How To Inhibit Lipopolysaccharides (LPS), Lipoglycans, and Endotoxins

How Endotoxins Cause Chronic Health Conditions


Recent data suggests that chronically low levels of circulating LPS may be associated with the development of metabolic diseases such as insulin resistance, type 2 diabetes, atherosclerosis and cardiovascular disease. R

In this post, we will discuss how LPS affects the body and how to reverse endotoxemia. 


  1. Basics
  2. Main Causes Of High LPS Levels
  3. How LPS Affects The Body
  4. Protocol To Prevent And Reduce LPS Invasion
  5. Lipopolysaccharide Inhibitors
  6. Mechanism Of Action
  7. Genetics
  8. More Research


Basically, lipopolysaccharides (LPS) are little pieces of gram-negative bacteria cell wall that activate the immune system (tells the body that a bacteria infection is happening) and act in the body as endotoxins. R R

Some common gram-negative bacteria: (not exclusive list)

  • Brucella R
  • Chlamydia R
  • H. Pylori R R
  • M. tuberculosis R
  • P. gingivalis R
  • Salmonella R

Some people like to call LPS “little pieces of sh*t”.

LPS is so good at inducing inflammation of the immune system, it is the standard way to stimulate the immune system in bacterial infection-based experiments. R R R

LPS is normally benign, but when it gets into the blood it can cause harm (LPS get in through tight junctions in the body, then activates the immune system).

Some ways they get through tight junctions are by:

  • Drinking and Eating
  • Inhalation (ie smoking, dust, exhaust) R R
  • Injection (some vaccines) R
  • Skin Contact (ie direct contact, cuts, burns, or wounds)

Main Causes Of High LPS Levels

High LPS levels can happen from or signify:

  • Alcohol Intake R
  • Dysbiosis R R
  • High Fat Diet or High Carb Diet R
  • Immune cells are being activated (most likely T-cell activation) R
  • Infection R R
  • Leaky Gut R
  • Lectins R
  • Overeating R
  • Social Isolation R R
  • Smoking R
  • Stress R

Looking at alkaline phosphatase (ALP) levels may be an indicator of LPS levels. R

How LPS Affects The Body

1. Causes IBD, IBS, SIBO, And Dysbiosis


LPS in the intestinal tract promotes inflammation when the gut is compromised (for example low sIgA levels). R

For example, high LPS levels are commonly seen in patients with irritable bowel disorders (IBD), which further increases inflammation. R R R

This is because LPS can work (with or without lectins) to open the intestinal barrier and contribute to leaky gutR R

Once LPS gets past the intestinal barrier (or any barrier, ie the skin/lungs), it can get into the blood and cause metabolic endotoxemia. R 

LPS can be a marker for dysbiosis (imbalance between good and bad bacteria) and/or a microbial infection. R

High LPS levels also may mean high levels of biofilms. R

Those with high LPS levels usually have high TH1 and TH17 markers as well. R R R

These high levels of TH1 and TH17 work on reducing T-reg levels (t-regs are important for bowel/oral tolerance, and help with food intolerance and inflammation). R R

LPS also causes the vagus nerve to decrease its tone (when chronically exposed). R R R

2. May Cause Autoimmunity

LPS is a marker of T-cell activation. R

Chronically activated T-cells (via infection such as chronic LPS) can cause the immune system to attack itself, as seen in autoimmunity. R

3. Induces Sickness Behavior And Fatigue

LPS endotoxemia is one of the main causes for sickness behavior. R R R R

Some of the symptoms from LPS includes fever (high enough LPS levels create fever response), inadequate organ perfusion, multi-organ failure, and death observed in septic shock. R R R

LPS levels contribute to fatigue levels.

