endotoxin and LPS exposure along with the ongoing systemic inflammatory response. This connects directly to SIRS dynamics.
The body functions more as a city for microbes rather than a single organism. Latest data indicates a microbiome exists in the brain. During pregnancy, the gut allows Lactobacillus species into the bloodstream, where they hitch a ride on red blood cells to translocate to the mammary glands and lactiferous ducts, eventually appearing in breast milk without immune intervention. This demonstrates symbiosis extending beyond the gut.
Beyond the gut, which contains the largest biomass, the nasopharynx represents another critical microbiome location. This area has received attention in studies related to abrasive therapy and within the Shoemaker protocol, which focuses heavily on MARCoNS and nasal microbiome dynamics.
The nerves in the microbiome of the mouth and nose are critical because they signal the nervous system to respond. When higher energy is needed, rapid mouth breathing during exercise sends signals indicating a need for more adrenaline and catabolic energy. Conversely, deep nasal breathing signals parasympathetic activation for rest, reset, and recovery.
Nasal dysbiosis, such as overgrowth of fermenting species seen in MARCoNS, creates inflammation that disrupts parasympathetic signaling even when nasal breathing appears normal. Restoring glycogen stores and parasympathetic balance from sympathetic bias requires restricted nasal breathing and healthy nervous system signaling from the nose. Untreated nasal dysbiosis and inflammation tend to keep individuals stuck in sympathetic bias.
Microbes reside in biofilms in different body locations and respond to host signaling. When the nervous system remains in sympathetic excess, this signaling can trigger opportunistic pathogens to proliferate. These fermenting species then create barrier dysfunction through proteolysis, breaking down barriers to access nutrients. This represents a cycle where host metabolism promotes growth of opportunistic pathogens.
Once barrier dysfunction occurs, invaders are inside the castle walls. Circulating biofilms result, with recent studies identifying species such as P. gingivalis, Streptococcus, and Staphylococcus in atherosclerotic plaques. Oral plaques show striking similarity to arterial plaques due to shared species. This leads to chronic immune activation, oxidative stress, immune dysregulation, and ongoing burden through inflammatory signaling that alters mineral transporters.
In chronic inflammatory states, the body intentionally shuts down mineral transporters in the gut.
MicroGenDX, a lab in Lubbock, Texas, represents the best current option for sinus microbiome testing. They use Illumina and other platforms and accept specimens from various microbiomes and tissues. Reports draw from a database of over 60,000 microorganisms, providing a richer picture than typical MARCoNS testing that only examines a handful of species. This allows assessment of both beneficial and problematic organisms rather than focusing solely on overgrowth of Staphylococcus or Candida.
Sympathetic dominance extends beyond mental and emotional stress to include physical factors. Sleep breathing disorders represent a major contributor. CPAP needs may stem from mitochondrial dysfunction, localized pathogens, or tissue prolapse that prevents proper muscle activation. Treating dysbiosis in affected tissue may reduce or eliminate the need for sleep aids like CPAP.
Occlusion, bite issues, and CCI (craniocervical instability) can also drive sympathetic dominance.
Clostridium butyricum from the Pendulum product helps with acetaldehyde. Addressing aldehydes requires a combination approach: fixing NAD redox so aldehyde dehydrogenase enzymes can function, addressing zinc and other mineral deficiencies that progressively impair aldehyde processing, and reducing production from maladaptive microbes like Candida and Streptococcus. Host metabolism resilience to aldehydes matters as much as microbial burden.
Downstream effects of acetaldehyde include the endogenous opioid cascade. Removing acetaldehyde too early, before correcting the underlying sympathetic overdrive and glycogen metabolism issues, risks driving further sympathetic excess. The protocol avoids touching aldehyde-related interventions until glycogen metabolism and parasympathetic signaling have been addressed.
Stage three of the protocol focuses on clearing biofilms to prevent future susceptibility to host signaling that allows opportunistic species to proliferate.
Z Biotics serves as one intervention. Thiamine binds to acetaldehyde and is used in the protocol. Individuals with functional thiamine deficiency may show high serum thiamine levels because the vitamin is bound to acetaldehyde and not bioavailable. Large doses of B1 can be used to work around this, though other approaches exist.
Dihydromyricetin promotes aldehyde dehydrogenase activity and is used as a hangover remedy, but it still depends on functional NAD redox. Mitochondrial function restoration must precede successful aldehyde dehydrogenase activity.
The protocol uses spiral diagrams to illustrate the specific order of interventions, where each remediation step progressively opens metabolism and benefits subsequent sections.
