Normally housed safely in the gut, lipopolysaccharides become toxic by entering the blood through infection, a leaky gut, or with high-fat meals. Once in the blood, they exert many damaging effects on the brain and body.
Read on to learn how lipopolysaccharides cause inflammation, and how you can minimize their harm.
What are Lipopolysaccharides (LPS)?
Lipopolysaccharides (LPS) are one of the main causes of systemic, low-grade inflammation. In fact, intravenous LPS is often used in research experiments to cause inflammation .
Exposure to LPS causes both rodents and people to display “sickness behavior,” including depression, impaired cognitive function, and social withdrawal .
LPS is normally present in the blood at very low levels. In certain infections, LPS levels increase substantially, causing sepsis. LPS can also enter the blood during leaky gut or with certain types of fat .
LPS are found on the outer membrane of Gram-negative bacteria. Gram-negative bacteria, such as E. coli and Salmonella, are a type of bacteria that often cause health problems and resist antibiotics (many probiotics, on the other hand, are gram-positive bacteria).
Gram-negative bacteria colonize the respiratory, urinary, and GI tracts, including the mouth and gut. The largest concentrations are found in the gut.
LPS are large molecules that are composed of three distinct sections :
- O-antigen or O-specific chain (chain of many simple sugars, capable of being recognized by the immune system)
- Core oligosaccharide (a small chain of simple sugars)
- Lipid A (two glucosamine molecules bound to many fatty acids)
The fat component of LPS, called lipid A, is responsible for the toxic and inflammatory properties of LPS.
Lipid A is anchored to the cell membrane, while the rest of the LPS projects from the cell surface into the surrounding environment. However, once the bacteria dies, and the cell membrane falls apart, the lipid A is exposed and can cause damage .
Mechanism of Action
LPS is a potent stimulator of the immune system. If LPS remains in the gut, it doesn’t activate the immune system and cause harm. The ability of LPS to promote inflammation depends on its ability to enter the blood .
Besides infection, the two main ways LPS can enter the blood from the gut are leaky gut (increased intestinal permeability) and through fat-containing chylomicrons.
Chylomicrons are fat transporters responsible for the absorption and transfer of dietary fat and cholesterol from the gut to the blood. LPS bind to chylomicrons and can be carried through the gut wall into the blood .
Binding and transport of LPS by chylomicrons is a natural process that helps remove LPS and take it to the liver for detoxification. However, not all of the LPS transported by chylomicrons gets detoxified quickly, and some can remain unbound in the blood .
These transcription factors then stimulate the production of inflammatory cytokines TNF-a, IL-1b, IL-6, and CRP. LPS can also increase the production of nitric oxide, superoxide (a free radical), and eicosanoids (products of fat breakdown that increase inflammation, such as PGE2) .
An enzyme in the gut called alkaline phosphatase can remove phosphate groups from LPS, which reduces its inflammatory effects. If enzyme levels are low, less LPS is broken down and circulating LPS levels are increased .
Causes of Elevated Blood LPS Levels
The condition of elevated LPS in the blood (endotoxemia) occurs most severely during infection when large amounts of gram-negative bacteria enter the blood.
Hospitals measure their patients’ LPS levels to predict survival after an infection or procedure .
An example of an infection causing endotoxemia is periodontitis, where high levels of LPS from the mouth enter the blood and cause systemic inflammation .
Another common infection causing endotoxemia is Neisseria meningitidis, which can spread from the back of the nose and throat to elevate LPS levels throughout the body. This leads to meningococcal diseases such as inflammation of the membranes (meninges) surrounding the brain and spinal cord, or meningitis .
2) Leaky Gut
LPS are large molecules and are too big to pass through the tiny gaps in the gut of a healthy person. However, when the gut lining becomes damaged and bigger gaps arise, LPS can pass through this leaky gut into the blood.
In a study of 44 patients undergoing pancreas surgery, systemic LPS levels correlated with leaky gut in an almost perfectly linear relationship .
However, another study found that leaky gut caused by aspirin did not lead to increased LPS levels in the blood .
In mice, leaky gut causes increased LPS and systemic inflammation .
