Overview

Lipopolysaccharide (LPS), also known as endotoxin, is a fundamental component of the outer membrane of Gram-negative bacteria. ^[1] It is a large molecule that is part lipid and part polysaccharide, that forms a protective outer shield for the bacterium and serves as a potent trigger of the host’s immune response. In essence, LPS is the signature glycolipid of Gram-negative bacteria, crucial for their structural integrity and notable for its ability to stimulate strong innate immune reactions. Clinically, LPS is infamous as the endotoxin responsible for fever and shock in severe Gram-negative infections. Even minute quantities can induce fever (it is a potent pyrogen) and, if large amounts enter the bloodstream, a cascade of inflammation may lead to septic shock with multi-organ failure.^[2]

Role of LPS in Gram-Negative Bacterial Physiology

As a defining feature of the outer membrane in Gram-negative bacteria, lipopolysaccharide (LPS) is densely arranged in the outer leaflet, forming a rigid, protective layer that performs multiple essential functions. It serves as a molecular “brick-and-mortar” wall that fortifies membrane integrity, restricts the entry of harmful agents, and shields the bacterium from host immune responses. The lipid A and core oligosaccharide components form a hydrophobic and electrostatic barrier, while the variable O-antigen extends outward to obstruct complement deposition and immune recognition. In addition to its defensive roles, LPS contributes to bacterial adherence and biofilm development, facilitating colonization and environmental adaptation. Though some exceptional strains (e.g., Neisseria, Moraxella) can survive with modified outer membranes, most Gram-negative bacteria rely on LPS for viability.^[3] Thus, LPS is not merely a structural component but a multifunctional determinant of survival, virulence, and immune evasion.

Function	Mechanism / Significance
Structural Integrity	LPS reinforces the outer membrane’s architecture. Lipid A–core regions provide mechanical strength; mutants lacking lipid A are typically non-viable.
Permeability Barrier	The dense packing of lipid A acyl chains and cross-linked sugars restricts penetration of bile salts, detergents, and many antibiotics.
Immune Evasion	Long O-antigen chains sterically hinder complement deposition and antibody access, conferring resistance to opsonization and lysis.
Surface Attachment and Biofilms	Polysaccharide chains mediate adhesion to host tissues and surfaces. LPS-containing outer membrane vesicles promote biofilm formation and bacterial signaling.
Environmental Adaptability	Structural variability, especially in the O-antigen, allows bacteria to evade host immune recognition and adapt to specific niches or hosts.

Immunological Significance of Lipopolysaccharide (LPS)

From the perspective of the host’s immune system, lipopolysaccharide (LPS) is a prominent red flag indicating a Gram-negative bacterial invasion. It is one of the quintessential pathogen-associated molecular patterns (PAMPs) recognized by the innate immune system. When Gram-negative bacteria infect a host or LPS enters the body (for instance, through a breached gut barrier or an infection focus), the immune system rapidly detects it.

What is the immunological significance of LPS?

Immunological Process	Description and Significance

TLR4 Recognition

LPS, specifically its lipid A moiety, binds to Toll-like receptor 4 (TLR4) on immune cells with the help of MD-2 and CD14. This initiates a signaling cascade activating NF-κB and other transcription factors, leading to transcription of pro-inflammatory cytokine genes. LPS effectively functions as an innate immune alarm signal.

Cytokine Storm Trigger

Activation of immune cells by LPS leads to rapid secretion of inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) and lipid mediators (e.g., prostaglandins). These mediators induce fever, increase vascular permeability, and recruit leukocytes. Even low doses of LPS can provoke robust inflammatory responses.

Balance of Responses

Low levels of LPS exposure (e.g., from commensals) may promote immune tolerance or priming, while high systemic levels (e.g., from infection or gut translocation) can trigger excessive cytokine release, leading to tissue injury, hypotension, and multi-organ dysfunction – the clinical picture of endotoxin shock.

