Did you know?
Even in small amounts, LPS can provoke a severe immune response when released into the bloodstream. This response can lead to systemic inflammation, multiple organ failure, and potentially death, highlighting the potent nature of this endotoxin.
Lipopolysaccharide (LPS)
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
Lipopolysaccharide (PS), a potent endotoxin present in the outer membrane of Gram-negative bacteria that causes chronic immune responses associated with inflammation.
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Karen Pendergrass
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
Overview 
Research Feed 
References 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. |
Adapted from Caroff M, Novikov A. Lipopolysaccharides: structure, function and bacterial identification. OCL. 2020;27:31-31. [4]
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. |
Lipopolysaccharides and Inflammation
Lipopolysaccharides promote inflammation mainly by signaling through Toll-like receptor (TLR) 4 on macrophages, monocytes, and other innate immune system cells. [x] Emerging data supports the association of TLR4 and TLR4 polymorphisms with several diseases with an inflammatory etiology, including cancer, atherosclerosis, and autoimmune conditions. Several studies also suggest a possible role of TLR4 in cardiovascular disease [x,x], inflammatory bowel disease [x], Alzheimer’s disease [x], rheumatoid arthritis [x], renal disease [x], obesity, and both type I and type II diabetes [x]. The increasing body of evidence suggesting a link between TLR4 and many diseases suggests that developing therapeutics that target this receptor may generate some tremendously important advances in the coming years.
What conditions have found an etiological role Lipololysaccharides?
| Chronic Disease | Lipopolysaccharide Involvement |
| Obesity | Recently, it has been shown that obesity is associated with chronic and systemic low-grade inflammation which is due to an innate immune response to LPS. It is considered an endotoxin and found at low concentrations in the blood of healthy persons. But substantially high concentrations of LPS have been demonstrated in obese individuals, where the obesity is diet-induced and has a genetic predisposition. Studies found that plasma levels of LPS were elevated in obese individuals compared with controls (P <0.001) and were reduced after bariatric surgery [x], suggesting that translocation of gut bacteria are a potential trigger for obesity and diabetes and that the antidiabetic effects of bariatric surgery may be owed to this mechanism. |
| Diabetes Type II | Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both [x] .The prevalence and incidence of DM have increased recently, especially in Western countries [x]. Short and long-term complications due to uncontrolled glycemia lead to high human, social, and economic burdens [x]. Therefore, understanding the features involved in the pathophysiology of DM is of considerable value in treating DM and preventing its progression. The data indicate that DM favors LPS endotoxin translocation across the intestinal barrier, leading to its mild increase in concentration in the bloodstream [x]. The Lipid A component is responsible for much of LPS toxicity. Toll-like receptors (TLR) of the innate immune system recognize lipid A and then trigger immune and inflammatory responses in DM models [x]. Systematic Reviews find that diabetic subjects present higher fasting and postprandial LPS concentrations compared to lean non-diabetic subjects and/or obese subjects. [x] Evidence also suggests that LPS endotoxin is involved in the onset of Type 1 Diabetes Mellitus since LPS concentrations were also higher at the disease onset [x,x]. |
| Autism | In recent years, there has been an emerging interest in the possible role of the gut microbiota as a co-factor in the development of autism spectrum disorders (ASDs), as many studies have highlighted the bidirectional communication between the gut and brain (the so-called “gut-brain axis”). Accumulating evidence has shown a link between alterations in the composition of the gut microbiota and both gastrointestinal and neurobehavioural symptoms in children with ASD. A maternal high-fat diet during pregnancy alters the microbiota in neonates and appears to be associated with ASD in humans [x] A considerable number of subjects with ASD have significant gastrointestinal dysfunction, particularly altered bowel habits and chronic abdominal pain that accompany their neurological alterations [x]. Further, the gastrointestinal (GI) symptoms of individuals with ASD seem to correlate strongly with the severity of their ASD [x]. In recent years, several studies have shown significant changes in the composition of the gut microbiota in children with ASD [x,x] and have suggested that GI symptoms in ASD may be a manifestation of the underlying inflammatory process [x]. In particular, dysbiosis is associated with a disruption of the mucosal barrier that leads to increased intestinal permeability of exogenous peptides of dietary origin or neurotoxic peptides of bacterial origin such as lipopolysaccharide [x]. The microbiota and its metabolites are crucial in maintaining epithelial barrier integrity; therefore, dysbiosis in ASD patients may alter gut permeability [x]. This condition, called “leaky gut” [x], may allow the passage of bacteria, toxins such as lipopolysaccharides, and metabolites that activate the immune response and induce an inflammatory state into the bloodstream [x]. |
Research Feed
[ajcn.2009.28584] Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression 1–3
April 9, 2010
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Lipopolysaccharide (LPS) •
Lipopolysaccharide (LPS)
Did you know?
Even in small amounts, LPS can provoke a severe immune response when released into the bloodstream. This response can lead to systemic inflammation, multiple organ failure, and potentially death, highlighting the potent nature of this endotoxin.
Gram-Negative Bacteria •
Gram-Negative Bacteria
Did you know?
Gram-negative bacteria can trigger deadly septic shock by releasing toxins from their outer membrane when they are destroyed.
Orange juice with a high-fat meal prevented postprandial inflammation and endotoxemia: no rise in LPS or TLR2/4 expression.
What was studied?