For example, LPS levels are high in those with chronic fatigue syndrome (CFS). R R

4. Worsens Allergies

LPS may enhance stimulation of IgE-mediated allergic responses. R

LPS can activate mast cells. R R

5. Increases Mortality

Higher levels of LPS endotoxins may increase mortality especially in critically ill patients. R R

6. Contributes To Arthritis 



LPS activates the immune system thus creating an inflammatory response that damages joints. R R

7. Causes Gum Inflammation

Dybiosis in the mouth can cause LPS to cause inflammation. R

For example, periodontitis from Porphyromonas gingivalis causes inflammation in the mouth. R

8. Inflames The Lungs

Inhalation, aerosols or intranasal administration of LPS can cause increased airway inflammation. R R R 

LPS causes the permeability of the pulmonary endothelial barrier. R

LPS in the lungs can exacerbate chronic obstructive pulmonary disease (COPD). R

Mice that inhaled LPS has shown to lead to emphysema-like changes which persisted for up to 4 weeks. R R 

9. Induces Diabetes And Insulin Resistance

LPS induces insulin resistance. R R R

For example, LPS can increase inflammation in diabetes and significantly increase the secretion of insulin. R R R

It is common in obese non-diabetic and type 2 diabetic patients to have significantly elevated plasma LPS levels. R

For example, higher LPS concentrations are found in diabetic patients than in nondiabetic individuals. R

This is because LPS impairs clearance of insulin, which amplified insulin receptor signaling. R

LPS causes stress to the endoplasmic reticulum in pancreatic cells and can cause them to die. R

10. Plays A Role In Polycystic Ovary Syndrome (PCOS)

LPS may also play a role in polycystic ovarian syndrome (PCOS). R

For example, serum LBP is associated with insulin resistance in women with PCOS. R

11. Worsens Atherosclerosis And The Vascular System


A high fat diet alone (like a standard western american diet) is not enough to cause cardiac problems. R

For example, mice born with sterile microbiomes that are fed a high fat diet do not get heart disease. R

This may suggest the microbiome and possibly LPS causes many of the problems seen in the vascular system. R R

Circulating LPS in endotoxaemia is also called systemic inflammatory response syndrome (SIRS), which is characterized by excessive production of pro-inflammatory cytokines and potentially life-threatening impairments of organ and vascular function. R

LPS exposure increases procoagulant tissue factor expression on monocytes, contributing to coronary artery disease. R

Chronic inflammation from LPS may contribute to heart attack. R

This is because LPS endotoxemia causes the heart to not contract and reduces left ventricular pressure. R

It may damage the arteries and cause acidosis. R

12. Impairs Kidney And Adrenal Function

LPS has been shown to cause acute kidney injury (AKI). R R

If LPS is high enough in number and causes septic shock, it may result in adrenal insufficiency, as damage can happen to the kidneys and adrenals. R

13. Inflames The Liver

LPS cause inflammation of the liver and is closely associated with metabolic syndrome. R R

LPS may contribute to the pathology of Non-Alcoholic Fatty Liver Disease (NAFLD). R

LPS may cause liver failure. R

Elevated LPS plasma levels increase the risk of progression to chronic liver disease in hepatitis C-infected. R

This is because LPS binds to Kupfer cells, up-regulating the expression of proinflammatory and profibrogenic cytokines such as tumor necrosis factor alpha (TNFα), interleukin 1(IL-1), IL-6 and IL-12. R

LPS may also cause leakage of the blood-biliary barrier. R

14. Contributes To Weight Gain

LPS contributes to weight gain. R

For example, LPS levels are found to be higher in obese patients. R

Low grade inflammation from LPS-induced gut permeability is commonly seen in obesity. R

LPS can cause increased inflammation fat cells. R

LPS also modulates appetite (via leptin and AgRP) and may contribute to leptin resistance. R R

15. May Play A Role In Eczema

LPS can cause inflammation in skin cells, thus contributing to atopic dermatitis. R R

Those with acne may have high levels of LPS from E. Coli. R

16. May Cause Psoriasis

LPS can increase levels of hypoxia-inducible factor-1α (HIF-1α), which participates in angiogenesis and inflammation in psoriasis. R

17. Impairs Sleep



LPS levels are correlated with higher levels of daytime sleepiness. R

One reason for this may be by its ability to lower REM sleep. R

18. Causes Bone Resorption

LPS can cause bone resorption. R R R

19. Causes Anxiety 

LPS has shown to induce anxiety in animal models. R R R

LPS can also increase cortisol levels. R

20. Causes Depression

LPS has shown to induce anhedonia and depression in animal models. R R R

LPS can cause depression by destruction of tryptophan in the kynurnine pathway. R

