How Endotoxemia is the most important driving force behind chronic illness
Endotoxemia is one of the most important risk factors involved in prolonged activation of the immune system. The term endotoxemia refers to a high concentration of endotoxins in your bloodstream. These toxins enter your blood from within your body. Not just from your gut, but from all barriers after they’ve become hyperpermeable, so also from your mouth, nose, skin or lungs. So endotoxemia is basically your enemy within.
When your gut lining has become compromised and you have dysbiosis in your gut (or mouth), you most likely have some level of endotoxemia. Read on to learn about metabolic endotoxemia, its causes, and potential treatments and management solutions.
What is Metabolic Endotoxemia
Endotoxemia is the presence of too much endotoxins in your blood. A very high level of endotoxemia can lead to (endotoxic) septic shock, while a lower concentration of endotoxins in the bloodstream is called metabolic endotoxemia.
- Endo – inside
- Tox – toxins
- Emia – blood
So endotoxemia is simply a medical term for “toxins in the blood coming from inside the body”.
And the word metabolic implies that endotoxemia can occur as a byproduct of metabolism. Your metabolism is the term for how your body takes food and turns it into energy and building blocks, while eliminating wastes produced as a byproduct of these processes.
Now you’re wondering what are endotoxins? In current terminology, the term endotoxin is often used synonymously with lipopolysaccharides (LPS), although there are several endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.
So by far the biggest endotoxins of concern are lipopolysaccharides (LPS). Le’t dive into that now.
What Are Lipopolysaccharides (LPS)?
LPS is a major component of the outer cell membrane of “gram-negative” bacteria. “Gram positive” bacteria do not incorporate LPS into their membranes. “Gram positive” and “gram negative” just refer to structural differences in bacterial membranes. When microbiologists view bacteria under a microscope, the outer membranes of gram-positive and gram-negative bacteria will “stain” differently when being plated for observation.
So LPS is located in the outer membrane of gram-negative bacteria. When the bacteria die, this LPS component is released.
It is important to note that gram negative bacteria are commensal bacteria in our digestive tract, up to a certain amount. This means that a certain level of LPS release in your gut is normal. An intact gut lining provides an effective mucosal barrier, so that LPS ends up in the blood only in small quantities.
The problem starts with an inflammatory diet and an unhealthy, leaky gut, where LPS can enter abnormally in the bloodstream, resulting in metabolic endotoxemia and activation of your immune system.
Metabolic endotoxemia is defined by an increased level of LPS in the bloodstream at 2-3 times higher than normal concentrations.
What bacteria contain LPS?
The largest family of gram-negative (LPS-containing) bacteria is Enterobacteriaceae. Enterobacteriaceae includes, along with many harmless symbionts, many of the more familiar pathogens, such as Salmonella, E.Coli, Klebsiella, and Shigella. Other disease-causing bacteria in this family include Enterobacter and Citrobacter. Most of these bacteria have a preference to use protein as their fuel. An overgrowth of these bacteria can cause a rotting-flora, and subsequently a high release of histamine.
We made a list of the most important LPS-containing bacteria:
| LPS-bacteria | Translocation | Notes |
| Citrobacter spp | Urinary tract (bladder) | |
| Clostridium difficile | Collitis, Diabetes | |
| Clostridium ssp | ||
| Enterobacter app | Urinary tract, kidneys, airways | |
| Escherichia Coli (E.Coli) | Urinary tract | |
| Klebsiella spp | Urinary tract | Correlated with MS (multiple sclerosis) |
| Prevotella spp | P.Copri correlated with RA (rheumatoid artritis) | |
| Proteus spp | ||
| Providencia spp | ||
| Pseudomonas spp | Joints | Correlated with RA (rheumatoid artritis) and fibromyalgia |
| Salmonella spp | ||
| Serratia spp | Gluten | |
| Shigellae spp | ||
| Sutterella spp | ||
| Yersiniae spp |
What causes Metabolic Endotoxemia?
There are many factors that contribute to endotoxemia. Here we will address the biggest three.
1. Hyperpermeable barriers (gut, mouth, nose, skin, lungs)
Endotoxins, such as LPS, can only get in your blood in high amounts through hyperpermeable barriers. Endotoxemia can be of intestinal origin, but it can also arise from your mouth, nose, skin or lungs. From all your important barriers. Let’s start with the gut.
Leaky Gut Syndrome
The gut normally has a functional barrier that prevents harmful substances from getting through. However, dietary changes and other factors, such as stress, can compromise this barrier and cause the gut lining to become hyperpermeable: more popularly known as “leaky gut.”
