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14 Factors that May Reduce Lipopolysaccharides (LPS)

Written by Matt Lehrer, PhD | Last updated:
Biljana Novkovic
Puya Yazdi
Medically reviewed by
Biljana Novkovic, PhD, Puya Yazdi, MD | Written by Matt Lehrer, PhD | Last updated:

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Increased gut permeability may let LPS sneak into the bloodstream

Lipopolysaccharides or LPS are bacterial toxins that can health issues if they reach the bloodstream. Normally housed safely in the gut, lipopolysaccharides can enter the blood if you have an infection, “leaky gut”, or eat too many fatty foods.

Read on to learn about the potential health risks of lipopolysaccharides and which factors may help reduce them.

Potential Health Risks of High LPS Levels

The conditions we discuss here are commonly associated with high LPS levels, but this single symptom is not enough for a diagnosis.

Because they have been studied in cohort studies, we cannot conclude for certain that high LPS levels caused these conditions.

Work with your doctor to discover what underlying condition might be causing your high LPS levels and to develop an appropriate plan to improve your health.

1) Fatigue

Fatigue is reliably caused in humans by the administration of LPS, as part of LPS-induced “sickness behavior” [1].

LPS increased fatigue and inflammation (TNF-a, IL-6) in a small trial with 11 healthy participants. Pre-treatment with citalopram (SSRI) prevented the increase in fatigue [2].

In studies of 168 patients, LPS levels were greater in those with chronic fatigue syndrome and were associated with symptom severity, including fatigue, concentration problems, and failing memory [3, 4].

2) Poor Memory

In a small trial on 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 [5].

Administration of LPS increased anxiety, depression, cortisol, and blood norepinephrine in another trial on 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 [6].

3) Anxiety and Low Empathy

In a clinical trial on115 healthy people, LPS decreased participants’ ability to accurately understand the emotional state of a person by looking at their eyes [7].

In a small trial on 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 [8].

Scientists can experimentally induce fatigue, impaired memory, and anxiety with LPS, but more research is needed.

4) Depression and Social Disconnection

LPS administration consistently increased depression in numerous studies [9].

Injection of LPS increased feelings of social disconnection, depression, and inflammation (IL-6, TNF-a) in a trial of 39 participants [10].

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 [11].

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 [12].

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.

LPS increased fatigue and decreased vigor and social interest in a trial on 10 healthy people [13].

5) Inability to Experience Pleasure

Injection of LPS increased depressed mood and lowered the brain response to monetary reward cues (decreased ventral striatum activity) in a clinical trial on 39 people [14].

In animals, LPS consistently lowered preference for palatable foods, stimulation-seeking behavior, and exploration of new environments [9].

In small human experiments, LPS seems to impair mood, social behavior, and the ability to feel pleasure; large-scale data are lacking.

6) Disturbed Sleep

LPS disrupted sleep and lowered REM sleep in healthy humans [15, 16].

LPS also lowered non-REM sleep and increased sleepiness during the day in a study of 10 men [17].

7) Fever

Fever is a sign of elevated LPS levels. LPS stimulates the release of prostaglandins (PGE2), which bind to their receptors in the hypothalamus to raise body temperature [18].

8) Poor Reproductive Health in Women

In a study of 45 women undergoing in vitro fertilization treatment, LPS levels were associated with ovarian inflammation and reduced progesterone production. Ovarian inflammation and progesterone deficiency indicate impaired reproductive health and are associated with infertility [19, 20].

9) Reduced Appetite

In humans, low-dose LPS reduced food intake in the first 4 hours. Reductions in food intake were associated with blood levels of TNF and IL-6 [5, 21].

LPS is hypothesized to disturb sleep, reproductive health, and appetite, but only preliminary findings are available.

10) Low Pain Tolerance

In a study of 11 healthy men, LPS administration increased sensitivity to rectal pain and lowered pain tolerance [22].

LPS also decreased tolerance to pressure, mechanical pain, and cold, in a clinical trial of 59 healthy men [23].

11) Diabetes

Elevated LPS is associated with an increased risk of developing diabetes [24].

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 [25].

Impaired lipoprotein metabolism in type 2 diabetes patients reduces LPS breakdown and may increase LPS-related inflammation [26].

In a study of 477 people with type 1 diabetes, high LPS activity was associated with the development of diabetic kidney disease [27].

