LPS (Lipopolysaccharide)

Lipopolysaccharide (LPS), also known as endotoxin, is a component of the outer membrane of Gram-negative bacteria. While LPS is contained within the gut under normal conditions, when it escapes into the bloodstream—a condition called metabolic endotoxemia—it triggers powerful inflammatory responses linked to numerous chronic diseases [^cani2007].

What Is LPS?

Structure and Origin

LPS is not something bacteria "make" as a product—it's part of their structure:

• Structural component of Gram-negative bacterial outer membrane
• Released when bacteria die or multiply
• Contains lipid A: The toxic portion that triggers inflammation
• Universally present wherever Gram-negative bacteria exist

LPS in the Gut

Your gut contains trillions of Gram-negative bacteria:

• Massive amounts of LPS in the intestinal lumen
• Healthy gut barrier keeps LPS contained
• Some LPS naturally crosses into blood (at low levels)
• Problems arise when barrier is compromised

Metabolic Endotoxemia

Definition

Metabolic endotoxemia refers to chronically elevated blood LPS levels—not high enough to cause acute sepsis, but sufficient to drive chronic low-grade inflammation [^cani2007].

How LPS Enters the Blood

Several routes allow LPS translocation:

1. Leaky gut: Compromised tight junctions allow paracellular passage
2. Chylomicron transport: Fat absorption carries LPS [^ghoshal2009]
3. Transcellular passage: Active transport through intestinal cells
4. Damaged epithelium: Direct passage through injured gut lining

The High-Fat Diet Effect

High-fat meals particularly increase blood LPS:

• Fat triggers chylomicron production
• LPS binds to chylomicrons
• "Hitch-hikes" into bloodstream
• Explains post-meal inflammation in some people

Inflammatory Cascade

TLR4 Activation

LPS triggers inflammation through a specific receptor:

1. LPS binds LBP (LPS-binding protein) in blood
2. LBP-LPS transfers to CD14 on immune cells
3. CD14 presents LPS to TLR4 receptor
4. TLR4 activation triggers inflammatory signaling
5. NF-κB activation → Inflammatory cytokine production

Consequences

This activation produces:

• TNF-α (tumor necrosis factor)
• IL-1β, IL-6 (interleukins)
• Inflammatory enzyme activation
• Oxidative stress
• Insulin resistance
• Fat tissue inflammation

Diseases Linked to Metabolic Endotoxemia

Obesity and Metabolic Syndrome

LPS may be a key driver of obesity-related inflammation [^cani2007]:

• Obese individuals have higher blood LPS
• Weight loss reduces LPS levels
• LPS administration causes metabolic changes in animals
• May explain "unhealthy" obesity phenotype

Type 2 Diabetes

The LPS-diabetes connection:

• Elevated LPS predicts diabetes development
• LPS causes insulin resistance directly
• Contributes to beta cell dysfunction
• May trigger diabetes in susceptible individuals

Non-Alcoholic Fatty Liver Disease (NAFLD)

LPS and liver disease:

• LPS reaches liver via portal vein
• Activates Kupffer cells (liver macrophages)
• Promotes liver inflammation and fibrosis
• May drive progression to NASH

Cardiovascular Disease

LPS contributes to atherosclerosis:

• Promotes arterial inflammation
• Accelerates plaque formation
• Increases cardiovascular events
• May explain gut-heart connection

Neuroinflammation and Brain

LPS affects the brain:

• Can cross blood-brain barrier when compromised
• Activates microglia (brain immune cells)
• Promotes neuroinflammation
• Linked to depression, cognitive decline

Autoimmune Conditions

LPS may trigger or worsen autoimmunity:

• Activates autoreactive immune cells
• Breaks immune tolerance
• May contribute to rheumatoid arthritis, IBD, others

Factors That Increase Blood LPS

Dietary Factors

• High-fat meals: Especially saturated fat
• Western diet: High fat, low fiber
• Processed foods: Multiple harmful components
• Alcohol: Increases gut permeability

Gut Health Factors

• Dysbiosis: Overgrowth of Gram-negative bacteria
• Reduced beneficial bacteria: Loss of barrier-supporting microbes
• Low fiber intake: Weakens gut barrier
• Intestinal inflammation: Damages tight junctions

Lifestyle and Medical

• Obesity: Associated with higher LPS
• Chronic stress: Increases gut permeability
• Sleep deprivation: Compromises gut barrier
• Certain medications: NSAIDs, PPIs may increase LPS
• Infections: Acute infections raise LPS

Reducing LPS Exposure

Strengthen the Gut Barrier

Dietary Strategies:

1. High-fiber diet: Especially fermentable fiber
2. Polyphenols: Support barrier integrity
3. Omega-3 fatty acids: Anti-inflammatory
4. Bone broth/collagen: May support gut lining
5. Glutamine: Fuel for intestinal cells

Avoid Barrier Damage:

1. Limit alcohol
2. Avoid unnecessary NSAIDs
3. Address food intolerances
4. Treat underlying gut conditions

Support Beneficial Bacteria

• Prebiotics: Feed barrier-supporting bacteria
• Probiotics: Some strains strengthen barrier
• Fermented foods: Support microbiome diversity
• Avoid unnecessary antibiotics

Reduce Gram-Negative Overgrowth

• Address SIBO if present
• Support bacterial diversity
• Avoid excessive sugar/refined carbs
• Consider targeted interventions if needed

Lifestyle Modifications

• Regular exercise (reduces LPS)
• Adequate sleep
• Stress management
• Maintain healthy weight

Testing for Metabolic Endotoxemia

Available Tests

Direct LPS Measurement:

• Research assays primarily
• Not widely available clinically
• Technical challenges with measurement

Indirect Markers:

• LPS-binding protein (LBP): More stable, better for clinical use
• Zonulin: Marker of gut permeability
• sCD14: Soluble CD14 levels
• Inflammatory markers: CRP, cytokines (less specific)

Interpretation

• Elevated LBP suggests LPS exposure
• Combine with other gut health markers
• Consider clinical context
• Serial measurements may be useful

The LPS-Diet-Microbiome Triangle

How Diet Affects LPS

High-Fat Diet → Chylomicron LPS transport → Higher blood LPS
              → Dysbiosis → More Gram-negative bacteria
              → Barrier damage → Increased permeability

How Microbiome Affects LPS

• Beneficial bacteria maintain barrier
• Balanced microbiome limits Gram-negative overgrowth
• SCFAs strengthen tight junctions
• Mucus layer provides physical barrier

Breaking the Cycle

1. Dietary change: Less fat, more fiber
2. Microbiome shift: Toward beneficial species
3. Barrier repair: Reduced permeability
4. Less LPS exposure: Reduced inflammation
5. Improved metabolism: Weight loss, insulin sensitivity

Practical Recommendations

For Prevention

1. Mediterranean-style diet
2. High fiber intake (30+ g/day)
3. Limit saturated fat
4. Regular exercise
5. Maintain healthy weight

For Those with Elevated LPS/Inflammation

1. Work with healthcare provider
2. Consider gut-healing protocol
3. Emphasize barrier-supporting foods
4. Address underlying conditions
5. Monitor inflammatory markers

Important Caveats

• Acute illness raises LPS—not concerning in that context
• Some LPS exposure is normal
• Complete elimination is impossible and unnecessary
• Focus on chronic, low-grade elevation