Leaky gut syndrome occurs when the junctions between cells of the small intestine are loose enough to allow food particles – and whatever else might be in the gut – to enter the bloodstream. Partially digested food particles leaking through can cause food sensitivities and allergies. LPS and other endotoxins leaking through can cause endotoxemia.
There are many things that can cause a hyperpermeable gut lining, read about them here: xxxxx , but the most important one is stress.
All stress factors (including toxic thoughts) open up the gut barrier, this is pure physiology. In a stressful situation we need glucose, sodium and water to support our fight-or-flight response, and that is taken from the intestines. In the case of short-term stress and healthy intestinal flora, this is not a problem, but the longer the barriers are open and the more pathogens are present in the intestinal flora, the greater the chance that these bacteria and their endotoxins enter the body through your barriers, creating endotoxemia.
Leaky Mouth Syndrome
In addition to your intestines, your mouth is a reservoir for bacterial colonization. In healthy periodontal conditions, the physiological oral flora consists mainly of gram-positive bacteria. In the case of gingivitis, the amount of gram-negative bacteria in the dental plaque increases significantly. People suffering from periodontitis have an increased risk of translocation of the LPS endotoxins into the blood via the oral mucosa. Endotoxemia caused by an unhealthy mouth!
And chronic smoking will compromise the nasopharyngeal space, opening up the barriers there, resulting in endotoxemia from your nasopharynx (the upper part of your throat behind your nose). This is one not well-known but very big reason why smoking is a bad idea!
2. Dysbiosis (gut, mouth, nose, skin, lungs or infiltration of fat tissue)
If you have a healthy balanced gut microbiome, the problem of a hyperpermeable gut lining wouldn’t be as big, but how many intestines do we see in our modern Western world that are still in pristine shape?
It appears that the prevalence of leaky gut is reaching epidemic proportions. Researchers estimate that 50% of the people in Western countries have some degree of metabolic endotoxemia.
There are centenarian societies who live in valleys in remote mountain ranges; they still have a healthy gut and they don’t have any problems with endotoxemia. Maybe that’s their secret. But for us, WEIRD people (Western, Educated, Industrialized, Rich and Democratic), gut dysbiosis is very common.
Gut dysbiosis means that the balance of bacteria in the gut has been disrupted, with an overgrowth of bad bacteria, such as LPS-producing bacteria. When there’s a high level of LPS in the gut, this too can leak through the gut lining and enter your bloodstream, resulting in metabolic endotoxemia.
3. High fat diet
Many studies suggest a link between high-fat or high-calorie diets and metabolic endotoxemia. This is because a high-fat diet can cause changes to bacterial diversity, as well as increase the leakiness and reduce the integrity of the gut barrier. A high-fat diet can cause insulin resistance as well.
How does this work? A high-fat diet has been shown to change the composition of the gut microbiota; specifically it increases the production of LPS. Plus, when the gut barrier becomes leaky, more LPS can enter the bloodstream. This shows again that gut dysbiosis is a key driver of metabolic endotoxemia.
Postprandial inflammation
The postprandial inflammation response (PPIR) is observed after consumption of a meal high in fat, and also after meals high in refined carbohydrates, processed sugar, HFCS (high-fructose corn syrup), linoleic acid (omega-6 fatty acids) or other high-calorie foods. High-calorie meals can induce endotoxemia, characterized by increased endotoxin activity in blood plasma, which triggers PPIR, resulting in inflammation.
One of the characteristics of endotoxemia is an increase in LPS within five hours after eating a meal. High-calorie meals tend to have a much greater impact than low-fat meals with fewer calories.
PPIR has even been observed after a modest meal containing cereals.
How Metabolic Endotoxemia affects your body
Once in the blood, LPS triggers a powerful immune response. LPS will interact with your fat cells and immune cells through inflammatory messengers called cytokines. When the LPS keeps entering your bloodstream, the production of cytokines and the immune response will persist, and it’s only a matter of time until the endotoxemia leads to low-grade inflammation (LGI). LGI is systemic chronic inflammation, that means in every tissue in the body.
This is the basis of almost all diseases.
Diet & Lifestyle (stress, toxins, etc.) => gut dysbiosis + leaky gut => metabolic endotoxemia => constant production of cytokines => prolonged low-grade activation of your immune system => LGI.