12) Obesity

LPS activity and LPS binding protein were associated with obesity in a study on over 3,500 adults [28, 29].

LPS given to mice for 4 weeks caused a weight gain comparable to that induced by a high-fat diet [30].

13) 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 [31].

In a study of 192 ethnically-diverse adults, LPS levels were associated with increased waist circumference, waist-to-hip ratio, total cholesterol, triglycerides, and insulin levels, and reduced HDL-cholesterol [32].

LPS activity and LPS-binding protein were associated with metabolic syndrome in a study on over 3,500 adults [28, 29].

LPS has been linked with obesity, diabetes, and metabolic syndrome, but whether it causes any of these conditions is unknown.

14) Heart Disease

LPS levels are consistently increased in patients with heart disease and hardening of the arteries [33].

Among patients with high fasting blood sugar levels, LPS was associated with platelet activation in a study of 70 patients. Increased platelet activation contributes to blood clotting, which may increase heart disease risk [34].

15) Non-Alcoholic Fatty Liver Disease

People with non-alcoholic fatty liver disease had elevated LPS levels in a study of over 900 adults. Interestingly, modest alcohol consumption was associated with lower levels of LPS [35].

16) Inflammatory Bowel Disease

High levels of LPS are consistently seen in patients with inflammatory bowel disease (IBD) [36, 33].

Elevated LPS was found in 94% of Crohn’s disease patients and 88% of ulcerative colitis patients in a study of 64 patients. Additionally, IBD severity was associated with LPS levels [37].

17) Cancer

Higher LPS levels were associated with an increased incidence of colorectal tumors in a study of 462 adults [38].

LPS also increased the ability of colorectal cancer cells to spread [39].

18) Alzheimer’s Disease

High levels of LPS and inflammatory cytokines were associated with Alzheimer’s disease in a study of 69 patients [40].

Similarly, antibodies to periodontal gram-negative bacteria were associated with Alzheimer’s disease in a study of 158 participants [41].

19) 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 [42].

20) Autism

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 [43].

21) HIV

Transport of LPS from the gut to the blood is associated with a more rapid progression of HIV infection [44].

22) Retinal Disease

Pigment cells of the retina died due to exposure to LPS-induced inflammatory cytokines (IL-6 and IL-8) [45].

Can Low-Dose LPS Ever Be Good?

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.

How to Reduce Lipopolysaccharides (LPS) and Inflammation

The following lifestyle changes may help you reduce the inflammatory response triggered by LPS. Discuss with your doctor if any of these strategies may help in your case. Never implement them in place of what your doctor recommends or prescribes.

1) Prebiotics

In three clinical trials 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 [48, 49, 50].

Resistant starch lowered LPS, oxidative stress, and insulin resistance in another trial of 56 women with type 2 diabetes [51].

Inulin-like fructans increased Bifidobacterium levels, which was associated with lower LPS levels in a trial on 30 obese women [52].

2) Probiotics

In a trial on 30 patients with cirrhosis (liver damage), Lactobacillus GG taken for 8 weeks lowered LPS and TNF-alpha levels [53].

In another trial 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 [54].

In a trial on 44 HIV patients, 12-week treatment with Saccharomyces boulardii reduced LPS and systemic inflammation (IL-6) [55].

In a trial on 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 [56].

B. infantis 35624 reduced TNF-alpha and IL-6 production caused by LPS in a trial of 22 healthy participants [57].

Both pre- and probiotic supplementation has been linked with lower LPS levels, but larger trials are needed.

3) Polyphenols

Grape extract rich in polyphenols lowered blood LPS in a study of 29 adults [58].

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 [59].

In mice, a polyphenol-rich cranberry extract reduced LPS response to a high-fat meal [60].

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 [61].

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 trial of 20 individuals [62].

Remember that the potential health effects of red wine may be outweighed by the multiple risks of alcohol, especially if consumed in high amounts.

5) Omega-3 Fatty Acids

High-dose omega-3 supplementation (3.6 g/day) reduced fever and moderately lowered inflammatory cytokines due to LPS administration in a trial of 60 healthy people [63].

Omega-3 supplementation (2.5 g/day) lowered LPS-stimulated IL-6 production and anxiety symptoms in another trial of 68 participants [64].

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 [65].

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 clinical trial on 49 people with metabolic syndrome [66].

