The Microbial Translocation of Lipopolysaccharide – A Key Mediator of Disease

“A decrease in the desirable gastrointestinal bacteria will lead to deterioration in gastrointestinal, neuroendocrine or immune relationships and ultimately disease” (Cryan, 2011). Contributing to our on-going focus on neurodegenerative disease, in this week’s blog we take a look at lipopolysaccharide (LPS) and the wide-reaching impacts it can have on human health, particularly in relation to the brain.

Lipopolysaccharide (LPS)

There are two types of bacteria that reside in the gut – gram-positive bacteria and gram-negative bacteria, which are differentiated by gram staining. Typically, gram-negative bacteria tend to be the more harmful type of bacteria and are associated with a range of health problems.

LPS provides structural function to the membrane of certain gram-negative bacteria residing in the gut and is formed through a combination of lipids and sugars. If exposed to the bloodstream, LPS (a potent endotoxin) acts as an inflammatory stimulus and immune-stimulatory molecule and can drive an inflammatory cascade.

Once recognised by the immune system, its associated toxicity is mediated through systemic monocyte/macrophage and endothelial cell activation and the release of inflammatory cytokines (Zhang et al., 2009). Inflammation is now known to be at the heart of most chronic diseases of our era.

Two factors that underpin the increase we are seeing in LPS toxicity are firstly; an increase in dysbiotic bacteria residing in the gut (dysbiosis refers to an overgrowth of undesirable bacteria) and secondly; intestinal permeability – dysbiotic bacteria have been shown to have detrimental effects on the tight junction proteins of the gastrointestinal tract and contribute to ‘leaky gut’. Both are intrinsically linked.

LPS in the intestinal lumen is not always problematic per se. Normally, in a healthy intestine, the barrier is impermeable to large molecules, such as LPS and is separated from the bloodstream due to tight junction control. It is when LPS infiltrates the intestinal barrier that it is able to wreak havoc on health. Leaky gut therefore acts a trigger and mediator for the translocation of LPS.

The Blood-Brain Barrier

Neuro-inflammation is defined as the brain’s activation of the innate immune system and it has been well established that it is actively involved in disorders such as Alzheimer’s and Parkinson’s disease. Peripherally produced cytokines stemming from a dysfunctional gut potentially impact on the brain through active transport across the blood-brain barrier or via the vagus nerve where activation of astrocytes and microglia can occur.

The barrier is a multiplex structure formed of endothelial cells and tight junctions, which keep apart the extracellular fluid of the CNS from the bloodstream in the brain. Under normal conditions, large molecules cannot pass through the blood-brain barrier.

LPS has however, been shown to threaten the integrity of the blood-brain barrier and may contribute to the pathogenesis of neurodegenerative disease. Many experimental models have demonstrated that peripherally administered LPS can infiltrate the blood-brain barrier and cause a strong immunological response in the hippocampus and cerebellum.

It has been found that many people with neurodegenerative disorders often present with elevated markers of LPS. A study by Forsyth et al (2011) showed that subjects with Parkinson’s disease exhibited considerably greater intestinal permeability than controls and this also significantly correlated with increased serum LPS levels.

LPS administration has been used extensively in research to induce an inflammatory response in human and animal models. Numerous diseases such as Alzheimer’s, Parkinson’s, Multiple Sclerosis, and Diabetes have been induced in laboratory settings using LPS.

Lee et al (2008) demonstrated that the administration of LPS in to the abdomen of mice generated inflammation in the brain, induced memory loss and raised beta-amyloid deposition, indicating LPS in neurodegenerative disease.

Diabetes has also been associated with elevated serum levels of LPS. For example, intravenous administration of LPS in animal models resulted in the development of insulin resistance. There has been much research on the pathophysiological connection between insulin resistance and Alzheimer’s disease.

LPS toxicity is not confined to neurodegenerative disease. Once in the bloodstream LPS can bind to various receptor sites. For example, binding to leptin receptor sites can increase the likelihood of leptin resistance, binding to insulin receptor sites can affect insulin sensitivity and so on. LPS can therefore affect any part of the body depending on the receptor site it binds to, potentially contributing to a myriad of disease processes.

How can we reduce our exposure to LPS?