Conditions Associated with Elevated LPS

Elevated levels of lipopolysaccharide (LPS) in circulation, a state known as endotoxemia, are clinically significant because LPS is a potent trigger of inflammation via Toll-like receptor-4 (TLR4) on immune cells.^[6] While acute, high-grade endotoxemia (as in Gram-negative sepsis) can induce a cytokine storm and septic shock, even chronic low-grade elevations of LPS (“metabolic endotoxemia”) provoke persistent systemic inflammation. This sustained inflammatory tone is implicated in the pathogenesis of numerous chronic conditions, linking gut microbial dynamics to metabolic and cardiovascular disease.^[7][8] Below are key clinical conditions hallmarked by elevated LPS levels, with a brief explanation of the mechanistic or clinical significance in each case:

Condition	Mechanistic/Clinical Association with Elevated LPS
Gram-negative Sepsis (Septic Shock)	Severe Gram-negative bacterial infections release large amounts of LPS into the bloodstream, triggering an overwhelming TLR4-mediated cytokine cascade (cytokine storm). Endotoxin levels are extremely high in septic shock patients, who often develop multi-organ failure (acute kidney injury, hepatic dysfunction, coagulopathy) as a result. [9] “Endotoxic” septic shock is thus directly driven by LPS.
Obesity & Metabolic Syndrome	High-fat diets can induce a 2–3 fold rise in plasma LPS – a phenomenon termed metabolic endotoxemia – which in turn promotes chronic low-grade inflammation and insulin resistance.[10][11] Obese individuals often exhibit increased gut permeability, enabling LPS translocation from the gut into circulation. The resulting endotoxemia is thought to initiate adipose tissue inflammation and metabolic disturbances characteristic of obesity and metabolic syndrome.
Type 2 Diabetes Mellitus (T2DM)	Persistent low-grade endotoxemia is a feature of T2DM and a driver of its inflammatory complications. Chronically elevated LPS activates innate immune cells, impairing insulin signaling. Prospective studies have shown that higher baseline endotoxin is associated with increased risk of developing T2DM.[12][13] Thus, endotoxemia-linked inflammation contributes to the insulin resistance and beta-cell stress in diabetes.
Non-Alcoholic Fatty Liver Disease (NAFLD/NASH)	Gut-derived endotoxin plays a key role in the liver inflammation seen in NAFLD and its progression to steatohepatitis (NASH). Patients with NAFLD show higher circulating LPS and pro-inflammatory cytokines, indicating that endotoxemia drives hepatic Kupffer cell activation and fibrogenesis. Intestinal barrier dysfunction in NAFLD allows LPS to enter portal circulation, exacerbating liver injury and inflammation.[14]
Atherosclerosis & Cardiovascular Disease	Chronic low-grade endotoxemia is implicated in atherosclerosis and heart disease by promoting endothelial inflammation and foam cell formation. Elevated LPS has been correlated with increased cardiovascular risk (e.g. higher C-reactive protein and incidence of events) in population studies. Notably, endotoxemia is considered a molecular link between distant infections (such as periodontal disease) and cardiometabolic disorders.[15] In essence, circulating LPS contributes to the inflammatory milieu that accelerates atherogenesis.
Chronic Kidney Disease (CKD)	CKD patients experience “uremic” endotoxemia due to a combination of gut dysbiosis, impaired immune clearance, and intestinal barrier defects. Even at early stages, CKD is associated with significantly elevated plasma LPS levels. [16] This endotoxin burden drives systemic inflammation and malnutrition in CKD and is linked to vascular complications. Dialysis patients in particular have repetitive exposure to endotoxin (e.g. translocation during hemodialysis), which may contribute to chronic inflammation and cardiovascular mortality in CKD.
Alzheimer’s Disease	Neurodegenerative disorders such as Alzheimer’s dementia (AD) have been linked to peripheral endotoxemia. AD patients often exhibit higher serum LPS levels and an enhanced immune response to LPS, suggesting chronic exposure to endotoxin (for example, from periodontal or gut microbes) may trigger neuroinflammation. [17] LPS can activate microglia in the brain, and repeated low-dose endotoxemia is hypothesized to accelerate neurodegenerative pathology. Recent studies have found that chronic periodontitis and the associated endotoxin load precede and possibly promote AD development.[18]