Throwing probiotics into an unsupportive system fails because organisms pass through without colonizing. The host environment must be welcoming. Barrier function and mucin must be restored, butyrate production increased, and then beneficial species introduced. Antimicrobials, diet, and probiotics work synergistically but follow a specific order. Feeding species without surface adhesion results in loss rather than retention.
The process involves identifying missing species, feeding them appropriately, and making space by removing less helpful species. Over sufficient time, the system corrects itself when foundations are present.
Lyme, Borrelia, Bartonella, Babesia, viruses, parasites, and fungal colonization from water-damaged buildings all participate in cycles. They both signal underlying problems and create new ones. Fixing mitochondrial metabolism breaks down HIF-1-alpha, which removes viral reactivation triggers. This frees the immune system to address other threats including Lyme, parasites, and tissue infiltration.
Fixing energy systems benefits immune response beyond muscle and brain function. Buildup of Bartonella, Babesia, and similar organisms reflects both immunocompromise and poor metabolism. Approximately 40% of the population may carry Bartonella and Babesia asymptomatically when mitochondrial metabolism functions properly. The speaker carries grade three Babesia and grade one Bartonella with no symptoms, detected via Walter Torello's microscopy and staining. These became symptomatic only after COVID disrupted glycogen storage.
Epstein-Barr reactivation occurred alongside the COVID infection. The key distinction lies between host metabolism and the pathogenic landscape.
LDL serves as a proxy for NAD redox inhibition. When ALDH2 is inhibited, HMG-CoA reductase becomes dysregulated. Elevated cholesterol can signal deeper systemic problems. Elevated serum B6 indicates problems with pyridoxal kinase activity and aldehyde dehydrogenase activity breaking down pyridoxal into pyridoxic acid. Elevated beta-carotene or retinol also proxy for inhibited aldehyde dehydrogenase or NAD redox.
All these markers intersect at the same metabolic point.
Environmental exposures in homes and workplaces contribute to fungal colonization in the sinuses, gut, and systemically, including organisms like aspergillus and other molds. Constant rhinitis or sinusitis often signals an ongoing environmental burden. Host resilience determines outcomes: individuals with functional glutathione metabolism, intact methylation, and adequate oxPPP access can tolerate higher exposure levels with minimal symptoms, while those already metabolically compromised experience significant deterioration from the same burden. Reducing environmental load improves overall trajectory.
Organic acids testing (OAT) from Mosaic, Therium Aristotle, Vibrant, Genova, and others provides valuable data despite varying marker density. Less comprehensive panels still cover key intersections, while richer panels like Therium Aristotle Plus offer greater resolution across glycolysis, glycogen synthesis, and glycocalyx pathways. Results should always be interpreted alongside the ionome and mineral status to identify cofactor dependencies.
When metabolites appear elevated or low, the reactions producing them are examined for required cofactors such as NAD and magnesium. Direct measures from Aristotle Plus or inferred values calculated from OAT patterns allow identification of specific deficiencies. This multi-layered approach reveals root causes rather than isolated outcomes. Once data is available, patterns at pathway intersections become visible.
Lactic acid to pyruvic acid ratio and oxalic acid elevations serve as proxies for prolohydroxylase inhibition and cytosolic NAD redox favoring lactate dehydrogenase. 2-hydroxybutyrate elevation relative to alpha-ketobutyrate indicates NAD redox status and inhibits BCAT1 and BCAT2, thereby suppressing branched-chain amino acid catabolism at the pathway entrance. TCA cycle status affects carnitine synthesis through hydroxylase reactions requiring vitamin C and iron, plus ALDH9A1 activity dependent on NAD. Impaired carnitine production reduces fatty acid transport into mitochondria, promoting cytosolic accumulation seen in non-alcoholic fatty liver disease.
Microbiome-derived alcohol and acetaldehyde replicate the metabolic effects of alcohol consumption, producing identical NAD redox impairment, TCA cycle disruption, and carnitine shuttle dysfunction.
OAT data reveals synthesis and degradation patterns for catecholamines and serotonin, along with kynurenine pathway activity. Dopamine synthesis requires magnesium and P5P at the AADC step; oxidative stress or low zinc can limit BH4 availability. BH4 synthesis depends on methylation and microbiome-derived QE (from wheat germ and dairy), which also supports QOC production. Bottlenecks appear as elevated phenylalanine or tyrosine. COMT activity shows through DOPAC to HVA ratios, while NADH and ALDH issues appear as low DOPAC with elevated L-DOPA or dopamine. Elevated kynurenine diverts tryptophan away from serotonin and melatonin production.
