What is LPS? Lipopolysaccharide (LPS) is a sugar-based macromolecule that makes up the outer cellular membrane of some species of bacteria, such as Salmonella, pathogenic E. coli and others. Due to its molecular features, which are recognized by the human immune system and trigger inflammatory immune responses, LPS is also often called endotoxin. Genetic factors, diet and the gut microbiome all contribute to a person’s risk for inflammation-related health issues caused by LPS. In this article we’ll explore LPS and gastrointestinal disease and steps you can take to promote a healthy microbiome and reduce the likelihood of LPS-associated disease.

What is LPS?

LPS, or lipopolysaccharide, is a sugar molecule produced by some species of bacteria that is necessary for the ability of bacteria to cause disease. The primary purpose of LPS is to act as a barrier against environmental stressors, like the presence of antibiotics. In humans, LPS plays a detrimental role in stimulating the immune system. The problem is not just LPS in general, but the specific species of Gram negative bacteria — since some species produce LPS variations that are less immunogenic than others. LPS in our system leads to a type of pre-programmed cell death called pyroptosis. The chronic loss of intestinal epithelial tissue and inflammation caused by the presence of LPS is associated with the development of many types of diseases.

The most common types of diseases associated with LPS are septic shock and endotoxemia, conditions that most commonly occur in patients who experience chronic exposure to LPS. In a condition known as metabolic endotoxemia, chronic LPS exposure alters the structure of epithelial cells in the gastrointestinal (GI) tract, compromising the protective barrier they create. After the intestinal barrier is compromised, LPS leaks into the bloodstream, causing systemic low-grade inflammation and the development of cardiometabolic disease. LPS has also been associated with or directly linked to several other chronic diseases:

• Inflammatory bowel disease (IBD)
• Diabetes
• Obesity
• Non-alcoholic fatty liver disease (NAFLD)
• Chronic kidney disease
• Various mental health disorders 

Risk factors for LPS-mediated inflammation and disease

• Genetically-linked conditions, such as IBD or obesity, can cause environmental conditions in the gut that promote an imbalanced gut microbiome with an outgrowth of specific species that produce LPS.
  
  
• Lifestyle factors, which include poor dietary choices along with pre-existing health conditions, are associated with LPS induced inflammation. Some of these risk factors include antibiotic usage (note: you should always take antibiotics when your doctor prescribes them, but always take them as directed and never take them if your doctor hasn’t prescribed them); alcohol consumption; and consumption of a high-fat, low-fiber (i.e., Western) diet. 

LPS and metabolic disease

The relationship between metabolic disease, LPS-mediated inflammation and gut dysbiosis is complex and bidirectional. Because LPS is derived from bacteria, it mostly comes from our gut microbiomes. A number of different bacterial species can produce LPS, and studies have shown that LPS from different bacteria can have more severe or more mild impacts on the immune system. LPS produced by one species can even block the immune system from reacting to LPS produced by another species. 

Healthy individuals rarely have large amounts of LPS-producing bacteria in their guts (and if they do, they are of the sort that produces LPS variations that have a reduced ability to elicit an immune response and are held in check by other members of the microbiome). But when something such as disease, certain medications or poor diet causes the microbiome to become imbalanced, conditions favoring inflammation can occur. This can manifest in a number of different ways:

• Obesity: Obesity is associated with low-grade chronic inflammation, which appears to be associated with microbiome imbalances promoted by a high-fat diet.
  
  
• Diabetes: Studies have detected higher levels of LPS, in addition to several other markers of inflammation, in the blood of individuals with type 2 diabetes compared with those without diabetes. Similarly, these individuals suffer from poor lipid and glycemic control.
  
  
• IBD: This disorder results from a complex interplay between genetic predisposition and environmental factors such as diet and the gut microbiome. Interestingly, some of the genetic elements linked to IBD include genes associated with cellular adhesion (how well cells stick together) and the immune system. Mutations in these genes increase intestinal permeability (also known as “leaky gut”) and facilitate the transfer of LPS across the intestinal barrier and into the circulation, causing systemic inflammation and worsening of symptoms. Because tight junctions (TJs) between cells (maintaining a healthy barrier) are found in other tissues, including the brain, the resulting systemic inflammation could have widespread effects. In fact, many studies have observed mood and anxiety disorders in IBD patients.

Eating for gut health

The old adage, “food is medicine,” is more than just a cliché. The typical Western diet is generally considered the primary culprit for microbiome dysbiosis that can lead to a number of health conditions, including LPS that promote systemic inflammation and resulting disease. In fact, several dietary factors have been associated with LPS in the gut:

• The general Western diet (high-fat, high-sugar, low-fiber)
• Animal-based protein 
• Saturated fatty acids 
• Sweeteners like Sucralose 
• Emulsifiers 

Fortunately, diet is one of the fastest ways we can change our gut microbiomes. Although the scientific community does not know the precise interactions that govern microbial associations or metabolism, hundreds of studies all seem to agree that an overall, balanced diet containing plentiful amounts of the following foods is associated with a healthier gut:

• Fruits and vegetables 
• Fermented foods
• Nuts 
• Polyunsaturated and monounsaturated fatty acids
• Polyphenols 

The Mediterranean diet, which has been linked to several measures of improved health over decades of study, is rich in fiber-rich whole fruits and vegetables, nuts and seeds and healthy fats — which combined are associated with promoting a microbiome associated with significantly lower irritation related to LPS levels. The Mediterranean diet has also been shown to alleviate GI tract discomfort in LPS-mediated inflammation. A recent study has specifically shown that following the Mediterranean diet reduces GI tract discomfort propitatied by LPS induced inflammation. 

Researchers are also exploring whether other dietary components and interventions, such as probiotics or prebiotics, can help promote GI health:

• Probiotics that contain bifidobacteria have been shown to prevent LPS-associated disease by preventing gut barrier-disrupting inflammation. 
  
  
• Beyond the whole foods that contain prebiotics, like the vegetables and fruits so plentiful in the Mediterranean diet, certain prebiotic supplements may also play a role in reducing gut inflammation by promoting the growth of bacterial species that suppress LPS-producing bacteria. 

Key takeaways

When your gut microbiome becomes imbalanced, it is difficult for “good” bacteria to keep potential harmful bacteria in check. This can lead to the presence of a bacterial molecule called LPS (lipopolysaccharide), which can cause inflammation linked to several chronic diseases — including IBD, diabetes, obesity and more. The species identity of the GI microbiome can introduce LPS variations produced by specific types of bacteria that cause inflammation more than others. Because of the intimate connection between the microbiome, diet and gut health, much research has focused on dietary interventions to keep our microbiomes healthy. Developing a healthy GI microbiome (via yet-to-be-studied mechanisms) promotes “benign LPS” in the gut. The Mediterranean diet, so rich in healthy fats and nutrients, promotes a healthy GI tract typically characterized by lower levels of “LPS-related irritation.” Certain studies suggest that probiotics might help, too; but probiotics alone are not sufficient if a poor diet is continued. So, why not sit back and enjoy that healthy arugula, almond, avocado, melon and mint salad?!