We wrote about this earlier; low-grade inflammation is the underlying factor in most chronic diseases, such as obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, autoimmunity, neurodegenerative diseases, and mood disorders such as depression and anxiety.
https://valeolife.co/how-a-silent-low-grade-inflammation-is-behind-your-chronic-health-problems/, So endotoxemia is correlated to all of these. But more specifically, metabolic endotoxemia seems to be the link between obesity and the risk for cardiovascular disease.
The mechanism: how LPS triggers your immune system
Endotoxins can bind to receptors in the body called toll-like receptors (TLR4). This triggers a series of immune responses, one of the most important being the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells).
NF-κB plays a key role in regulating the immune response to infection, it is the first responder to harmful cellular stimuli. NF-κB is the switch that turns on pro-inflammatory signals in the body, specifically the cytokines, IL-1, IL-6 and TNFɑ (tumour necrosis factor-alpha). These cytokines turn on inflammatory responses across the whole body, escalating inflammatory symptoms. In extreme cases this can result in the development of conditions like sepsis or septic shock. Incorrect regulation of NF-κB has been linked to inflammatory and autoimmune diseases and cancer.
TNFα is a cytokine that triggers the innate immune response. The innate immune system, as its name implies, is a primitive type of immunity that all living organisms have. In contrast to the adaptive immune system (which is found in humans and other higher-order species), there are no actual distinguishing features between cells belonging to the innate system or adaptive immune system – they simply look different. TNFα activates more TLR4 which results in more TNFα. As you can see, it becomes a vicious cycle leading to chronic inflammation.
In addition to the release of pro-inflammatory cytokines, NF-κB induces the production of reactive oxygen and nitrogen radicals. The resulting oxidative and/or nitrosative stress can result in mitochondrial dysfunction and disruption of energy metabolism.
How Detoxification can get Compromised
The central organ for the elimination of endotoxins (and all toxins) from the blood is your liver. Free endotoxin is bound in the blood by lipoproteins, which neutralizes the biological activity of the endotoxin. In the liver, endotoxin is taken up and metabolized by the Kupffer cells (sessile macrophages of the liver tissue) and then released to the hepatocytes. The next detoxification step is excretion via bile and intestines. So the liver and other detoxification pathways can handle a normal amount of endotoxins.
However, a continuous mild or moderate increase in the endotoxin level in the blood overloads the detoxification capacity of the liver. On top of that one could have liver damage, as in fatty liver disease, which reduces the detoxifying capacity even further. This is a big problem.
We’re living in a more and more toxic world – we are more exposed to toxins than ever before, with environmental pollutants, glyphosate (pesticides), EMF radiation, toxic cosmetics, sunscreen, plastics and household products and excess processed food in our diets – and its impact on the body is detrimental. This is why managing your toxic load is so important!
Leaky barriers open the doors for Bacterial Translocation
By now you’ve learned that endotoxemia is only possible in the presence of leaky barriers and unbalanced flora. Endotoxins enter the bloodstream through leaky barriers. It can get even worse as the pathogens (bad bacteria) themselves can enter your bloodstream also, and then migrate to remote places in your body.
Biopsies of fluid in intervertebral discs in rheumatoid arthritis has shows that they all have pathogenic bacteria there, which normally occur in the mouth! How do they get there? The bacteria look for an anaerobic place to infiltrate, because oxygen will kill them. So they infect red blood cells (which have no mitochondria and therefore have an anaerobic environment) and switch to a dormant state so that your immune system doesn’t detect them. In this way they can translocate (migrate) via the blood circulation to a remote place that is low in oxygen (anaerobic). This way they like to infiltrate your intervertebral discs, synovial joints, your non-dominant shoulder, even in organs and fat cells (few mitochondria, anaerobic).
At first the immune system is unaware of it because the pathogens are in dormant state, but there are situations that can cause the bacteria to start multiplying, such as sudden high availability of iron (their favorite fuel). Then your immune system comes in with a powerful response; this is an important pathway to developing auto-immune disease. Your immune system starts attacking the pathogens and your body’s own cells get caught in the crossfire.
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Vicious Cycles
When the LPS enters the bloodstream via the weakened intestinal junctions, inflammation occurs all over the body. This is the first step of entering you into a vicious cycle that is hugely detrimental to your health, it will further inflame any existing health issue, this includes leaky gut.
And because of the increased inflammation from leaky gut, your digestive system suffers more. Consequently, less nutrients are effectively absorbed, leading to nutrient deficiencies. Your immune system can get less equipped to protect you due to the lack of nutrients, it can become weakened.