Interventions That Reduce LPS

Mitigating endotoxemia has become a therapeutic target to reduce inflammation in metabolic and inflammatory diseases. Approaches to lower systemic or compartmentalized LPS levels focus on either preventing LPS generation/absorption at its source or neutralizing its effects downstream. Notably, diet and microbiome-directed interventions can strengthen the intestinal barrier and alter gut flora to produce less endotoxin.^[19] For example, increasing dietary fiber and polyphenols favor beneficial microbes and improve tight junction integrity, thereby reducing LPS translocation from the gut. In parallel, pharmacological strategies (including certain antibiotics and experimental agents) aim to directly decrease LPS-producing bacteria or bind and detoxify LPS. Anti-endotoxin therapies such as polymyxin B which binds the lipid A portion of LPS, or antibodies against LPS O-antigen have shown the ability to neutralize endotoxin in preclinical models.^[20] Below is a summary of interventions with evidence for reducing LPS levels or activity, from human trials or robust preclinical studies:

Intervention	Mechanism and Effect on LPS Levels
Apigenin	Apigenin is a dietary flavonoid (abundant in chamomile, parsley, etc.) with gut-targeted anti-inflammatory effects. It beneficially modulates the gut microbiota and fortifies the intestinal barrier, thereby reducing LPS absorption. In high-fat diet models of obesity, apigenin supplementation markedly lowered systemic LPS levels and associated low-grade inflammation. [21]
Orange Juice	Polyphenol- and vitamin C-rich orange juice has been shown to blunt postprandial endotoxemia. In a human clinical study, co-ingesting orange juice with a high-fat, high-carbohydrate meal prevented the usual meal-induced rise in plasma endotoxin and Toll-like receptor (TLR4) expression on immune cells. [22] Subjects who drank water or glucose with the same meal had significant increases in LPS, whereas orange juice abolished this LPS spike and the accompanying inflammatory oxidative stress response. This effect is attributed to citrus flavonoids (like hesperidin and naringenin) that improve gut barrier function and have direct LPS-neutralizing or anti-inflammatory properties.
Probiotics	Supplementing beneficial bacteria can reduce endotoxemia by competing with LPS-producing Gram-negative flora and enhancing mucosal barrier integrity. For instance, a 30-day trial of an oral spore-based probiotic (containing Bacillus species) in healthy adults significantly reduced the incidence of dietary endotoxemia, as fewer subjects showed LPS elevation after a fatty meal compared to placebo.[23] This suggests improved gut barrier function (lower permeability) and altered microbiota. Likewise, traditional probiotics (e.g. Lactobacillus, Bifidobacterium strains) have demonstrated reductions in circulating LPS and inflammatory markers in conditions like metabolic syndrome.[24] Overall, probiotics help sequester or degrade luminal LPS and tighten junctions, thus lowering systemic endotoxin exposure.
Inulin	Prebiotic fibers such as inulin stimulate growth of LPS-suppressing commensals and increase production of short-chain fatty acids (SCFAs) that heal the gut lining. In a randomized controlled trial of women with T2DM, 8 weeks of daily inulin supplementation led to a 27.9% decrease in plasma LPS levels (compared to placebo), alongside significant reductions in inflammatory cytokines and insulin resistance. [25] The improved metabolic profile was attributed to inulin’s modulation of gut microbiota and reinforcement of tight junction proteins, which curtailed LPS translocation. This evidence underscores dietary fiber as a viable strategy to reduce endotoxemia and inflammation in humans.
Rifaximin	Rifaximin is a gut-specific antibiotic that targets Gram-positive and Gram-negative bacteria without systemic absorption. By reshaping the intestinal microbiota, rifaximin can lower the endogenous production of endotoxin. In patients with NASH (non-alcoholic steatohepatitis), 28 days of rifaximin therapy significantly reduced serum endotoxin levels (endotoxin activity dropped, P = 0.03) and also improved liver enzymes and inflammatory markers.[26] Similarly, rifaximin has been used in cirrhosis and metabolic syndrome to alleviate endotoxemia and related inflammation.[27] The mechanism involves decreasing LPS-producing gut bacteria and intestinal permeability. Notably, because rifaximin is non-systemic, it reduces LPS at its source (the gut) while minimizing systemic side effects.
Curcumin	Curcumin has demonstrated the ability to reduce LPS-mediated inflammation by strengthening the gut barrier and detoxifying endotoxin. In rodent models of diet-induced metabolic syndrome, curcumin supplementation increased intestinal alkaline phosphatase activity (which dephosphorylates and neutralizes LPS) and preserved tight junction structure, thereby preventing rises in plasma LPS. [28] Diabetic rats on a high-fat diet showed significantly elevated serum LPS and TNF-α, but curcumin treatment decreased both LPS and inflammatory cytokine levels back toward normal.[29] These effects are linked to curcumin’s reshaping of the gut microbiota (enriching beneficial taxa) and its direct inhibition of LPS-induced signaling pathways in intestinal cells. Some preliminary human studies echo these findings, supporting curcumin as a therapeutic adjunct to reduce endotoxemia and inflammation in metabolic diseases.

