In Episode 8 I will introduce endotoxin or lipopolysaccharide.
What is it and why would you care? This is the first in a series on endotoxin the next few podcasts will be on endotoxins role in creating obesity and diabetes.
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Hey folks welcome to Biocast episode eight, endotoxin. In this episode I will be looking at an overview of endotoxin, what it is, and the elements it seems to have a large part in causing. Briefly, endotoxin is part of the structure of some bacteria and is implicated in obesity, diabetes, heart disease, liver disease, dementias, clotting disorders, hypothyroidism and blood pressure problems.
Okay so what is endotoxin?
Endotoxin is part of the structure of gram-negative bacteria. It is mostly interchangeable with the term lipopolysaccharide though endotoxin refers to a larger and unrefined structure of sugars and fats. In contrast to gram-positive bacteria, endotoxin producing gram-negative bacteria are surrounded by an inner and an outer membrane. Endotoxins are part of the outer membrane of gram-negative bacteria.
The structure of the refined lipopolysaccharide is in three main parts called the O-antigen, which is a variable sequence of glycans, a large number of sugars linked together, the core oligosaccharide which is mostly multiple chains of sugars with some non-carbohydrate components and thirdly lipid A. The o antigen is target for recognition for the host immune response while the lipid a is largely responsible for the toxic effect of endotoxin after degradation of the lipopolysaccharide structure.
The word endotoxin refers to the fact that the toxin is located inside the bacteria, it was originally theorised to exist and that the endotoxin would be released only once the bacteria dies. It has been since proven that small amount of endotoxin leak as part of the normal metabolism of the bacteria. Though the majority stays inside a cell until it is destroyed.
An exotoxin on the other hand is something thought to be secreted by bacteria before it is destroyed. Both endotoxin and exotoxins produce strong immune response.
The idea of the endotoxin was postulated in the late 1800s. Robert Koch and Richard Friedrich Pfeiffer worked on the theory in the 1890s that a heat-stable bacterial poison was responsible for the consequences of certain infectious diseases. They had been working on cholera and had vended that some bacteria could be disabled by keeping blood plasma whereas others were unaffected.
Endotoxin is the major component of the error membrane of gram-negative bacteria it serves to stabilise the structure and protect from certain chemical attacks.
LPS binds to receptors like TLR4 or CD14 which then initiate an inflammatory response through various cytokines, nitric oxide, and ecosanoids.
Human blood serum contained antigens to part of the structure of endotoxin namely lipooligosaccharides, the variability of these structures determine some of the differing immune response to them.
Endotoxin in the gastro-intestinal tract is an irritant and higher levels of LPS there can mean increased permeability, usually there are other factors involved in permeability and it it once the endotoxin gets out of the GI system and into circulation that they do most of the damage.
Humans seem to have a much lower threshold for damage from circulating endotoxin than other animals. Acute high levels of circulating endotoxin is known as the major factor in sceptic shock, also know as endotoxemia, this is the leading cause of death in intensive care units the western world(2). Stress, the inability of the organism to meet energetic demands leads to degradation of the GI barrier function and then increased plasma endotoxin. Severe sepsis has mortality rates of 30-50%.
There are many other factors creating lower level of endotoxin circulation leading to disease. As the effect of LPS on inflammation, mediated by signalling proteins called cytokines is not dependent on the viability of the bacteria symptoms can continue long after the bacteria have died. Endotoxin triggers release of serotonin from platelets in the blood and increases nitric oxide, having potentially major negative effects on mental health and cancer respectively.
Endotoxin causes all of the markers of metabolic syndrome, at least when the transport into the blood is facilitated by high fat, specifically high polyunsaturated fatty acid containing meals or diets. Alcohol is also very good at destroying the ability of the digestive system to keep endotoxin out of the blood stream. Studies in rodents show a high fat diet and gut bacteria are necessary for the development of diabetes and metabolic syndrome. Some studies in humans have shown an increase in markers after a high fat meal, though there aren’t any studies in germ free humans.
Endotoxin may be causal in energetic disorders like CFS and Fibromyalgia, though the case is not quite as clear as in T2D and obesity.
SIBO is a cause of increased endotoxin transport and that is associated strongly with hypothyroidism. Circulating endotoxin will lower thyroid hormones while increasing TSH and RT3. Endotoxin is strongly associated with coronary artery disease and other heart problems.
Endotoxin increases cholesterol, as this is one of the methods of detoxifying it, also in causing hypothyroidism it will increase cholesterol.
Endotoxin probably causes many liver problems including NAFLD and NASH non-alcoholic steatohepatitis.
Endotoxin is closely linked with dementias, alzheimers and parkinsons through a number of mechanisms, the increase in blood serotonin leads to an increase in the brain which inhibits oxidative metabolism in the brain. Likely through the increase in serotonin endotoxin causes many behavioural disorders in animals, the neuro-inflammation in rodents leading to what is termed LPS-induced sickness behaviour, that includes anorexia, weight loss and social withdrawal. LPS is also is also tied to depression, anhedonia, increased cerebral cytokine response or inflammation, addictive behaviours, aggression, social isolation and lack of exploratory behaviour.Endotoxin induced increases in IL-1 and core body temperature precedes the sickness response in rodents, leading to suppression of social interaction in rodents.
Aside from modulating thyroid hormones endotoxin has a large effect on estrogen, partly through lowering estrogen detox capacity of the liver by using resources it also increases the synthesis of estrogen. Progesterone reduces the inflammatory response to LPS through IL-6.
Endotoxin is causal in some asthma’s, though there’s also evidence that lack of early exposure might be part of an increased response to later exposures. Endotoxin is also involved in inflammatory pain, to the extent that microbiota are seen to be essential for it’s development.
That is an overview of endotoxin and some of the reasons why it might be interesting or relevant. Im the next few podcasts I’ll look at more specific aspects of it’s effects and how to mitigate them.