Advanced Topic: Metabolic Endotoxemia

Metabolic Endotoxemia

endotoxemia Metabolic endotoxemia refers to a situation in which bowel flora species die and release something called lipopolysaccharide, or LPS, a component of their cell walls. LPS is released into the intestines, then cross the intestinal wall and enter the bloodstream. Because LPS is known to be toxic when it enters the bloodstream, it is labeled an “endotoxin” and, because it becomes blood-borne, it causes “endotoxemia.”


LPS is highly toxic. Injecting just 1-2 micrograms into the bloodstream would promptly cause fever, followed by death. Yet the total content of LPS in the human intestinal tract is at least thousands of times more than the lethal dose, but nearly all of it safely sequestered within the confines of the intestines.

So-called Gram-negative bacteria that comprise approximately 70% of all bowel flora are the species that contain LPS. This includes species such as E. coli, Campylobacter, Klebsiella, Enterobacter, Citrobacter, Shigella, and others that are also potentially pathogenic, i.e., disease- and infection-causing. Only a decade ago, it was thought that higher blood levels of LPS only occurred with sepsis (blood infections) and ulcerative colitis. But it has since been demonstrated that common conditions such as obesity, insulin resistance, type 2 diabetes, fatty liver, neurodegenerative conditions and others all share higher LPS blood levels. LPS levels are not as high as that occurring with sepsis, i.e., overwhelming blood borne bacterial infection that complicates, for instance, pyelonephritis (bacterial kidney infection) or pneumonia. The more common situation of metabolic endotoxemia is associated with LPS levels that are typically no more than 10% of levels associated with sepsis, but more modest increases of LPS in the bloodstream of around 1.5 to 2-times normal nonetheless hold potential for adding to or causing health problems.

It is not clear what degree of intestinal dysbiosis is required for LPS levels to pose a risk to health. But it is virtually certain that SIBO, small intestinal bacterial overgrowth, yields an overwhelming quantity of LPS or metabolic endotoxemia, as this 30-foot length infection provides plenty of opportunity for Gram negative Enterobacteriaceae to shed LPS. It is also becoming clear that SIBO is now at epidemic levels in the U.S.

This chronic, 24-hour-a-day, low level of endotoxemia has real consequences outside of the dysbiosis and SIBO that create it. Among the conditions that are associated with increased blood levels of LPS are:
  • Increased insulin resistance—There is a 35% reduction in insulin sensitivity, a process that contributes to weight gain and obesity, pre-diabetes and type 2 diabetes, and increased potential for heart disease, cancer, and dementia. Accordingly, people with type 2 diabetes have substantially higher blood levels of LPS, typically 200% higher than non-diabetic people.
  • Overweight and obesity—Increased levels of metabolic endotoxemia likely underlie the increase in numerous health conditions associated with excess weight.

  • Fatty liver–The portal vein that receives blood draining the intestines carries ten-fold higher levels of LPS than the systemic circulation, meaning the liver receives a large burden of this inflammatory mediator.

  • Amyotrophic lateral sclerosis (Lou Gehrig’s Disease) and Alzheimer’s dementia—with 200-300% higher LPS levels that than in controls (keeping in mind that “healthy controls” may not really be that healthy). LPS levels also correspond with severity of disease with levels increasing as disease progresses.

  • Reduction in Bifidobacteria species that play a major role in preserving the intestinal barrier

The list of potential health consequences of increased LPS levels/metabolic endotoxemia is growing rapidly. It is also increasingly looking like heightened levels of LPS is virtually synonymous with small intestinal bacterial overgrowth, SIBO. The increased LPS levels associated with the proliferation of Gram-negative Enterobacteriaceae of SIBO likely accounts for why this situation is associated with conditions outside of the intestines such as fibromyalgia and neurodegenerative conditions.

Killing off undesirable bacterial species during treatment for small intestinal bacterial overgrowth, SIBO, can worsen metabolic endotoxemia temporarily. The flood of LPS is a big part of the reason why “die-off” reactions occur with SIBO treatment, as dying bacteria shed their cell wall LPS.

Unfortunately, because metabolic endotoxemia was first observed in mice fed a high-fat diet, this has led many to interpret this to mean that a high-fat diet in humans also cultivates the same. This is an overly-simplistic interpretation, as prebiotics, various probiotics, and other factors can completely ‘turn off” the rise in blood LPS levels. The rise in LPS may also represent an acute effect that does not persist over time. People with insulin resistance, pre-diabetes, type 2 diabetes, and overweight/obesity have approximately 70-200% higher blood LPS levels, but also show much larger increases in LPS with dietary fat consumption, an effect that is minimal in people without these conditions. It is suspected that the increased LPS levels in these populations is due to changes in bowel flora composition, specifically reduced Bifidobacteria species and reduced Akkermansia.

Among bowel flora, species within the Lactobacillus, Bacteroides, Akkermansia, and Roseburia genera are among those that help reduce LPS levels, principally by strengthening the intestinal barrier and mucous lining. The most effective means of increasing the populations of these species is by obtaining plentiful prebiotic fibers in the diet.

