Metabolic Endotoxemia

A Driving force Behind Chronic Illness

Written by Kiran Krishnan, Microbiologist, Clinical Researcher and CSO of Microbiome Labs, USA

Metabolic endotoxemia is a condition that is estimated to affect approximately 33% of the western population. The condition is characterized by increased serum endotoxin (typically lipopolysaccharide) concentration during the first five hours of the post-prandial period following consumption of a meal. Meals that are high in fat and dense in calories seem to impact the condition more so than low fat and low-calorie meals. This increase in serum endotoxin concentration is followed by systemic inflammation that is marked by measurable increases in interleukin-6, interleukin-1-alpha, interferon-gamma, triglycerides and post-prandial insulin. Chronic metabolic endotoxemia and the associated inflammation has been shown to have significant correlation to a variety of chronic diseases. To date, studies support a strong correlation between metabolic endotoxemia (ME) and the risk or onset of conditions such as cardiovascular disease, diabetes, obesity, hypogonadism, autoimmunity, and even mood disorders such as anxiety and depression.

Causes and Pathophysiology of Metabolic Endotoxemia

ME is essentially an innate immune response that results in sub-clinical, persistent, and low-grade inflammation because of increased circulating endotoxins. The primary endotoxin of concern is lipopolysaccharide (LPS); LPS is a major component of the outer cell membrane of gram-negative bacteria. LPS contains 3 major components: a hydrophobic lipid section (lipid A), a hydrophilic core polysaccharide chain, and a repeating hydrophilic side chain called the O-antigen. The Lipid A portion is responsible for the toxicity of LPS, and the O-antigen is specific to certain bacterial serotypes. LPS endotoxemia was originally studied as high-dose endotoxemia in cases of sepsis and septic shock which has allowed for the accumulation of a sizable body of information on the immune signaling pathways associated with LPS. It is important to note that a majority of the microbes in the digestive tract are gram negative bacteria, including clostridium sp., enterococcus sp., escherichia sp., and bacteroides sp. Trillions of commensal bacteria in the gastrointestinal tract contain LPS, and they are the primary source of this toxin in chronic, low-dose endotoxemia and low-grade inflammation. Low- dose endotoxemia may be a more significant version of ME due to a suppressive mechanism.

We now understand that circulating LPS can trigger a potent inflammatory cascade via the innate immune system and TLR4 activation. Innate immune activation and subsequent inflammation can occur anywhere in the body – even at sites very distal to the intestines, such as the blood brain barrier. We also know that chronic, low-dose endotoxins can suppress the cellular anti-inflammatory protective mechanisms and thus lead to more damaging consequences compared to high-dose LPS endotoxemia. These pathological consequences are a result of LPS from the intestinal tract entering the circulatory system. This means that the LPS had to pass through the mucosa and the intestinal barrier (intestinal epithelium cells) to enter the basolateral space, where it gains access to our circulatory system. The logical question here is what causes LPS to “leak” from the intestinal lumen into the circulatory system? With high-dose ME, the cause is typically a systemic bacterial infection.

However, there are 6 lifestyle choices that have been linked to low-dose, chronic ME, including:

  • Chronic alcohol consumption
  • Diet induced low microbial diversity in the microbiome
  • Chronic smoking
  • Obesity and high fat diet
  • Periodontal disease
  • Aging

Disease Consequences of Low-Dose, Chronic Endotoxemia

Numerous conditions are known to be associated with metabolic endotoxemia – some are well-studied, while others are just now being elucidated. The three most well-studied conditions associated with ME are atherosclerosis, diabetes, and obesity. There are several other conditions associated with elevated serum LPS (ME) that have good scientific support. These conditions are listed in Table 1 below.

Metabolic endotoxemia could very well be the primary driver of most chronic illnesses plaguing the western world. The causes of ME do not seem to be genetic or congenital, but rather due to lifestyle choices. The promise here is that there is significant opportunity to change health outcomes for millions of people, by making different lifestyle choices. A 2015 published review paper in Frontiers of Immunology found:

“In combination with modern life-style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a low-grade inflammatory state. We support this hypothesis with numerous studies finding associations with non-communicable diseases and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of low-grade inflammationand its related diseases.”