3) High-Fat Meals
In a study of 20 participants, consumption of two meals with an equivalent amount of calories (one with high fat, one with low fat) showed that the higher fat meal increased LPS, reactive oxygen species, and NF-κB activity .
In a study of 12 men, eating a mixed breakfast with 33% calories from fat increased LPS and the inflammatory cytokine IL-6 2 hours after the meal .
Increased levels of LPS in blood and chylomicrons were found 3 hours after consumption of 50 g fat (10 g saturated fat, 30 g monounsaturated fat, and 10 g polyunsaturated fat) in a study of 40 obese patients .
A person’s body fat may affect how their LPS levels respond to fat. In a study of 16 men, only obese individuals had higher post-meal LPS levels after 40 g of dairy fat compared to normal-weight people. The chylomicrons of obese people were more saturated with LPS than those of normal-weight people as well .
Similarly, in a study of 54 people, those with type 2 diabetes, impaired fasting glucose, and obesity had elevated LPS levels in response to a high-fat meal, while lean, healthy people did not. LPS levels increased by 124% in type 2 diabetes patients .
In a study (RCT) of 75 metabolic syndrome patients, a high saturated fat diet increased LPS levels compared to a high monounsaturated fat diet, a low-fat, complex carb diet, and a low-fat, complex carb diet supplemented with omega-3s .
In a study of 8 adults, a one-month high-fat (40% of total calories) and saturated fat (20% of total calories) diet increased LPS levels by 71%, compared to a low-fat, high-fiber diet in which LPS levels dropped by 31% .
In a study of 48 healthy people, 300 calories of pure cream increased LPS levels up to 5 hours after consumption, while equal calories of sugar, orange juice, and water did not .
In a study of 20 healthy adults, 16 g of coconut oil (82% saturated fat) increased LPS, but omega 3 consumption resulted in a lower LPS response. There were no LPS increase from grapeseed oil (omega-6 fatty acid) .
In a study of 28 people, 3 weeks of a diet high in the saturated fat palmitic acid increased blood TNF-a levels induced by LPS. However, consumption of a high-oleic acid (monounsaturated fat) diet for 3 weeks lowered LPS-induced IL-1b, IL-18, IL-10, and TNF-a .
Emulsified fat has had a compound (such as lecithin) added to it in order to mix more easily with water. Emulsifiers are common in many foods, including mayonnaise and ice cream. Emulsification also increases the ability of dietary fats to break down in the digestive system.
In a study (RCT) of 16 men, consuming 40 g of emulsified milk fat increased levels of LPS bound to chylomicrons, compared to consuming 40 g of non-emulsified milk fat .
In animals, consumption of emulsified sunflower oil elevated post-meal LPS levels more than non-emulsified sunflower oil. Emulsification increases the surface area of oil and facilitates fat absorption and storage into chylomicrons .
4) High-Calorie Diets
Overfeeding by 760 calories/day for 8 weeks increased LPS levels by 160% in a study of 18 healthy men. LPS was positively associated with IL-6 .
5) Excessive Alcohol Intake
Increased intestinal permeability (leaky gut) and higher circulating LPS levels were observed in a study of 54 patients with chronic alcohol abuse .
However, compared to nondrinkers, moderate alcohol consumption was associated with lower LPS levels in a study of 922 adults .
6) Gut Dysbiosis
Gut dysbiosis is an imbalance of the gut bacteria, where normally dominant species are reduced and/or normally reduced species are increased (such as small intestinal bacterial overgrowth, or SIBO).
In mice, probiotic bifidobacteria can reduce LPS levels by improving gut barrier function. In contrast, increasing the proportion of gram-negative bacteria can increase intestinal permeability and lead to higher blood LPS levels .
In a study of 30 healthy adults, subjects with lower fecal bacteroidetes levels had increased LPS levels .
In a study (RCT) of 39 women, those who completed a stressful task in the presence of a critical audience had greater LPS-stimulated production of TNF-a than those who performed the task without an audience .
In a study of 72 women, delivering a mock job interview followed by a difficult puzzle-solving task increased LPS-stimulated production of TNF-a and IL-6 .