FAQs

What is LPS and where does it come from?

Lipopolysaccharide (LPS) is a large glycolipid molecule found in the outer membrane of Gram-negative bacteria. It is released either during bacterial growth or cell lysis and acts as a potent endotoxin capable of triggering host immune responses via Toll-like receptor 4 (TLR4) activation.

What is metabolic endotoxemia?

Metabolic endotoxemia refers to a 2–3 fold increase in circulating LPS levels, typically due to increased gut permeability. Unlike septic endotoxemia, it induces low-grade, chronic inflammation and is implicated in obesity, type 2 diabetes, NAFLD, and cardiovascular disease.

How is LPS detected in research and clinical studies?

The Limulus Amebocyte Lysate (LAL) assay is most commonly used, but it has limitations including false positives due to β-glucans and lipoproteins. Alternative or complementary methods include LBP (LPS-binding protein) assays and endotoxin activity assays (EAA).

Research Feed

References

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2. Clinical Sepsis and Death in a Newborn Nursery Associated with Contaminated Parenteral Medications.. CDC.gov. (Brazil, 1996. Cdc.gov.)
3. Lipopolysaccharides: structure, function and bacterial identification.. 1. Caroff M, Novikov A.. (OCL. 2020;27:31-31.)
4. Lipopolysaccharides: structure, function and bacterial identification.. 1. Caroff M, Novikov A.. (OCL. 2020;27:31-31.)
5. Lipopolysaccharides: structure, function and bacterial identification.. 1. Caroff M, Novikov A.. (OCL. 2020;27:31-31.)
6. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
7. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
8. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
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11. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
12. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
13. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
14. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions.. Mohammad S and Thiemermann C.. (Front. Immunol. 11:594150. (2021))
15. Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia.. Pussinen PJ, Kopra E, Pietiäinen M, Lehto M, Zaric S, Paju S, Salminen A.. (Periodontol 2000. 2022 Jun;89(1):19-40.)
16. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease.. McIntyre CW, Harrison LE, Eldehni MT, Jefferies HJ, Szeto CC, John SG, Sigrist MK, Burton JO, Hothi D, Korsheed S, Owen PJ, Lai KB, Li PK.. (Clin J Am Soc Nephrol. 2011 Jan;6(1):133-41.)
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18. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability.. de Punder K and Pruimboom L. (Front. Immunol. 6:223. (2015))
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20. The role of endotoxin in septic shock.. Kellum, J.A., Ronco, C.. (Crit Care 27, 400 (2023).)
21. Apigenin Alleviates Obesity-Associated Metabolic Syndrome by Regulating the Composition of the Gut Microbiome.. Qiao Y, Zhang Z, Zhai Y, Yan X, Zhou W, Liu H, Guan L and Peng L. (Front. Microbiol. 12:805827. (2022))
22. Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression.. Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, Mohanty P, Dandona P.. (Am J Clin Nutr. 2010 Apr;91(4):940-9.)
23. Oral spore-based probiotic supplementation was associated with reduced incidence of post-prandial dietary endotoxin, triglycerides, and disease risk biomarkers.. McFarlin BK, Henning AL, Bowman EM, Gary MA, Carbajal KM.. (World Journal of Gastrointestinal Pathophysiology. 2017;8(3):117-117.)
24. Effect of Probiotic Supplementation on Intestinal Permeability in Overweight and Obesity: A Systematic Review of Randomized Controlled Trials and Animal Studies.. DiMattia Z, Damani JJ, Van Syoc E, Rogers CJ.. (Adv Nutr. 2024 Jan;15(1):100162.)
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27. Rifaximin: beyond the traditional antibiotic activity.. Calanni, F., Renzulli, C., Barbanti, M. et al.. (J Antibiot 67, 667–670 (2014).)
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29. Improvement of intestinal barrier function, gut microbiota, and metabolic endotoxemia in type 2 diabetes rats by curcumin.. Huang J, Guan B, Lin L, Wang Y.. (Bioengineered. 2021 Dec;12(2):11947-11958.)