Hexa-acylated Lipopolysaccharide: How this key metabolite plays a role in inflammation

Author: Anita Tait

March 2021

Could the gut microbiome play a part in inflammation?

Research linking the gut microbiome with diet and disease has come a long way in the last decade. This scientific evidence is currently in a new era with advancements in technology allowing us to accurately measure the abundance and amount of microorganisms as well as their genetic potential to reveal the functions of the gut microbiome. We know the microbes living in our gut produce thousands of compounds called metabolites which act systemically throughout the entire body in ways that can be detrimental or beneficial to health.

Hexa- acylated lipopolysaccharide (hexa-LPS) is one of these metabolites which has been shown to trigger immune activation and systemic inflammation. High levels of hexa-LPS in the blood have been observed in individuals with metabolic and inflammatory conditions such as obesity, heart disease, type 2 diabetes, non-alcoholic fatty liver disease and Alzheimer’s Disease¹.

 

How does our gut microbiome produce Hexa-LPS?

Each bacterial species has its own unique LPS (lipopolysaccharide) signature located within the cell wall. LPS, also known as an endotoxin, is recognised by toll-like receptors (TLR) on immune cells with the lipid A component of LPS being the most important component in terms of interaction with the immune system². Most species of bacteria within the Proteobacteria phylum produce lipid A with 6 (hexa) or 7 (hepta) fatty acids acyl chains which have strong immunostimulatory power².

 

 

To identify pathogenic bacteria immune cells have a TLR4/MD-2 complex that binds to the lipid component of LPS². If the LPS has 6 or more acyl chains (hexa-acylated) the sixth acyl chain interacts with a second TLR4 triggering activation of the inflammatory cascade resulting in the generation of pro-inflammatory cytokines².

Inversely, our commensal bacteria contain different LPS signatures, which often contain 5 or less fatty acid acyl chains. Without this 6^th fatty acid acyl chain the TLR4/MD-2 complex does not trigger the inflammatory cascade resulting in immune tolerance. This is how our immune system learns to live in harmony with our commensal and good bacteria while reacting to pathogens.

 

 

It is important to consider that hexa-acylated LPS isn’t a problem until it crosses the gut barrier to interact with the immune system in the systemic circulation. In particular, saturated fat has been shown to help LPS cross the intestinal barrier and enter the bloodstream³. Research shows that saturated fat increases postprandial blood LPS levels while omega-3 fatty acids decrease postprandial blood LPS levels³. This is where diet can play an integral role in terms of clinical interventions when the potential for the gut microbiome to produce hexa-LPS is shown to be higher than the optimal range.

The Insight gut microbiome analysis identifies individuals whose microbiomes have a high potential to produce hexa-LPS which allows for targeted dietary interventions for patients at risk of or with existing inflammatory conditions.

 

What dietary interventions can reduce hexa-LPS production?

If the microbial potential to produce hexa-LPS is found to be sitting in the high range within an Insight gut microbiome analysis result, personalised dietary recommendations include limiting saturated fat intake and maximising omega-3 fatty acid and fibre intake.  These recommendations also align with Mediterranean dietary patterns which are backed up by an abundance of long-standing scientific research highlighting the links to positive health outcomes^8,9.

 

Limiting saturated fat

Limiting saturated fat in clinical practice is commonplace when it comes to recommendations for a healthy diet and reducing the risk of Cardiovascular Disease. Therefore, these interventions are not necessarily a new concept for many Healthcare Practitioners, however, targeting this intervention based on the gut microbiome can maximise effectiveness.

Avoiding excessive intake of saturated fat can help reduce the ability of hexa-LPS to enter the bloodstream³. Reducing saturated fat within the diet can be achieved through the reduction of foods such as processed meats, butter, high-fat dairy (ice-cream), ultra-processed snack foods (biscuits, cakes chocolate), coconut oil and tropical oil-based products.  The Suggested Dietary Target for saturated and trans-fat recommends limiting intake to less than 10% of total daily energy intake⁷.

 

Increasing omega-3 fatty acids

Inversely, increasing omega-3 fatty acids to optimal levels through long term dietary patterns rich in fish has been shown to be associated with lower plasma LPS levels⁴. The three main omega-3 fatty acids that have been shown to have anti-inflammatory properties include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Increasing dietary sources of omega-3 fatty acids can include foods such as oily fish (canned sardines or salmon) and for those individuals on a vegan or vegetarian diet flaxseeds, flaxseed and canola oil, chia, walnuts, soybean and soy products. Algae supplements can also be an excellent way of increasing EPA and DHA types of omega 3 fatty acid for those who do not eat fish.

The Heart Foundation provides useful guidelines for the recommended amount of omega-3 fatty acids which suggest consuming 250-500mg of EPA/DHA per day (2-3 serves of oil fish per week) and 1 gram of ALA per day (1 teaspoon of flaxseed oil or 3 teaspoons of flaxseeds)⁵.

 

 

Another dietary intervention to consider includes increasing fibre intake from a range of fruits, vegetables and wholegrains. Research shows that increasing fibre intake protects the gut barrier which prevents LPS from crossing the gut barrier and reduces inflammation.  A dietary intervention study showed that consuming 3 serves of fruit and vegetables or 3 serves of wholegrains per day resulted in a reduction in the marker of LPS and inflammation in the blood⁶.

​In addition, we have a growing body of evidence that suggests that the metabolites butyrate and 3-indolepropionic acid (IPA) are associated with an improved gut barrier function.  Studies have indicated that consuming foods high in dietary fibre, and in particular rye (found in bread, pumpernickel, cereals, crackers) can help increase IPA production¹⁰. While consuming foods high in resistant starch¹¹ (found in lentils, peas, beans, cooked and cooled potatoes, rolled oats) have been shown to increase butyrate levels.

 

Summary

Research confirming the link between the gut microbiome and disease is allowing us to broaden the scope of clinical conditions that are associated with the gut microbiome. We can now broaden our thinking to investigate the function of the gut microbiome for not only those patients with gut symptoms but for those that have an existing chronic disease and those that may be at risk of developing inflammatory or metabolic conditions.

In particular, gut microbiome analysis can measure the genetic potential for the production of hexa-LPS which we know has a central role to play in immune activation and systemic inflammation as well as a range of different metabolic and inflammatory conditions. Dietary interventions such as increasing omega-3 fatty acids, decreasing saturated fat and increasing prebiotic fibre can help to reduce LPS blood levels, reduce inflammation and keep our precious gut barrier healthy.

Insight into the gut microbiome to bring about more detailed and more personalised dietary interventions just may be what individuals need as a key motivator for behaviour change which we know is the key to the kingdom when it comes to creating positive health outcomes.