8) Social Isolation
In a study of 115 participants, individuals more sensitive to social disconnection showed increased inflammatory molecules (TNF-a and interleukin-6) in response to LPS and increased activity of multiple inflammatory genes .
In two studies, participants who had more feelings of loneliness had greater LPS-stimulated production of TNF-a, IL-6, and IL-1 in response to a stressful task compared to those who were less lonely [41, 42].
9) Unpredictable Childhood Environment
Exposure to an unpredictable and stressful childhood environment was related to greater LPS-stimulated IL-6 production in a study of 135 adolescent girls .
A single smoked cigarette contains high levels of biologically-active LPS due to the bacteria on the tobacco leaves .
Possible Health Benefits of Low-Dose LPS Supplementation
There is some evidence from animal studies that oral administration of LPS may help in disease prevention by keeping immune cells called macrophages in alert mode. In this scenario, low-dose LPS “primes” macrophages to remove nearby waste products, without being strong enough to cause inflammatory cytokine release [46, 47].
More human research is needed to determine if this is an effective method of disease prevention.
Negative Effects of High LPS Levels
1) LPS Causes Fatigue
Fatigue is reliably caused in humans by the administration of LPS, as part of LPS-induced “sickness behavior” .
LPS increased fatigue and inflammation (TNF-a, IL-6) in a study (DB-RCT) of 11 healthy participants. Pre-treatment with citalopram (SSRI) prevented the increase in fatigue .
2) LPS Impairs Memory
In a study (DB-RCT) of 20 healthy men, intravenous LPS impaired verbal and nonverbal memory and increased anxiety and depression. Inflammatory cytokine secretion was associated with a decrease in memory performance .
Administration of LPS increased anxiety, depression, cortisol, and blood norepinephrine in a study (DB-RCT) of 34 men. Low-dose LPS impaired long-term memory, while high-dose LPS increased reaction time. The authors stated that inflammation may increase short-term alertness, although this is speculative on their part .
3) LPS Impairs Social and Emotional Processing
In a study (DB-RCT) of 115 healthy people, LPS decreased participants’ ability to accurately understand the emotional state of a person by looking at their eyes .
In a study (DB-RCT) of 18 men, LPS administration worsened mood and increased anxiety. LPS also increased the activation of the right inferior orbitofrontal cortex in response to emotional visual stimuli. This brain region is associated with fear and anger recognition, so increased activity may have increased negative emotions towards the stimuli .
4) LPS Causes Social Disconnection
Injection of LPS increased feelings of social disconnection, depression, and inflammation (IL-6, TNF-a) in a study (DB-RCT) of 39 participants .
LPS increased fatigue and decreased vigor and social interest in a study (DB-RCT) of 10 healthy people .
5) LPS Lowers Ability to Experience Pleasure or Reward
Injection of LPS increased depressed mood and lowered the brain response to monetary reward cues (decreased ventral striatum activity) in a study (DB-RCT) of 39 participants .
In animals, LPS consistently lowered preference for palatable foods, stimulation-seeking behavior, and exploration of new environments .
6) LPS Disturbs Sleep
LPS also lowered non-REM sleep and increased sleepiness during the day in a study of 10 men .
7) LPS Causes Fever
8) LPS Is Associated with Poor Female Reproductive Health
In a study of 45 women undergoing in vitro fertilization treatment, LPS levels were positively associated with ovarian inflammation and negatively associated with progesterone production. Ovarian inflammation and progesterone deficiency indicate impaired reproductive health and are associated with infertility [61, 62].
9) LPS Reduces Appetite
10) LPS Lowers Pain Tolerance
In a study of 11 healthy men, LPS administration increased sensitivity to rectal pain and lowered pain tolerance .
How to Measure LPS
The best measurement of LPS is blood LPS-binding protein (LBP). Although direct measurement of LPS is possible, LBP is generally considered a more reliable, accurate, and better biomarker of total bacterial load .
Produced mainly in the liver, LBP binds to LPS and amplifies immune responses. Thus, LBP is a biomarker of both LPS load and the associated innate immune response .
Dietary modification of gut bacteria due to lifelong calorie restriction reduced LPB in mice .