On top of that, due to the exposure to more toxins in our modern world, your risk of leaky gut is higher than ever, as is your risk of endotoxemia, which further increases toxicity overload in your body. The vicious cycles keep piling up.
Metabolic endotoxemia as the primary driver of most chronic illnesses
Metabolic endotoxemia could very well be the primary driver of most chronic illnesses plaguing the western world, such as:
- Through inducing insulin-resistance and other mechanisms.
- The American Diabetes Association identified bacterial lipopolysaccharide (LPS) as the inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes.
- Irritable bowel syndrome
- Chronic pain and chronic fatigue
- Non-alcoholic fatty liver
- Cardiovascular disease, such as atherosclerosis and vascular inflammation
- Auto-immune disease, such as MS, Rheumatoid Artritis, etc. Through molecular mimicry.
- Associated with Chronic Fatigue Syndrome (CFS)
- Neurodegenerative disease, such as ALS, Alzheimer’s disease, Parkinson’s disease: Inflammation induced by LPS can induce cellular senescence, as has been shown for the lung epithelial cells and microglial cells (the latter leading to neurodegeneration).
Signs and symptoms you may be suffering from Metabolic Endotoxemia
Because chronic endotoxemia triggers LGI, many of the signs and symptoms are similar:
- Fatigue
- Chronic constipation
- Food sensitivities and histamine intolerance
- Receding, painful and bleeding gums (open mouth barrier)
- Skin disorders or a non-heald wound (open skin barrier)
- Nutrient deficiencies (B12, ferritin/iron, minerals and fat soluble vitamins)
- Mood disorders such as depression and anxiety
- Anorexia and other eating disorders
- Cognitive decline, brain fog and memory issues
- Insulin resistance
- Leptin resistance and weight gain
- Liver inflammation
- Inflammatory obesity
- Neuroinflammation
Blood markers:
- Occludin/Zonulin IgG, IgA and IgM antibodies: tests for paracellular permeability
- Actomyosin IgA: tests for transcellular permeability – the most destructive
- Lipopolysaccharides or LPS IgG, IgA and IgM antibodies
Other blood markers:
- High total cholesterol
- High triglycerides (a type of fat in the blood)
- Low HDL (good) cholesterol
- Elevated C-reactive protein and other inflammatory markers
- HOMA index (insulin resistance)
- Low testosterone
Markers in feces (stool testing):
- Presence and amount of LPS bacteria
- Beta-defensin (increased defenses because of high pathogen load)
- Alpha-1-antitrypsin and zonulin (markers for leaky gut)
These signs and symptoms highlight the importance of preventing and treating metabolic endotoxemia to prevent the development of chronic diseases.
Extreme endotoxemia is called sepsis and has typical strong symptoms, such as fever, chills, rapid heart rate, low blood pressure, confusion and fatigue.
Take Control! How we can Help
We hope we didn’t give you the impression that reversing endotoxemia is impossible in todays modern world. We’re all about educating, by giving you deep learnings and showing the mechanisms and pathways behind issues, and then showing you the way to thriving health.
You can take back control!
Try to see it as a positive thing that endotoxemia is primary caused by epigenetic factors, such as diet, stress, environment and lifestyle. This means there is significant opportunity for you to improve your health, by making different lifestyle choices and optimizing your environment.
There are many steps you can take now to reverse endotoxemia, and reduce your risk for all of the above diseases. Or if you’re struggling with chronic disease there are many steps you can take to restore health and balance to your body and systems.
Of course, strengthening the barriers in your mouth and gut and rebalancing the flora is a central strategy here. Read part II: how to heal Metabolic Endotoxemia to find out more.
There’s no need to go through this alone, at Valeo Life we can help you make the right diet and lifestyle changes to support gut and immune health. We will guide you through your journey.
Summary & Conclusion
Metabolic endotoxemia demonstrates the critical link between diet, gut health, and chronic disease. Recognizing its impact on conditions like obesity, diabetes, and neurodegenerative diseases underscores the need for proactive measures to prevent its development.
Metabolic endotoxemia highlights the link between the gut barrier, gut microbiota, and chronic health issues. Addressing diet, gut health, and inflammation is a crucial part of managing or preventing metabolic endotoxemia and its associated conditions.
References
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Kalyan M, Tousif AH, Sonali S, Vichitra C, Sunanda T, Praveenraj SS, Ray B, Gorantla VR, Rungratanawanich W, Mahalakshmi AM, et al. Role of Endogenous Lipopolysaccharides in Neurological Disorders. Cells. 2022; 11(24):4038. https://doi.org/10.3390/cells11244038
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