In a study of 28 healthy and obese 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 [67].

7) Orange Juice

When consumed with a high-fat meal, orange juice prevented the increase in LPS, oxidative stress, and inflammation compared to water or sugar water in a clinical trial on 30 people [68].

8) Peanuts

In a trial 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 [69].

9) Bilberries

Consumption of 400 g/day of bilberries for 8 weeks reduced LPS, CRP, IL-6, and IL-12 in a small trial of 27 participants [70].

10) Exercise

Sedentary people have higher blood LPS levels than highly-trained people [71].

Participation in a 12-week interval exercise program lowered LPS levels in a study of 20 obese women [72].

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 [73].

However, exercise has also been shown to increase intestinal permeability and LPS levels in the short-term [74].

11) Vagus Nerve Stimulation

In a small trial of 20 people, the use of a noninvasive vagus nerve stimulator (gammaCore) 3 times in one day increased anti-inflammatory cytokine (IL-10) levels in response to LPS [75].

Vagus nerve stimulation by acetylcholine lowered the release of inflammatory cytokines (TNF-a, IL-1B, IL-6, IL-8) in macrophage cells [76].

12) Meditation, Breathing, and Cold Exposure

In a trial 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 [77].

13) Lactoferrin

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 [78].

In a cell study, lactoferrin prevented the production of the pro-inflammatory cytokine IL-8 caused by Escherichia coli LPS [79].

14) Activated Charcoal

In one study, activated charcoal completely removed LPS from human plasma (the liquid component that’s left after red and white blood cells and platelets are removed from blood). This result suggests that activated charcoal can bind to and remove LPS [80].

Use caution, however: charcoal does not cross the intestinal barrier, so it can only remove LPS from the intestine. Any toxins that have crossed into the bloodstream are beyond the reach of activated charcoal.

In addition, charcoal is a powerful adsorbent that also binds to (and prevents absorption of) important vitamins and other nutrients. If you use activated charcoal often, you may risk nutrient deficiency. Never take activated charcoal without consulting your doctor [81, 82, 83].

For a deep dive into activated charcoal’s strengths and limitations, check out this post.

Experimental

The factors listed below are not recommended. We bring them up for informational purposes. Do not take any drugs unless recommended by your doctor. 

Nicotine

Using a nicotine patch increased the anti-inflammatory response (increased cortisol and IL-10) to intravenous LPS in a study of 12 healthy men. The only medically acceptable use of nicotine patches is for smoking cessation, though [84].

However, keep in mind that nicotine causes addiction, withdrawal syndrome, and adverse effects such as headaches, nausea, accelerated heartbeat, muscle pain or stiffness, and problems sleeping.

Needless to say, the multiple health risks of smoking cigarettes outweigh the potential benefit of nicotine to reduce LPS-induced inflammation.

Antibiotics

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 [85].

Colistin (an antibiotic) reduced LPS-induced inflammation (IL-6, IL-8, TNF-a) in a study of 15 people [86].

Importantly, never take antibiotics unless prescribed by a doctor. Taking antibiotics when you don’t need them can make bacteria develop resistance.

Misoprostol

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 [87].

Misoprostol may help reduce LPS-induce inflammation if you are already on this medication, but never start taking it or increase your dose for this reason. Always follow the treatment plan prescribed by your doctor.

Takeaway

Lipopolysaccharides (LPS) are bacterial toxins that may enter the blood if you have an infection or “leaky gut.”

Limited research has associated LPS with many chronic health problems–from heart disease to diabetes to IBS to sleep issues.

These small particles are thought to trigger systemic inflammation and other nonspecific symptoms. For example, scientists can use LPS to experimentally induce fatigue, poor memory, anxiety, and social disconnection.

However, more research is needed to understand if LPS plays a significant role in causing any disease.

Potential healthy ways to reduce LPS include cooking with olive oil and eating foods high in pre- and probiotics, polyphenols, and omega-3 fatty acids. Meditation and vagus nerve stimulation might also help, according to limited research data.

Learn More

About the Author

Matt Lehrer

Matt Lehrer

PhD
Matt is a PhD candidate at The University of Texas at Austin and has a MS from The University of Texas at Austin.
As a scientist, Matt believes his job is not only to produce knowledge, but to share it with a wide audience. He has experience in nutritional counseling, personal training, and health promotion.

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