Metabolic pathway overlay tools allow visual identification of specific bottlenecks when OAT markers are combined with mineral data. This supports precise intervention decisions and represents a fundamentally different approach to evaluating and remediating chronic conditions.
Aerobic metabolism generates ATP more efficiently while minimizing lactic acid production. Anaerobic glycolysis activates when oxygen delivery, blood glucose, or glycogen stores prove insufficient relative to energy demand, or when TCA cycle flux is limited. Prolohydroxylase failure triggers the shift. In chronic illness, basal metabolism alone can drive lactic acid production; even minimal activity such as standing or walking 1,000 steps may suffice in severe cases. Prolonged time in this acidic state causes electrolyte and zinc excretion, accelerating progression. Pacing helps maintain patients outside lactic acid metabolism so repletion of resources can occur.
Post-exertional malaise (PEM) is addressed by avoiding lactic acid states to permit resource recovery. Figure 12 illustrates mitochondrial dysfunction at the center, connected to mineral losses, hyperoxaluria, renal excretion, chronic viral reactivation, barrier dysfunction, and hypermobile Ehlers-Danlos syndrome-type metabolism. The latter is viewed as secondary to mitochondrial impairment and mineral depletion. Resolution of the underlying metabolic issues has been observed to reverse connective tissue manifestations. Genetic arguments are challenged by cases where long COVID triggers new connective tissue problems accompanied by oxalate elevations, proline/hydroxyproline changes, and glycine alterations.
Therium Aristotle Plus already measures NAD, NADH, NADP, NADPH, and ATP directly, eliminating need for separate Mitome or NAD panels. Electron transport chain diagrams include feeder enzymes beyond the standard complexes: choline dehydrogenase, GPD1/2, ETF/ETF QO, proline dehydrogenase, and hydroxyproline dehydrogenase. These FAD-dependent inputs must balance NAD-derived input at complex one to maintain proton motive force and prevent reverse electron flow.
Mosaic Tox Detect and Vibrant Total Toxic Burden panels measure 2-hydroxyethyl mercapturic acid (HEMA) as an acetaldehyde indicator. Impaired glutathione metabolism and NAD redox limit detoxification capacity, allowing mycotoxins and heavy metals to accumulate intracellularly. Initial testing may show low excretion (tip-of-the-iceberg phenomenon) until methylation and glutathione function improve, at which point enhanced excretion appears. Patients may feel temporarily worse despite clinical improvement. Binders can reduce total load during this phase. Neil Nathan is credited for the tip-of-the-iceberg concept.
Environmental assessment of home and workplace is recommended when chronic rhinitis or sinusitis is present. ERMI testing and similar evaluations help identify ongoing sources. Remediation options include addressing moisture issues, considering relocation when remediation is impractical, and selective use of ozone with awareness of its limitations. Focus shifts to supporting detoxification pathways while reducing exposure.
ERMI testing can provide some indication of mold presence but has limitations. Healing does not require a perfect environment. Joshua Leisk healed from his own ME-CFS while remaining in the same moldy environment. Restoring the terrain, regaining nervous system control, and supporting detox systems can reverse the condition even without relocation. Removing environmental mycotoxin sources improves outcomes when possible.
Moving to a new environment such as a hotel or different house often results in fungal issues reappearing in bedrooms, windows, blinds, and bathrooms because the individual acts as the carrier. Mold is a normal component of ecosystems that breaks down unfit organisms. The goal is to improve fitness so the body is no longer susceptible to these insults. Visible mold should be removed. Since most mycotoxins are aerosolized gases, cleaning up sources reduces the burden.
Recommended labs include blood type, comprehensive blood chemistry, metabolic panel, iron, LDH, lactate, lipids, B6, and vitamin D. When evaluating LDH isoenzymes, the key is determining which cells are producing or metabolizing lactic acid. A typical pattern shows elevation in LD4 and LD5, indicating muscles are producing lactic acid while the liver recycles it back into glucose. This reflects an upregulated Cori cycle, creating an endurance-athlete metabolic state even in bedridden or housebound individuals. Other isoenzyme elevations may point to vascular issues or lung dysbiosis, asthma, or COPD.
Standard CMP panels report only total LDH, which can mask individual isoenzyme elevations. A total LDH of 160 or higher in a sedentary person may indicate hidden isoenzyme bumps, yet values within the broad reference range of 120-250 often appear normal to clinicians. Isoenzyme panels reveal when LD4 and LD5 are markedly elevated while the total remains unremarkable. Joshua Leisk recommends that New Zealand health regulators update policy to include LDH isoenzyme testing rather than total LDH alone.
