Leaky Gut, Autoimmunity, and Lipopolysaccharide (LPS) – Oh My!

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Harm from one kind of bacteria, healing from another

What’s LPS, and why should I care?

Lipopolysaccharide, or LPS, is the major component of the outer membrane of gram-negative bacteria. LPS contributes to the structural integrity of the bacteria, protecting the membrane from certain kinds of chemical attack. LPS is of crucial importance to gram-negative bacteria, and for the most part, it remains associated with the cell wall until disintegration of the organism.

LPS is also known as endotoxin, which, as the name implies, is toxic. So, while LPS is a good and necessary thing for the bacteria they’re found on, they can be harmful to us humanoids, although small amounts are necessary for stimulation of normal immunity. These products of bacterial die-off not only stimulate a further immune response and inflammation, they also can adversely affect organ and systemic function, sometimes critically.[1],[2] A Jarisch-Herxheimer reaction (also commonly referred to as “Herxing” or “die-off”) is the symptoms that transpire due to the uncontrolled release of endotoxin, as well as endotoxin-like products, during lysis of the gram-negative bacteria which many natural and pharmaceutical antibiotics impact.[3]

Molecular mimicry: how LPS can trigger an autoimmune response

Lipooligosaccharides (LOS) are shorter versions of bacterial LPS that also are found in the outer membrane of some types of gram-negative bacteria, such as Neisseria spp. and Haemophilus spp. LOS molecules can help these bacteria be less visible to the human immune system, as it makes the bacteria look like a protein or molecule that is normal in the human body. This can help it evade the body’s immune cells which respond to the infection. This concept is known as molecular mimicry and is kind of like hiding the bacteria in camouflage. Unfortunately, when the immune system is activated, this molecular mimicry also can trigger an autoimmune response in the body, as the immune system responders simultaneously attack the similar-looking molecule or protein that is normal to the human body.[4]

Molecular mimicry can trigger an autoimmune response in the body, as the immune system responders simultaneously attack the similar-looking molecule or protein that is normal to the human body.

For example, Campylobacter jejuni is a common gram-negative bacterium that can cause gastrointestinal infections in humans. C. jejuni exhibits molecular mimicry which can induce autoreactive antibodies to brain molecules known as gangliosides.[5] The core LPS of C. jejuni are associated with the development of the neurological disorder known as Guillain-Barré syndrome. Collective data suggest that the antibodies are induced by an infection with C. jejuni, and subsequently react with nerve tissue causing damage.[6] However, an immune response to LPS in general is not in itself autoimmunity unless aspects of molecular mimicry and self-immune reaction are at play.

LPS and leaky gut

As an endotoxin, LPS activates many types of infection-fighting cells in the human body, which help the body fight off the bacterial invaders, but it also creates inflammation in the process. When this inflammatory response occurs in the gut, it can harm the gut lining.[7],[8] The gut lining then becomes more permeable (commonly referred to as “leaky gut“) and endotoxin can transfer through into circulation, triggering a systemic immune response, inflammation, and burdening the liver and kidneys.[9] Consumption of a high-fat diet also affects the balance of the gut microbiota and has been shown to increase endotoxemia (measured by plasma LPS), as well as the related expression of inflammatory cytokines.[10],[11] There is evidence that the damage to the gut caused by LPS from gram-negative enterobacteria plays a role in a variety of diseases, including depression,[12] chronic fatigue syndrome,[13] liver disease,[14] heart disease,[15] obesity,[16] and even infertility.[17]

Zonulin and leaky gut

Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases.[18],[19],[20],[21] Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.[22] Gastrointestinal infections have also been shown to increase the production of zonulin and are accompanied by altered tight junction integrity. Altered zonulin expression in genetically susceptible individuals has been associated with autoimmune diseases, inflammatory conditions, and cancer – both in the digestive tract as well as in other parts of the body.[23]

Altered zonulin expression in genetically susceptible individuals has been associated with autoimmune diseases, inflammatory conditions, and cancer – both in the digestive tract as well as in other parts of the body.

One way to assess intestinal permeability through lab testing is to screen for an immune response to LPS and the proteins associated with the intestinal lining.[24] An immune response to LPS in combination with increased permeability may suggest that gram-negative enterobacteria are a source of immune activation and inflammation.

Do probiotics contain LPS?

Probiotics, by definition, are viable, non-pathogenic microorganisms (bacteria or yeast) that are able to reach the intestine in sufficient numbers to convey benefit to the host. This definition may be expanded to include non-viable (ie killed) micro-organisms (also known as immunobiotics) as some of these bacterial cell-wall fragments also have been demonstrated to deliver immune-supportive health benefits. Probiotics may have an effect on immunity, gut health, and many other things both systemic and local.[25]

Probiotics may be able to both prevent and correct problems associated with LPS, autoimmunity, and leaky gut. The most commonly used probiotics Lactobacillus spp. and Bifidobacterium spp. are gram-positive bacteria and are therefore do not contain LPS.[26] (Remember, LPS is found on gram-negative bacteria; not on gram-positive.)

Some strains of probiotics have been shown to improve intestinal tight junctions, which also may reduce LPS-associated endotoxemia.[27] Bifidobacterium spp. in combination with lactoferrin (a glycoprotein found in dairy that has antimicrobial and chelation properties) has been shown to reduce intestinal endotoxin levels.[28] Both live and heat-killed Lactobacillus rhamnosus GG have been shown to decrease LPS-induced proinflammatory mediators and increase anti-inflammatory mediators.[29] Many botanicals, such as quercetin and berberine both inhibit intestinal absorption of endotoxin by their action on tight junctions in the intestinal lining.[30],[31]

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