Furthermore, they concluded:

“Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation.”

This paper perfectly summarizes the impact of metabolic endotoxemia on our communities and the health of the general public. It is becoming increasingly clear that ME must be addressed in order to attain better prognosis of most chronic illnesses.

(Reference: De Punder K, Pruimboom L. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. Front Immunol. 2015;15(6):223.)

Solutions for Metabolic Endotoxemia

There are some basic lifestyle choices that will help reduce the risk and incidence of ME. Minimizing alcohol consumption, cessation of smoking, expanding the diversity of dietary macronutrients, and reducing fat intake can all have a significant impact on ME.

In addition to the above lifestyle modifications, there are some promising interventional targets that could help with decreasing ME, including:

1)  Increasing Secretory IgA – Secretory immunoglobulin A (sIgA) is the first line of defense against free LPS liberated in the lumen of the intestines. This liberated LPS will eventually make its way through the mucosa and the paracellular pathways in the intestinal epithelium, thereby causing ME. sIgA has the capability to bind and neutralize LPS in the lumen and mucosa itself. Many of the conditions associated with ME are also associated with low production of sIgA. Thus, increasing sIgA production could have a meaningful impact on ME. Nutrients that have been shown to have a positive impact on the production and secretion of IgA are essential omega fatty acids, glutathione, glycine, glutamine, phosphatidylcholine, vitamin C, zinc andcolostrum.

2)  Increasing Mucin Production – The mucosa is a key barrier to the entry of luminal LPS into the basolateral layer. When the mucosa suffers from inadequate production of mucin and inadequate viscosity, it fails to perform its barrier function and thus allows for the migration of LPS. Increasing mucin production can help restrict the movement of LPS towards the intestinal epithelial. Nutrients that have been shown to support increased mucin production are L-threonine, L-serine, L-proline, and L-cysteine.

3)  Modulating the Microbiome – Probiotics hold great promise to modulating the microbiome and offer protection in conditions like ME. It is clear that dysbiosis drives ME, and as a result, a healthy microbiome has the capability to protect the body from ME. The major issue with most probiotics is that they do not survive gastric passage to enter the small or large intestines intact and viable. There are, however, probiotic spores that have the capability to survive the harsh gastric passage and enter the intestines completely viable. To date, bacterial spores are the only strains that have been shown to treat metabolic endotoxemia, as described below in a study carried out to assess the impact of bacterial spores on metabolic endotoxemia.

Spores and Metabolic Exdotoxemia StudyAccess the full study here.

Probiotic spores in the product MegaSporeBiotic® were the subject of a university, double-blind, and placebo- controlled trial to evaluate the ability of the product to reduce or prevent metabolic endotoxemia induced by dietary challenge. In addition to assessing changes in dietary endotoxemia, the researchers also measured how this probiotic altered transient changes in cardiovascular disease (CVD) risk factors, other novel disease risk biomarkers, and the immune system itself, following a high-fat challenge meal.

Healthy volunteers were screened for the metabolic endotoxemia response to the challenge meal. If they showed the response, they were enrolled into the study and randomized into either the placebo group or treatment group.

They then consumed the placebo or treatment product for 30 days, with no other interventions or dietary/lifestyle changes. After the 30 days, they reported back to the lab for their “post-treatment” response and were given the challenge meal again. All the same blood work was run to access their levels of endotoxemia.

The data showed a clear shift to a protective microbiome with just 30 days of supplementation of the spores. The post-test challenge in the treatment group showed a drastic reduction in endotoxemia, whereas in the placebo group, there was either no change, or the condition had progressively worsened. These probiotic spores are likely the most promising therapy for metabolic endotoxemia, as no other probiotics or compounds have demonstrated this effect.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. Access the full study here.