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Metabolic Endotoxemia and Heart Disease

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December 6, 2023

Written by Acacia Young , Director of Scientific Affairs at Microbiome Labs

Among non-communicable diseases, metabolic endotoxemia is the leading cause of morbidity and mortality worldwide. Metabolic endotoxemia is a condition that stems from intestinal dysbiosis and a breakdown of intestinal barrier function. This condition triggers an innate immune response that results in sub-clinical, persistent, and low-grade inflammation due to increased circulating endotoxins – toxins produced by gut bacteria. The primary endotoxin of concern is lipopolysaccharide (LPS), a major component of the outer cell membrane of gram-negative bacteria.

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. However, these gram-negative bacteria play an important role in the gut microbiome. The goal is not to eradicate them from the gut, but rather to keep LPS from reaching the intestinal mucosa.

Interestingly, meals that are high in saturated fats and dense in calories seem to impact the condition more so than low fat, 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.

In the development of heart disease, chronic inflammation from ME can lead to the expression of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), both of which enhance the adhesion of monocytes and T cells to the endothelium. Once these immune cells attach, they migrate to the innermost layer of the vessel (intima) due to the expression of a powerful chemokine called MCP-1.

Once in the intima, macrophages convert into foam cells. These foam cells lead to a gradual accumulation of lipids in the intima which then leads to classical endothelium dysfunction, apoptosis, and necrosis – the core of an atherosclerotic plaque. This lethal progression that starts with inflammation and leads to a monolayer of activated foam cells as well as activated T cells is called the “fatty streak”.

With a strong understanding of the mechanism by which ME can lead to plaque formation, the larger cohort studies on circulating endotoxin levels and cardiovascular risk really begin to make sense. A large Italian cohort study found that subjects with circulating endotoxin levels of 50pg/ml had a 3-fold greater risk of cardiovascular disease than those with concentrations below 50pg/ml of LPS. A further study revealed that increased circulating endotoxin levels among different ethnic groups correlated strongly with risk for the development of cardiovascular disease.

The fatty streak develops into an atherosclerotic plaque when the adhered T cells begin to secrete TGFβ, growth factors and fibrogenic mediators that lead to migration and proliferation of smooth muscle cells into the area.

The cells responsible for forming the plaque also initiate plaque rupture. The macrophages at the core continue to secrete inflammatory mediators like matrix metalloproteinases (MMPs), which are responsible for degrading the extracellular matrix and can lead to the rupture of the plaque. Further inflammation is mediated by Th1 cells that secrete IFNγ, which causes a decrease in collagen formation and weakens the matrix that holds the plaque together. Thus, chronic inflammation from circulating LPS causes the formation of the plaque and increases the risk for plaque rupture, leading to severe morbidity or mortality.

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 saturated fat intake can all have a drastic impact on ME. Other interventions that can reduce the risk of ME include increasing secretory IgA production, increasing mucin production, and modulating the gut microbiome with spore-based probiotics.

Secretory immunoglobulin A (sIgA) has the capability to bind and neutralize LPS in the lumen and mucosa itself, thereby reducing the risk of ME. Nutrients that increase the production of IgA are essential omega fatty acids, glutathione, glycine, glutamine, phosphatidylcholine, vitamin C, zinc and colostrum. Additionally, 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.

Probiotics hold great promise in modulating the microbiome and offering protection in conditions like 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.

Outline of Probiotic Spores and Metabolic Endotoxemia Study

Access 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 spores to reduce or prevent diet-induced ME. 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 an endotoxic response to the challenge meal and enrolled in the study. They consumed the placebo or treatment product for 30 days, with no other dietary interventions or lifestyle changes. After the 30 days, they reported back to the lab for their “post-treatment” response and were given the challenge meal again.

The data showed a clear shift to a protective microbiome after just 30 days of supplementation of the spores. 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.

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