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Gut Health: Microbial Molecules – Lipopolysaccharides, Endotoxins and Endotoxemia

Updated: Nov 1, 2023

When assessing the health of the digestive tract great focus is placed on the role of the gut microbiome. The gut microbiome is an important mediator between the hosts internal and external environments, and plays a vital role in immune function, metabolism, detoxification, and brain function. Recent research suggests that the microbiomes of the gut, oral, sino-respiratory, genito-urinary tracts can interact and communicate with one another, further increasing the importance of considering these unique ecosystems in the role that they play in overall health.

During the early part of the 21st century the very mention of the words gut bacteria AND health were met with scoffs of quackery by the medical and scientific communities, however 2 decades later a PubMed search of gut microbiome generates over 41,000 papers.

Dysbiosis, is the term used to describe an imbalance of the microbial communities that adversely affect health and can present with an abundance of gram-negative and/or gram-positive bacteria, yeasts, fungi, viruses, protozoa or parasites.

Gram Negative Bacteria

According to the National Institute of Health, the World Health Organisation and Public Health England, Gram-negative bacteria are among the most significant public health problems in the world due to the high resistance to antibiotics. However Gram-Negative bacteria can sometimes be seen within a healthy microbiome.

Gram-negative bacteria refer to many diverse microbes of different shapes and sizes which have been able to adapt to a variety of environments. Although gram-negative bacteria do not always cause disease when present in the gut, if left unopposed or have the opportunity multiply they become pathogenic due to their ability to trigger inflammatory processes within the body.

Examples of gram-negative bacterial species seen in the gut

A common feature of all gram-negative bacteria is that they have an outer membrane containing structures called lipopolysaccharides (LPS), which are also referred to as endotoxins.

LPS are made up of a hydrophobic domain known as lipid A (or endotoxin), a non-repeating “core” oligosaccharide, and a distal polysaccharide (or O-antigen) and its purpose is to provide protection against antimicrobial assault and it is the actions of LPS that are thought to be a contributing factor in the development of antibiotic resistant infections. Additionally, bacteria can exchange genetic information with each other which further increases their resistance.

Membrane structure of Gram-Negative Bacteria taken from

Historically it was thought that the release of LPS only occurred when the bacteria died, however ongoing research has discovered that it is actively released as part of bacterial trafficking and communication. LPS are well recognised for driving acute inflammatory reactions, particularly in the context of sepsis. However, LPS can also trigger chronic inflammation. In this case, the source of LPS is not an external infection, but rather an increase in endogenous production, which is usually sustained by gut microbiota and LPS contained in food. The first site in which LPS can exert its inflammatory action is the gut, both the gut microbiota and gut-associated lymphoid tissue (GALT) are influenced by LPS that shift the immune systems towards an inflammatory pattern.

LPS activates TLR4 which produces a powerful immune response, by promoting NFκB, proinflammatory cytokines, iNOS, Cox-2, reactive oxygen species and B and T cell proliferation. Further pathways that are activated are P13K/AKT, MAPKs and mTOR which usually play a role in cell metabolism, growth, proliferation, and survival, however when all of these pathways become chronically activated they exacerbate autoimmune conditions, promote metabolic dysregulation and deplete the mitochondria, leading to increased pain and fatigue.

The levels of gram-negative bacteria and subsequent LPS from the gut can be a result of poor diet, dysbiosis, food allergy, impaired gastric function, small intestinal bacterial overgrowth, HPA axis and vagus nerve dysfunction. If intestinal hyperpermeability is present LPS/endotoxins can cross the gut wall, where they will end up in the bloodstream and this is referred to as endotoxemia.

Endotoxins and Endotoxemia are involved in several pathophysiological mechanisms

Functional Testing and Nutritional and Lifestyle Interventions

Gram negative bacteria should always be at the forefront of a practitioner’s mind when dealing with gut health in a clinical setting. Functional testing can provide some clues as to whether you need to be basing protocols around mitigating endotoxin production and subsequent endotoxemia.