LPS can also cause depression by its ability to lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex. R

Most antidepressant drugs have some anti-inflammatory effect against LPS. R

21. Induces Social Impairment And May Contribute To Autism

High LPS has shown to cause difficulty for patients to identify emotional states of others. R

LPS also causes social disconnection (in addition to depressed mood). R

The lowered ability in social behavior from LPS may contribute to Autism Spectrum Disorders (ASD). R

LPS can also reduce verbal fluency. R

22. Worsens Vision

LPS can cause inflammation in the eyes. R

Increasing LPS tolerance (seen below) may help with eye inflammation. R

23. Causes Neuroinflammation

LPS can into the brain and cause a leaky blood-brain barrier. R

LPS activation of the immune system contributes to brain infections and neurodegenerative diseases. R

LPS by activating the immune system in the brain can cause neuroinflammation. R

After LPS stimulation, microglia (brain cells) turn into a proinflammatory M1 state. R R

LPS also inhibits the activity of GABA and GLT-1/EAAT2 in the central nervous system (CNS), thus causing problems with glutamate-induced excitotoxicity. R

24. Induces Brain Fog

LPS causes brain fog in a few ways:

  • Glucose/Insulin dysregulation R
  • Neuroinflammation R
  • Reduced Cognition R R

LPS may inhibit the ability to form long term memories. R

25. Worsens Multiple Sclerosis

Activation of the immune system by LPS may contribute to demyleination as seen in Multiple Sclerosis (MS). R

For example, in animal models administering LPS can cause similar damage to the brain as seen in MS patients. R R

26. Plays A Role In Stroke

LPS makes brain injuries worse. R

LPS can induce blood clotting (causing hypercoagulation), leading to diseases associated with high coagulation factors (ie stroke). R

Hypoxia makes LPS inflammation in the brain worse. R

27. Worsens Alzheimer’s Disease



LPS causes neurodegeneration and may contribute to Alzheimer’s Disease (AD). R R

LPS are found in higher levels in AD patients. R

In models of AD, LPS can induce memory impairment. R

LPS can significantly induce tau hyperphosphorylation and beta-amyloid formation. R R

28. May Cause Parkinson’s Disease

LPS is toxic to dopamine in the brain and causes dopaminergic neurodegeneration. R R

Patients with Parkinson’s Disease (PD) have shown to have higher levels of LPS. R

In multiple animal studies, LPS has shown to cause dopaminergic dysfunction in PD. R

29. Plays A Role In ALS

LPS can stimulate microglia to be in a M1 proinflammatory state, which is common in ALS patients. R

30. Affects HIV

LPS is a marker of microbe infection, responsible for chronic immune activation in HIV-infected patients. R 

31. Impairs Reproductive Function

LPS can damage mitochondria in the testicles and impair the production of sperm. R R

LPS exposure may change the development of the ovaries and cause late-onset puberty. R

For example, LPS exposure during development significantly delays the day of vaginal opening (VO) in female rats. R R

By affecting body temperature, LPS can cause premature birth. R

LPS may lower levels of gonadotrophin secretion such as luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) and delay ovulation. R R

LPS may also lower levels of progesterone. R

32. Reduces Mitochondria And Antioxidant Status

LPS has shown to cause dysfunction of mitochondria in sperm cells and skeletal muscle cells. R R

Chronic LPS cause depletion of glutathione. R

33. Makes Pain Worse

LPS can reduce pain thresholds, making sensations more painful. R R

Are There Any Benefits To LPS?



Yes there are possible benefits, especially in cancer.

For instance LPS can activate LITAF, which increases tumor suppressor genes, such as P53. R

Although, LPS has shown to contribute to colon cancers. R


Tolerance to LPS and cross-tolerance to other bacterial components are beneficial for us as they prevent inflammation from immune reaction and limit the tissue damage during infection. R

Protocol To Prevent And Reduce LPS Invasion


Reduce Stress

Stress opens the intestinal gut barrier and can induce a leaky gut. R

Non-Alcoholic Fatty Liver Disease 

LPS in circulation of the blood is directed towards the liver for excretion. R

Having Non-Alcoholic Fatty Liver Disease (NAFLD) impairs the ability of the liver to clear systemic LPS. R R

You can read my post on reducing NAFLD here.