Micronutrient deficiencies, particularly minerals and B vitamins, play a central role in chronic illness. The OligoScan (also called VitaScan) is used alongside other micronutrient tests such as Genova NutrEval, Vibrant America, and Cell Science Systems cellular micronutrient analysis. Patterns commonly reveal both toxicity (for example high aluminum) and specific deficiencies.
B vitamins must reach their active coenzyme forms. Riboflavin (B2) converts to FMN (riboflavin-5-phosphate) and then to FAD, which participates in the TCA cycle at succinate dehydrogenase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase, as well as in fatty acid oxidation. Deficiencies impair mitochondrial electron transport and other pathways. Chronic disease patients often require higher intakes of active forms because oxidative stress and mineral shortfalls hinder conversion of inactive vitamins into active forms. Flooding the system with active B vitamins can compensate while upstream issues are addressed.
Approximately 2,600–2,700 metalloenzymes require minerals for catalytic activity. Lactate dehydrogenase requires zinc. Prolyl hydroxylases use zinc as a stabilizer and iron or silicon as the primary mineral, along with oxygen and vitamin C. Glycolysis enzymes such as PFK-1 and PFK-2 require zinc. Glucokinase and hexokinase need magnesium, which is also critical for glycogen metabolism and ATP-dependent reactions. Magnesium deficiency impairs glycogen formation and all subsequent ATP-requiring steps. Some B6 and riboflavin reactions can utilize cobalt ions. These mineral shortfalls create cascading disruptions in metabolite production, pathway regulation, and overall homeostasis.
Hepcidin is the master regulator of iron and other minerals. It is upregulated by cytokines including TNF-alpha, IL-1 beta, IL-6, IL-10, and IL-22. Elevated hepcidin inhibits divalent metal transporter 1 (DMT1) and ferroportin. These transporters handle iron and manganese with highest affinity but also transport at least eleven other metals, including the heavy metals cadmium and lead. In the duodenum, hepcidin blocks dietary absorption of these minerals. In other tissues, cells continue sequestering metals from serum, pulling iron, manganese, and heavy metals into the brain, liver, spleen, and kidneys.
In chronic inflammatory states this leads to progressive depletion of essential minerals alongside accumulation of heavy metals when glutathione metabolism is impaired. The pattern is sometimes labeled “anemia of inflammation,” yet iron dysregulation serves as an early indicator that other minerals and metals are similarly affected. In hemochromatosis or beta-thalassemia patterns, elevated iron may appear with transferrin saturation above the normal 40 percent set point, often accompanied by higher oxalate levels, increased heavy metal burden, and greater oxidative stress. Impaired iron redox and mitochondrial dysfunction contribute to these accumulations. As mitochondrial metabolism, oxidative stress, and glutathione redox are corrected, iron excess and dysregulation frequently resolve without direct intervention.
Lactoferrin is already present in the colostrum component of the protocol. While useful, addressing upstream inflammatory signaling restores normal absorption and metabolism more effectively. Full spectrum humic and fulvic acids plus direct mitochondrial and glutathione support also help regulate mineral transport during recovery.
Hepcidin elevation functions as an intelligent acute-phase response that limits microbial access to iron and manganese. In acute infection this favors the host. When the infection becomes chronic, the same mechanism turns into a long-term liability by progressively depleting essential minerals while sequestering heavy metals.
Dietary choices influence chronic illness through inflammatory reactions and nutrient absorption barriers. Avoiding inflammatory foods can limit nutrient intake even when absorption is possible. Maintaining glycogen stores becomes progressively harder because impaired glutathione metabolism and pentose phosphate pathway activity inhibit UGPA, reducing conversion of glucose-1-phosphate to UDP-glucose for glycogen synthesis. This produces glucose intolerance and insulin resistance, leaving excess glucose available as fuel for microbial organisms in tissues.
Oxalates passing through the kidneys into the bladder create surface damage and inflammation, allowing biofilms to adhere. Glucose secreted into the urine then feeds these microbial colonies, establishing biofilm communities in the bladder, kidneys, and other tissues.
The model describes a form of metabolic syndrome resembling type 2 or type 3 diabetes. Glycogen maintenance remains necessary, but the system responds poorly to large glucose spikes. Smaller meals spaced throughout the day help maintain glycogen without triggering excessive glucose elevations.
Histamine metabolism becomes dysregulated for multiple reasons. The cell danger response affects this process, with the nervous system exerting significant influence on mast cell degranulation, particularly when extracellular ATP levels change. People react to food compounds not because the substances are inherently harmful, but due to barrier dysfunction, immune responses to substances crossing the barrier, and nervous system reactions to pH changes and other factors when calcium channels are dysregulated downstream of sympathetic overdrive.