Prebiotic fibers are therefore the heroes for reducing LPS blood levels, typically reducing levels by 20-50% or more. Such reductions are in large part due to favorable changes in bowel flora composition, specifically increased Bifidobacteria and Akkermansia and decreased Enterobacteriaceae.

Other strategies that have been shown to minimize blood levels of LPS include:
  • Curcumin—Despite virtually zero absorption, curcumin exerts several important effects in strengthening the intestinal barrier and intestinal mucous lining, thereby reducing entry of LPS into the bloodstream.

  • Omega-3 fatty acids—The EPA and DHA of fish oil increase intestinal alkaline phosphatase that disables intestinal LPS and also increases the population of Akkermansia that also contributes to reduced LPS levels.

  • Akkermansia muciniphila—Akkermansia, when present at 3.0-5.0% of the total population of intestinal microbes, exerts intestinal barrier reinforcing effects and thereby reduces LPS levels in the bloodstream. Akkermansia populations are increased with prebiotic fiber and polyphenol intake (e.g., berries, peppers).

  • Polyphenols—Polyphenols, compounds in brightly colored fruits and vegetables such as grapes, blueberries, cranberries, peppers, and red onions have been shown to increase Akkermansia populations and reduce LPS levels.

  • Preliminary evidence suggests that capsaicin, a component of red peppers, reduces LPS levels, an effect mediated by changes in the microbiome and increased production of the fatty acid, butyrate.

Testing for LPS blood levels is not available, as it is currently only used for clinical study purposes. (Cyrex Labs offers LPS antibody tests, which offers a somewhat different perspective in that antibody levels do not necessarily correspond to actual LPS levels.)

Of course, if SIBO is suspected or its presence confirmed, then this should be addressed before increasing prebiotic fiber intake, since prebiotic fibers can make you ill in the presence of SIBO.

In summary, to minimize the contribution of metabolic endotoxemia to weight and numerous facets of health:
  • Manage SIBO, as this is the situation most associated with increased LPS/metabolic endotoxemia

  • Include omega-3 fatty acids from fish oil, as we do in the Undoctored Wild, Naked, Unwashed program

  • Include plentiful quantities of brightly colored vegetables and fruits

  • Include curcumin, 500-1000 mg per day, when managing SIBO and SIFO or when any inflammatory process is active

Go to Forum discussion.


Let's talk for a moment about something called metabolic endotoxemia.

Screen Text: Lipopolysaccharide

All that means is that many of the bacteria that live in your gastrointestinal tract, upon dying, release something called lipopolysaccharide (or LPS), from their cell walls. That lipopolysaccharide has the capacity to cross the intestinal barrier, and get into your blood stream; first into the portal system, that goes to the liver, and then into the systemic circulation for the rest of the body.

Even just a teensy-weensy micro-gram quantity of lipopolysaccharide causes metabolic endotoxemia, can cause fever, and heightens the risk for so many diseases. It increases insulin resistance dramatically — just that little bit. It can cause being overweight and obese. People who are overweight and obese already have higher levels of lipopolysaccharides, and lipopolysaccharides make those situations even worse. It makes you even heavier. It makes you even more insulin resistant.

It increases the likelihood that you'll get fatty liver. Because the lipopolysaccharide enters the portal system, that goes from the intestine to the liver, the liver receives about 10-fold higher quantities of lipopolysaccharides. So the liver is the recipient of a lot of this inflammatory phenomenon.

Metabolic endotoxemia with high levels of lipopolysaccharides, are now being identified as causes, or at least major contributors, to neuro-degenerative diseases, like Alzheimer's dementia, Lou Gehrigs's Disease, Parkinsonism.

This situation, where we have a lot of lipopolysaccharide, that gets into the blood stream, causing metabolic endotoxemia, is a very, very important situation.

Well, it's not entirely clear, what changes in the microbiome are necessary, that lead to more lipopolysaccharide. We know that having more Akkermansia protects you from it. We know that certain supplements, like curcumin, protect you from it. We know that polyphenols — these are the brightly-colored compounds in foods, like plums, or green peppers or red peppers, oranges — those also protect you. They somehow nourish healthy bacteria.

SIBO — small intestinal bacterial overgrowth — the situation in which all 30 feet of your gastrointestinal tract is essentially infected, with the organisms that are rich in lipopolysaccharide. This is how SIBO leads to conditions outside the intestine, like fibromyalgia, and neuro-degenerative diseases, and cancers, and inflammation of the skin, like rosacea.

In other words, the burden of bacteria, the gram-negative so-called Enterobacteriaceae — those are the bacteria of SIBO. They've ascended, up 30 feet, and are concentrated, and they release their lipopolysaccharide. Lipopolysaccharide enters the blood stream, and exports inflammation to other parts of the body. This is how SIBO, via metabolic endotoxemia and increased lipopolysaccharide levels — that's how SIBO exports its hazardous effects.

So, very important to have some appreciation for what this thing is all about. Also, it drives home just how dangerous it is to have SIBO, and not address it. So that's one of the most important things we do in the Undoctored program nowadays. We look for SIBO, and we manage it . We try to eradicate it.

See the detailed conversations elsewhere, other videos, and our Undoctored Protocol for SIBO, as well as the Advanced Topic for SIFO (small intestinal fungal overgrowth) to get a better appreciation for all these issues.