Diet = Low In Inflammatory Lectins

Lectins, which are in all foods, activate the immune system by binding to LPS and targeting TLR4. R

Follow this diet for low lectins.

Avoid alcohol consumption. R

Fasting (or not eating) obviously helps reduce the burden of LPS in the gut. R

High fat diets have shown to promote LPS-endotoxemia, while omega-3 fatty acids can reduce LPS load. R R R

Rebiosis = Restoring Normal Levels of Gut Bacteria

Increasing lactobacillus, bifidobacteria and butyrate-producing bacteria significantly helps reduce TH1/TH17 inflammatory levels, increase T-reg levels (incl IL-10), inhibit TLR4 activation and reduces plasma LPS levels. R R R R R R R R R R

Butyrate is also extremely important as it blocks long-chain fats (from a high fat diet for example) from allowing LPS (via chylomicrons) to get through the gut. R R


Stay away from Bifidobacterium animalis. R


More rebiosis techniques can be see in my gut-brain axis post

Vagus Nerve Stimulation

Strengthening the vagus tone is paramount for LPS tolerance. R R R

I usually use the Nervana for this.

I’ll have a post soon about the best ways to stimulate the vagus nerve (apart from the nervana).

Endocannabinoid System

LPS stimulates endocannabinoid synthesis, which regulates gut permeability. R R

For example, a high fat diet can increase endocannabinoid levels in different tissues, including the intestine, which is one way high-fat diet can increase LPS. R

Activating CB2 receptors and inhibiting CB1 helps protect against LPS’s ability to open tight junctions in the gut. R R

More about the endocannabinoid can be read here

Lipopolysaccharide Inhibitors


  • Acupuncture R
  • Combination Antiretroviral Therapy (cART) R
  • Exercise (Systemic endotoxin levels negatively correlate with physical activity, although exercise can induce a temporary leaky gut, similar to stress) R R R
  • Hydrogen (gas, water, injection) R R
  • LLLT R
  • Sympathetic Nervous System Activation (Meditation, Breathing Exercises, etc) R
  • Vagus Nerve Stimulation R








  • Acetaminophen R
  • Agomelatine R
  • Bexarotene R
  • Calixarene R
  • Chloroquine R R
  • Clozapine R
  • Danofloxacin R
  • Deferoxamine R
  • Dexmedetomidine R
  • Febuxostat R
  • Fenofibrate R
  • Gemfibrozil R
  • Glyburide R
  • Heparin R
  • Hydrophobic antibiotics R
  • H2S R R
  • Imipramine R
  • Isoflurane R
  • Ketamine R
  • Lidocaine R
  • Losartan R R
  • Lovastatin R
  • Metformin R
  • Micheliolide R
  • Midazolam R
  • Minocycline R
  • Misoprostol R
  • Modafinil R
  • Naloxone R
  • Naltrexone R
  • Nicotine (long term may be best) R R
  • Polamine R
  • Pentoxifylline R
  • Pitavastatin R
  • Prevastatin R
  • Propofol R
  • Roflumilast R
  • Roscovitine R
  • Rosiglitazone R
  • Salmeterol R
  • Saturated Hydrogen Saline R
  • Sevoflurane R
  • TAK-242 (TLR4 inhibitor) R
  • Thalidomide R
  • Thiopental R
  • Tianeptine R
  • UDCA/Ursodiol R
  • 7,8-Dihydroxyflavone (7,8-DHF – in Godmania aesculifolia, Tridax procumbens, and primula) R