Conditions that may present with high LPS and endotoxemia include:

  • Obesity

  • Metabolic Syndrome / Diabetes

  • Leptin or Insulin Resistance

  • Diets high in saturated fats, processed food, and refined carbohydrates

  • SIBO and dysbiosis

  • Leaky Gut

  • Excessive Stress

Some of my favourites tests include:

Gi EcoLogix by Invivo Health care £359.00

A very good and comprehensive report that provides a snapshot of the gut microbiome and gut function that includes intestinal inflammation and permeability markers as well as levels of LPS generating bacteria

Genova Organic Acids £225.00

Another comprehensive report via urine analysis to help to assess gut, neurotransmitter, mitochondrial function, vitamin and mineral status.

Some examples of Gram-Negative Bacteria detected by Gi EcoLogix

Some examples of the organic acids tested by Genova

Nutrition and lifestyle interventions

Phytochemicals, carotenoids, anthocyanins, and antioxidants have been found in many in vitro studies to neutralise LPS and this is one of the reasons that I always recommend a diet full of colour and diversity. Berries, grapes, and pomegranate contain high levels of phytochemicals and anthocyanins which have been shown to inhibit MAPK and NF-kB, help with the healing of the gut wall and counteract LPS-mediated diseases. Whereas carotenoids could be used to reduce the levels of inducible nitric oxide synthase and Cox-2 proteins.

Further research on antioxidants and LPS in the context of Covid-19 are summarised in this really good review

A diet high in saturated fats such as standard western diets and ketogenics diets can promote endotoxemia because LPS is able to use this particular type of fat to transport itself across the gut wall, further driving inflammation and other related conditions. Therefore consuming a low/moderate fat diet would be favourable while working on supporting the gut microbiome and supporting the healing of intestinal hyperpermeability. .

Lastly, because LPS in the bloodstream gets transported to the liver for detoxification, optimising liver function is important an consideration, as is supporting the gut microbiome by addressing oral health, optimising digestive secretions, preventing constipation, and targeting food around the promotion of beneficial flora.

Some supplements that I like to use are

  • BioClear EndoTox-LV by Invivo Healthcare, this is a beautiful herbal and nutrient blend to support the liver and LPS metabolism

  • Designs for health Digestzymes to support stomach acid production, promote healthy bile flow and support overall digestion of proteins fats and carbohydrates.

  • BioMe PreBio PHGG by Invivo which is a low FODMAP prebiotic fibre to promote healthy growth of beneficial bacteria

If you want more personalised support, please contact me for a free initial 30 minute consult to see how optimising your health through personalised nutritional and lifestyle interventions can benefit you.

Manabe, Y., Tomonaga, N., Maoka, T. and Sugawara, T., 2021. Multivariate analysis reveals that unsubstituted β-ring and c8-keto structures are important factors for anti-inflammatory activity of carotenoids. Nutrients, [online] 13(11), p.3699.

Gasparrini, M., Forbes-Hernandez, T.Y., Cianciosi, D., Quiles, J.L., Mezzetti, B., Xiao, J., Giampieri, F. and Battino, M., 2021. The efficacy of berries against lipopolysaccharide-induced inflammation: A review. Trends in Food Science & Technology, 117, pp.74–91.

Gasparrini, M., Forbes-Hernandez, T.Y., Cianciosi, D., Quiles, J.L., Mezzetti, B., Xiao, J., Giampieri, F. and Battino, M., 2021. The efficacy of berries against lipopolysaccharide-induced inflammation: A review. Trends in Food Science & Technology, 117, pp.74–91.

Khalil, A., Tazeddinova, D., Aljoumaa, K., Kazhmukhanbetkyzy, Z. A., Orazov, A., & Toshev, A. D. (2021). Carotenoids: Therapeutic Strategy in the Battle against Viral Emerging Diseases, COVID-19: An Overview. Preventive nutrition and food science, 26(3), 241–261.


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Rachel Jessey holds a Masters Degree in Personalised Nutrition and Diploma in Nutritional Therapy. She has undertaken extra training in function medicine and has a keen interest in the immune system and autoimmune conditions. As well as conducting ongoing research Rachel runs a busy eConsult clinic in the UK and has been in clinical practice for over 12 years.

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