 Heal the Gut – For a comprehensive 4 R protocol see Cytoplan Blog: Leaky Gut Syndrome – The Signs and Symptoms

 Nourish the Microbiome

Microbiota is increasingly being acknowledged as a symbiotic partner in health and also contributes to the integrity of the gut lining. Acknowledging that there is a strong relationship between gut microbes, their inflammatory cell wall components (LPS) and their ability to translocate and induce inflammation throughout the body (including the brain) indicates that intervention should begin with the gut. This can be achieved primarily by creating an environment that supports the growth of beneficial bacteria in the gut via diet.

Refined sugar, processed food and gluten-containing grains are pro-inflammatory and encourage pathogenic bacteria and dysbiosis, which are associated with leaky gut. Increasing the consumption of anti-inflammatory foods, fermented foods, and foods that support the growth of good bacterial colonies such as leeks, onions, artichoke, dandelion greens and other vegetables can be beneficial. Minimising exposure to toxins and pesticides by choosing organic unprocessed natural foods wherever possible.

Digestive Enzymes

Digestive enzymes are catalysts which break down food in to its basic components so that our bodies can absorb the nutrients it needs for health. They prevent undigested food from aggravating the lining of the gut which contributes to inflammation and permeability. Natural ways of increasing digestive enzymes are to consume raw vegetables and fruit (often lacking in the Western diet) and chewing food for longer as saliva contains enzymes that contribute to the digestive process.

Paleolithic Diet

 We have manipulated our environment from that known to our ancestors and a whole range of modern day disease has followed. By looking at the diet and lifestyles of our Palaeolithic ancestors and comparing them to the modern day it allows us to build a picture of why our current environment is so detrimental to health.

The Paleo diet is based on the foods our ancestors ate and is more in accordance with our genes. It incorporates foods such as healthy fats, grass-fed meat, fish, nuts/seeds, vegetable and fruits – all notably anti-inflammatory. The diet eliminates processed foods and sugars, legumes, dairy and grains which can be pro-inflammatory and can aggravate the lining of the gut, increasing permeability.

Due to the lower carbohydrate component of the diet and the removal of grains, pathogenic bacteria and yeasts are deprived the sugar that they thrive and proliferate on. Processed food is eliminated in the diet which minimises exposure to toxins and pesticides.

Support Glutathione Production and the Immune System

LPS administration in rats has been shown to cause a significant reduction in the master antioxidant – glutathione, with exposure shown to disrupt glutathione homeostasis. Glutathione is an important antioxidant in the brain and plays an important role in combating inflammation throughout the body.

In addition, stress, toxins, medications  and poor diet etc all further deplete glutathione. Most of the circulating toxins including LPS are primarily dealt with by the immune system and increase the need for the immune system. Supporting the body’s production of glutathione is crucial and can be done by increasing the consumption of sulphur-rich foods such as garlic, onions and cruciferous vegetables – these are often lacking in the Western diet.

Eating foods high in antioxidants such as vegetables and fruit or supplementing with alpha lipoic acid, vitamin C, E and Selenium can further support the immune system.

Conclusion

The radical shift in our diet and environment over such a rapid period of time is having detrimental effects on our health in ways we are only just beginning to understand. Repercussions of diet and lifestyle choices are presenting in the form of gastrointestinal abnormality and immune dysfunction and we have only just begun to really appreciate the potential for the complex contributions of the microbiome to the host, its integrated body systems and the development of disease.

Many in the medical profession still fail to acknowledge the impact diet and lifestyle can have on chronic disease, or the importance of taking preventative measures that incorporate nutrition and lifestyle. Importantly and encouragingly, increasing research is now creating potential therapeutic targets for many chronic diseases. The understanding and modification of the intestinal environment is an essential component of the future of medicine.


If you have any questions regarding the topics that have been raised, or any other health matters please do contact me (Amanda) by phone or email at any time.

amanda@cytoplan.co.uk, 01684 310099

Amanda Williams and the Cytoplan Editorial Team: Joseph Forsyth, Emma Williams, Simon Holdcroft and Clare Daley


References

1.      Cryan., 2011. The Microbiome gut-brain-axis: from bowel to behaviour. Neurogastroenterology Motility. 23(3):187-92

2.      Forsyth, C.B. et al., 2011. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PloS one, 6(12), p.e28032

3.      Lee, J. et al., 2008. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. Journal of Neuroinflammation, 5(1), p.37

4.      Zhang, R. et al., 2009. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). Journal of neuroimmunology, 206(1-2), pp.121–4


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