  • Adenosine A2A-receptor R
  • Ang1 R
  • Antithrombin R
  • A7-nAChR R R R
  • β2-Adrenergic Receptor R
  • CNTF R
  • COX-2 inhibition R
  • HDAC inhibition R
  • HDL – elevation of HDL cholesterol in the absence of leptin or function leading to a high level of LPS clearance R
  • HMG-CoA reductase inhibition R
  • HO-1 R R
  • Hsp70 R
  • IAP R
  • IDO inhibition R
  • Intermedin1-53 R
  • IL-4 R
  • IL-10 R R R R R R R
  • IL-13 R
  • IL-17 inhibition R R
  • IL-35 R
  • IL-37 R
  • MAPK inhibition R
  • Mer R
  • NRF2 R
  • PAF inhibition R
  • PARP-1 R
  • PDE inhibition (4 is strongest) R R
  • PPAR-alpha R R
  • PPAR-gamma R R
  • SLP inhibition R
  • TGFB1 R
  • TLR4 antagonism (TLR2 as well) R


  • A20 R
  • Caveolin-1(Cav-1) scaffolding domain (CSD) peptides R
  • LFG-500 R
  • Mycotoxins R
  • Propionate R
  • SP-A R
  • Tetrandrine R
  • WNT-3A and WNT-5A (must be in combination with LPS or will drive up inflammation) R

Mechanism Of Action




  • Increases APP R
  • Increases β-glucuronidase R
  • Increases beta-secretase R
  • Increases Caspase-4 R
  • Increases Caspase-5 R
  • Increases CCL-3 R
  • Increases CCL-4 R
  • Increases CCL-5 R
  • Increases CXCL1 R
  • Increases CXCL2 R
  • Increases CXCL6 R
  • Increases CXCL10 R
  • Increases Cortisol R
  • Increases COX-2 R
  • Increases CYP11A1 R
  • Increases CYP17A1 R
  • Increases CYP19 R
  • Increases C99 R
  • Increases Eotaxin R
  • Increases gamma-secretase R
  • Increases G-CSF R
  • Increases HIF1a R R R
  • Increases ICAM-1 R
  • Increases IDO R
  • Increases IFN-gamma R
  • Increases IL-1a R
  • Increases IL-1b R
  • Increases IL-3 R
  • Increases IL-6 R
  • Increases IL-8 R
  • Increases IL-9 R
  • Increases IL-10 R
  • Increases IL-12 R
  • Increases IL-13 R
  • Increases IL-17a R
  • Increases IL-18 R R
  • Increases iNOS R
  • Increases IRF3 R
  • Increases JNK R
  • Increases LRP-1 R
  • Increases KC R
  • Increases LDH R
  • Increases LITAF R
  • Increases MCP-1 R
  • Increases MDA R
  • Increases MMP9 R
  • Increases NF-Kb R
  • Increases NO R
  • Increases PGE2 R
  • Increases p38 R
  • Increases P53 R
  • Increaess ROS R
  • Increases SELE R
  • Increases SOCS3 (to protect) R R R
  • Increases StAR R
  • Increases TLR4 R
  • Increases TNF-α R
  • Reduces ADH R
  • Reduces Ascorbate R
  • Reduces CAT R
  • Reduces Gas6 R
  • Reduces GnRH R
  • Reduces GPx R
  • Reduces GR R
  • Reduces GSH R
  • Reduces HO-1 R
  • Reduces IL-4 R
  • Reduces Insulin R
  • Reduces IRS-1 R
  • Reduces Leptin R
  • Reduces LH R
  • Reduces SOD R
  • Reduces SPAG11 R
  • Reduces TGF-b1 R