The histamine response can dysregulate neurotransmitters, blood flow, and other physiological processes.
Dietary oxalates in the range of 50 to 100 milligrams are generally tolerable. Excessive oxalates inhibit the glycolysis pathway, disrupt thyroid hormone signaling, and alter branched-chain amino acid metabolism. Beyond forming calcium oxalate crystals and causing pain, oxalates function as signaling molecules that inhibit pyruvate kinase M2 while also inhibiting the enzyme responsible for producing lactic acid and 2-hydroxybutyric acid. This shifts metabolism away from glycolysis toward branched-chain amino acids.
These regulatory mechanisms function up to a point; when oxalates become excessive, they destabilize the system's ability to restore homeostasis, making the regulatory processes themselves problematic.
Foods feed both the human body and the microbiome. Removing foods due to reactions eliminates the microbial species needed to maintain balance. This creates a spiral toward oil, meat, keto, or carnivore diets to avoid gut responses, inflammation, and histamine reactions for symptomatic relief. However, this approach traps individuals in a cycle where they cannot reintroduce other foods because reactions persist to everything.
Keto diets can produce positive experimental outcomes, but restoring glycolysis remains critical not only for brain metabolism but also for immune regulation. Immune cells preferentially utilize glycolysis and glutaminolysis, making hepatic gluconeogenesis and dietary carbohydrate intake important for proper immune function.
Carnivore diets have the potential to reduce microbial diversity in the gut long-term. Studies show significant microbiome shifts within up to 12 weeks in keto or keto-carnivore environments. For severe dysbiosis and fermentation syndrome, a short-term intervention period on keto may help reduce fermenting species numbers, followed by reintroduction of carbohydrates once conditions stabilize to restore normal metabolism. Both the transition into and out of keto represent unpleasant shifts with multiple physiological adaptations.
Individuals with more severe conditions may produce ketones and remain in deep ketosis despite consuming mixed diets, due to severely impaired glycogen storage.
GLP-1 agonists act as a hack to increase sympathetic flux by mimicking adrenaline's role without the adrenaline itself. They affect CNPK pathways to drive greater flux through catabolic pathways and TCA cycle activity. This approach compensates for impaired sympathetic signaling, glycogen storage, and parasympathetic function.
Significant concerns exist around GLP-1 use, including gastroparesis, suicidal ideation, and other adverse effects documented in lawsuits and black box warnings. Cases of both gastroparesis and suicide have been observed in individuals pursuing this route. The approach pushes further into sympathetic pathways, moving away from long-term metabolic restoration goals.
Full doses of GLP-1 agonists are not recommended for any condition. Even at micro doses, discontinuation returns individuals to the same metabolic problems, including inability to produce collagen. GLP-1 use drives up gluconeogenesis, eroding muscle tissue to meet signaling requirements. While fat loss occurs, it results from compensatory sympathetic pathway activation rather than genuine metabolic improvement.
Environmental sources of endotoxins represent a drop in the ocean compared to the load from internal microbiomes and barrier function issues. Under normal circumstances, substantial LPS exists in the gut, produced by numerous species. LPS itself is not abnormal until it crosses the barrier and triggers inflammatory cascades. LPS causes significant damage in the brain and other tissues.
The focus should remain on maintaining barrier function rather than addressing LPS directly. Compounds like spermidine may help mitigate some effects, but the primary target is understanding why the barrier performs poorly.
In the Shoemaker approach to SIRS, endotoxins account for 28% of causation based on transcriptomics testing, though this considers only environmental exposure. Endogenous endotoxins produced internally also warrant consideration. Different LPS species exist, and not all are equivalent.
Genetic factors such as HLA variations in the context of SIRS are not viewed as significant drivers of disease. Genetics may color the experience within a compromised metabolic state but do not drive the condition. Low minerals, microbiome dysbiosis, nervous system dysregulation, poor parasympathetic signaling, and impaired energy storage make all other factors more relevant.
A 30% reduction in MTHFR metabolism due to genetics may predispose toward methylation, glutathione, and pentose phosphate pathway issues, but does not drive disease. Individuals with MTHFR and other mutations may require no special supplements or management when in a healthy metabolic state. These genetic factors become relevant only when metabolism is compromised, influencing symptom expression and susceptibility.
This concludes part one of the interview. Part two covers the immune system, structural issues, hypoxia, oxidative stress, inflammation, mitochondria, mast cell activation syndrome, and the Born Free protocol.
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