In patients with a bacterial infection, LBP levels were 33.41 mg/L, compared to 5.61 mg/L in healthy patients .
In healthy, normal-weight adolescents, LBP levels were 6 mg/L, compared to 7.8 mg/L in overweight and obese youth .
Diseases Linked with Elevated LPS
Elevated LPS is associated with an increased risk of developing diabetes .
Individuals with type 1 diabetes have 235.7% higher LPS levels than those without diabetes. Similarly, people with type 2 diabetes have 66.4% higher LPS levels than non-diabetic controls .
Impaired lipoprotein metabolism in type 2 diabetes patients reduces LPS breakdown and may increase LPS-related inflammation .
In a study of 477 patients with type 1 diabetes, high LPS activity was associated with the development of diabetic kidney disease .
3) Metabolic Syndrome
Metabolic syndrome is a group of factors that increase the risk of heart disease. These include high blood pressure, high blood sugar, high triglycerides, abdominal obesity, and low HDL cholesterol .
In a study of 192 ethnically-diverse adults, LPS levels were positively associated with waist circumference, waist-to-hip ratio, total cholesterol, triglycerides, and insulin levels and negatively associated with HDL-cholesterol .
4) Heart Disease
LPS levels are consistently increased in patients with heart disease and hardening of the arteries .
Among patients with high fasting blood sugar levels, LPS was positively associated with platelet activation in a study of 70 patients. Increased platelet activation contributes to blood clotting, which may increase heart disease risk .
5) Non-Alcoholic Fatty Liver Disease
People with non-alcoholic fatty liver disease had elevated LPS levels in a study of 922 adults. Interestingly, modest alcohol consumption was associated with lower levels of LPS .
6) Inflammatory Bowel Disease
In studies of 168 patients, LPS levels were greater in patients with chronic fatigue syndrome and were positively associated with symptom severity, including fatigue, concentration problems, and failing memory [83, 84].
Higher LPS levels increased the risk of colorectal tumors in a study of 462 adults .
LPS also increased the ability of colorectal cancer cells to spread .
LPS administration consistently increased depression in numerous studies .
TNF-alpha production is increased in the hippocampus of animals after LPS injection. This activation of immune cells in the brain is believed to contribute significantly to the selective brain cell injury associated with depression .
In a study of 9 participants, glucose metabolism (energy use) was increased in the insula and decreased in the cingulate cortex due to LPS-induced inflammation .
The insula is associated with negative emotions, while the cingulate is associated with positive mood. Thus, increased energy use by the insula and reduced energy use by the cingulate may both promote negative feelings.
10) Alzheimer’s Disease
Levels of LPS and inflammatory cytokines were positively associated with Alzheimer’s disease in a study of 69 patients .
Similarly, antibodies to periodontal gram-negative bacteria were associated with Alzheimer’s disease risk in a study of 158 participants .
11) Parkinson’s Disease
In a study of 19 individuals, patients with Parkinson’s disease showed elevated intestinal permeability and LPS levels in their gut compared to healthy participants .
In one study, LPS levels were higher in autistic compared to healthy individuals. LPS was also associated with worse social interaction among those with autism .
Transport of LPS from the gut to the blood is associated with a more rapid progression of HIV infection .
14) Retinal Disease
Pigment cells of the retina died due to exposure to LPS-induced inflammatory cytokines (IL-6 and IL-8) .
How to Decrease LPS and LPS-Related Inflammation
In three studies (DB-RCTs) of 119 obese and diabetic patients, inulin/oligofructose consumed daily for 8 to 12 weeks lowered LPS levels and inflammation, and increased bifidobacteria (beneficial gut bacteria) and blood sugar control [95, 96, 97].
Inulin-like fructans increased Bifidobacterium levels, which was associated with lower LPS levels in a study (DB-RCT) of 30 obese women .
In a study (RCT) of 30 patients with cirrhosis (liver damage), Lactobacillus GG taken for 8 weeks lowered LPS and TNF-alpha levels .
In a study (RCT) of 30 triathletes, daily supplementation of 30 billion CFU Lactobacillus and Bifidobacterium strains for 12 weeks reduced LPS pre-race and six days post-race .