  • Endotoxic effects differ depending on the type of gram-negative bacteria. R
  • LPS consists of lipid A, core oligosaccharide, and an O-specific polysaccharide. R
  • LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex in many cell types, but especially in monocytes, dendritic cells, macrophages and B cells, which promotes the secretion of pro-inflammatory cytokines, nitric oxide, and eicosanoids.
  • As part of the cellular stress response, superoxide is one of the major reactive oxygen species induced by LPS in various cell types that express TLR (toll-like receptor). R
  • CD14 acts as a membrane receptor for LPS-LBP complex, and binding of LPS to CD14 is enhanced by LBP. R
  • LPS (from LBP) the activates the innate immune system (require the presence of myeloid differentiation factor 2 (MD-2), as TLR4 alone cannot recognise LPS…hence, it must associate with the MD-2 before it can induce an immune response to a LPS challenge): R
    • In pericytes and mesenchymal stem cells (MSCs), LPS acts on TLR4-MD2 complex (Mal/TIRAP/MyD88/TRAM/TRIF/IFN) and induces proinflammatory gene upregulation of NF-Kb and IRF3 (such as CXCL10, CCL20, IL8, CXCL1, IL6, CCL2, IL1B, CXCL2, IL1A, CXCL6, ICAM1, VCAM1, and SELE). R
    • In microglia/astrocytes, LPS increases NF-kB and also increases iNOS, thus release of NO. R R
  • Plasma LPS levels and the frequency of circulating CD8 T-cells with an activated CD38+ HLA-DR + phenotype suggests that microbial translocation might directly, or indirectly via cytokines and chemokines, generate polyclonal T-cell activation. R
  • On arrival in the liver, LPS is deacylated by the lipase acyloxyacyl hydrolase (AOAH) in hepatic Kupffer cells, which selectively removes these moieties from LPS or lipid A, while leaving the glucosamine-linked fatty acids intact. R
  • Systemic tolerance of LPS is induced by an IL-10-mediated negative feedback loop that commences after initial exposure to high levels of endotoxic LPS. R
  • In the vascular system LPS binds to fibrinogen. R
  • LPS affecting blood pressure is dependent on Tyrosine Hydroxylase, BH4 -> NE. R
  • In the liver, LPS inhibits hepatic gluconeogenesis. R
  • In human myotubes, LPS increases JNK phosphorylation and MCP-1 and IL-6 gene expression, which this inflammatory response leads to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. R
  • In cancer, LPS induces lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α factor (LITAF), aka p53-inducible gene 7 (PIG7) to go to the nucleus. R
  • LPS stimulates GABA synthesis in preoptic neurons, which in turn inhibit the LH surge. R
  • LPS treatment completely represses androgen receptor co-repressor (ARR19) in the brain while not in the testis. R
  • LPS inhibits ion transports. R




    • C allele – increased stroke risk among smokers (OR = 2.05, 95% CI=1.09-3.86, p=0.03), but not among non-smokers (OR = 0.93, 95% CI=0.62-1.39, p=0.72) R
    • TT alleles along with rs2569191(CC) – associated with lower IgE R
    • TT homozygotes vs C carriers – Closely correlated with portal lymphoid aggregates and presence of portal lymphoid aggregates with hepatic inflammation (P = 0.003) and with bile duct damage (P < 0.001) R

    rs2569191 (I’m CC)

    • CC alleles along with rs2569190(TT) – associated with lower IgE R
    • T major allele variants had the prevalence of wheeze increased with increasing endotoxin concentration, whereas C was the opposite. R
    • associated with soluble CD14 (sCD14) levels R


    • CC alleles – significantly associated with the risk of sepsis (86.8%) R
    • CA – associated with the risk of sepsis (12.5%) R
    • AA – associated with the risk of sepsis (0.7%) R


    • increased risk of hospital admissions with acute domestic endotoxin exposure and asthma exacerbations R

    rs5744455 (I’m GG)

    • T allele – May affect CD14 expression and susceptibility to gastric carcinoma in relation to Helicobacter pylori R
    • T allele – had decreased risk of repeated hospital admissions compared with homozygotes for C allele R


    rs199396 (I’m CC)

    • C allele – reduced NF-κB activation R

    rs6853 (I’m AG)

    • GG or TT alleles – predisposes to human pulmonary tuberculosis R
    • G alleles – associated with poorer outcome to measles vaccine (lower antibody response) R

    rs7744 (I’m AA)

    • AA homozygote was significantly lower and that of the GG homozygote was significantly higher in the UC cases compared with those in the controls R
    • associated with Buerger disease but not with Takayasu arteritis in Japanese R


    See post on TLR4.

    More Research

    • Cyanobacterial LPSs show no toxicity or very low toxicity in comparison with classic Gram-negative LPSs when injected in mice. R