Researchers evaluated whether co-ingesting orange juice with a high-fat, high-carbohydrate (HFHC) meal can neutralize the meal’s proinflammatory and oxidative effects. The study specifically focused on post-meal plasma endotoxin (lipopolysaccharide, LPS) levels and Toll-like receptor (TLR2 and TLR4) expression on immune cells. In this clinical trial, various inflammatory and oxidative stress markers (e.g. reactive oxygen species, cytokine signaling proteins, TLRs, and endotoxin) were measured after an HFHC meal consumed with orange juice, versus with water or a glucose drink.
Who was studied?
The study involved 30 healthy, normal-weight adults (men and women, age 20–40, BMI 20–25) divided into three equal groups. Each group consumed a 900-kcal HFHC meal accompanied by one of three beverages: water, 75 g glucose (300 kcal), or an equivalent 300-kcal orange juice serving. Blood samples were collected fasting and at 1, 3, and 5 hours post-meal to assess metabolic and inflammatory responses.
Key Findings
Orange juice prevents TLR2/4 upregulation. Only the water- and glucose-drink groups showed significant postprandial increases in mononuclear cell TLR2 and TLR4 mRNA (peaking ~34–87% above baseline), whereas the orange juice (OJ) group had no significant change. Consistently, plasma endotoxin concentrations rose by ~60–70% within hours after the HFHC meal with water or glucose, but this endotoxemia surge was completely prevented when orange juice was co-ingested. Thus, OJ effectively blocked the gut-derived LPS–TLR inflammatory axis underpinning postprandial inflammation.
Orange juice also blunted oxidative stress. The HFHC meal led to a spike in reactive oxygen species (ROS) generation by leukocytes in the water and glucose groups, but co-ingestion of OJ significantly curbed this ROS burstajcn.nutrition.org. For example, at 1 hour post-meal, mononuclear cell ROS production increased by ~62–63% with water or glucose, versus only ~47% with OJajcn.nutrition.org. Likewise, neutrophil ROS rose markedly after the meal + water/glucose, but remained minimal with OJ. Furthermore, OJ abrogated the meal-induced rises in other inflammatory mediators: mononuclear NF-κB–related signals, MMP-9 (matrix metalloproteinase-9) expression and plasma levels, and intracellular MAPK p38 activation were all significantly elevated post-meal with water or glucose, yet virtually unchanged when OJ was included. In short, orange juice neutralized the HFHC meal’s pro-oxidative and proinflammatory impact, preventing increased endotoxin, TLR2/4, and downstream inflammatory signaling that were otherwise observed postprandially.
Clinical Implications
These findings have important clinical implications for metabolic and cardiovascular health. Repeated episodes of postprandial inflammation and metabolic endotoxemia (transient entry of gut bacterial LPS after meals) are thought to contribute to insulin resistance and atherosclerosis. By showing that a polyphenol-rich beverage like orange juice can buffer the inflammatory effects of a high-fat, high-carb meal, this study suggests a practical dietary strategy to mitigate meal-induced inflammatory stress. The orange juice prevented the LPS surge and TLR4 upregulation, thereby interrupting a key microbe-driven inflammatory pathway. Clinically, such an approach could reduce the cumulative burden of inflammation and oxidative stress after unhealthy meals, potentially lowering the risk of metabolic syndrome and cardiovascular events over time. In essence, dietary components can modulate host–microbial interactions: here, orange juice’s flavonoids (like hesperidin) likely counteracted gut-derived endotoxin effects, attenuating postprandial inflammatory responses.
This underscores the need to consider not just macronutrient content but also food combinations and bioactive nutrients that neutralize proinflammatory triggers in the diet. For clinicians, advising the inclusion of polyphenol-rich foods or beverages with indulgent meals might be a stepping stone toward blunting post-meal inflammation and improving metabolic health.
Lipopolysaccharide (LPS)
Lipopolysaccharide (LPS), a potent endotoxin present in the outer membrane of Gram-negative bacteria that causes chronic immune responses associated with inflammation.
Gram-Negative Bacteria
Gram-negative bacteria are resilient pathogens with antibiotic resistance, causing infections like UTIs, sepsis, and pneumonia.
Lipopolysaccharide (LPS)
Lipopolysaccharide (LPS), a potent endotoxin present in the outer membrane of Gram-negative bacteria that causes chronic immune responses associated with inflammation.
References
- Biochemistry, Lipopolysaccharide.. Farhana A, Khan YS.. (April 17, 2023.)
- Clinical Sepsis and Death in a Newborn Nursery Associated with Contaminated Parenteral Medications.. CDC.gov. (Brazil, 1996. Cdc.gov.)
- Lipopolysaccharides: structure, function and bacterial identification.. 1. Caroff M, Novikov A.. (OCL. 2020;27:31-31.)
- Lipopolysaccharides: structure, function and bacterial identification.. 1. Caroff M, Novikov A.. (OCL. 2020;27:31-31.)
- Lipopolysaccharides: structure, function and bacterial identification.. 1. Caroff M, Novikov A.. (OCL. 2020;27:31-31.)
CDC.gov
Clinical Sepsis and Death in a Newborn Nursery Associated with Contaminated Parenteral Medications.Brazil, 1996. Cdc.gov.
1. Caroff M, Novikov A.
Lipopolysaccharides: structure, function and bacterial identification.OCL. 2020;27:31-31.
1. Caroff M, Novikov A.
Lipopolysaccharides: structure, function and bacterial identification.OCL. 2020;27:31-31.
1. Caroff M, Novikov A.
Lipopolysaccharides: structure, function and bacterial identification.OCL. 2020;27:31-31.