In a study (DB-RCT) of 50 women given probiotics and a Japanese herbal medicine (Bofutsushosan), increased gut levels of the probiotic Bifidobacterium breve were linked to lower levels of LPS .
B. infantis 35624 reduced TNF-alpha and IL-6 production caused by LPS in a study (DB-RCT) of 22 healthy participants .
Grape extract rich in polyphenols lowered blood LPS in a study of 29 adults .
In a study of 10 healthy people, consumption of a resveratrol and grape polyphenol drink suppressed the LPS, oxidative stress, and inflammatory stress response to a high-fat, high-carbohydrate meal .
In mice, a polyphenol-rich cranberry extract reduced LPS response to a high-fat meal .
4) Red Wine
Red wine consumption for 20 days increased Bifidobacterium and Prevotella bacteria levels, which were associated with reduced LPS levels in a study of 10 men .
Red wine polyphenols decreased LPS producing-bacteria and increased the number of fecal Bifidobacterium and Lactobacillus (gut barrier protectors) and butyrate-producing bacteria in a study (RCT) of 20 individuals .
5) Omega-3 Fatty Acids
High-dose omega-3 supplementation (3.6 g/day) reduced fever and moderately reduced inflammatory cytokines due to LPS administration in a study (DB-RCT) of 60 healthy people .
Omega-3 supplementation (2.5 g/day) lowered LPS-stimulated IL-6 production and anxiety symptoms in a study (RCT) of 68 participants .
In mice, omega 3 supplementation and omega-6 reduction increased the production of alkaline phosphatase, caused favorable changes in gut bacteria composition, and lowered LPS production, gut permeability, and inflammation .
6) Olive Oil
A high-phenol olive oil breakfast limited the increases in LPS and inflammatory cytokines (NF-κB, IL-6, IL-1b, and CXCL1) .
In a study of 28 people, consumption of a diet high in palmitic acid for 3 weeks increased blood TNF-a levels caused by LPS. However, consumption of a high-oleic acid (the main fat in olive oil) diet for 3 weeks lowered LPS-induced IL-1b, IL-18, IL-10, and TNF-a .
7) Orange Juice
In a study (RCT) of 65 overweight men, consumption of a high-fat meal including peanuts lowered LPS levels compared to the same high-fat meal without peanuts. Consuming peanuts high in oleic acid had the strongest effect .
Using a nicotine patch increased the anti-inflammatory response (increased cortisol and IL-10) to intravenous LPS in a study of 12 healthy men .
Sedentary people have higher blood LPS levels than highly-trained people .
Participation in a 12-week interval exercise program lowered LPS levels in a study of 20 obese women .
A single session of high-intensity interval training lowered LPS-stimulated TNF-alpha release immediately following and one hour after exercise in a study of 19 participants .
However, exercise has also been shown to increase intestinal permeability and LPS levels in the short-term .
12) Vagus Nerve Stimulation
13) Meditation, Breathing, and Cold Exposure
In a study (RCT) of 24 healthy participants, activation of the sympathetic nervous system by one week of meditation, breathing exercises, and immersion in ice-cold water reduced inflammation caused by LPS .
In a study of 20 cirrhosis patients with impaired cognitive and motor function due to liver failure (minimal hepatic encephalopathy), rifaximin (an antibiotic) lowered LPS levels and improved cognitive function .
Colistin (an antibiotic) reduced LPS-induced inflammation (IL-6, IL-8, TNF-a) in a study (DB-RCT) of 15 people .
Misoprostol is a drug used to treat stomach ulcers by binding to the prostaglandin (PGE1) receptor. This type of prostaglandin reduces inflammation.
Misoprostol reduced LPS-induced TNF-a production and increased IL-10 production in a study of 9 people .
Lactoferrin is a protein found in milk, tears, and saliva that is part of the immune system and protects against bacteria and fungi.
Lactoferrin binds to LPS on bacteria and makes them more susceptible to destruction by the immune system or antibiotics. Additionally, lactoferrin binds to free-floating LPS and prevents it from causing inflammation .
In a cell study, lactoferrin prevented the production of the pro-inflammatory cytokine IL-8 caused by Escherichia coli LPS .