Lipopolysaccharides (LPS) are large, complex molecules found exclusively on the exterior of certain bacteria, functioning as a primary structural element of their outer surface. These molecules are also commonly referred to as “endotoxin.” LPS is structurally embedded within the bacterial cell wall and is released when the bacterial cell dies and breaks apart. Once released into the host environment, LPS molecules act as potent triggers, provoking a powerful and often damaging response from the human immune system.
Structure and Location of Lipopolysaccharides
Lipopolysaccharides are a major component of the outer membrane of Gram-negative bacteria, forming the outermost leaflet of this protective layer. The molecule is built from three distinct sections that are chemically linked together.
The innermost portion is the Lipid A component, a glycolipid that serves as the anchor, embedding the entire LPS molecule into the bacterial membrane. Lipid A is the most toxic part of the structure and is directly responsible for activating the host’s immune response. Attached to the Lipid A is the Core Polysaccharide, which is a short chain of sugar molecules.
The outermost section is the O-Antigen, or O-polysaccharide, which extends away from the bacterial surface. This section is highly variable between different species and strains of bacteria. The composition of this long sugar chain allows scientists to classify and distinguish between various types of Gram-negative bacteria, and it is a primary target for the host immune system’s antibodies.
The Role of LPS in Bacterial Survival
The LPS layer provides structural integrity to the bacterial outer membrane. The dense packing of the LPS molecules, facilitated by divalent cations, creates a formidable permeability barrier. This barrier is highly selective, preventing the entry of many harmful substances from the environment into the bacterial cell.
The LPS shield is effective at protecting the bacteria from external threats such as antibiotics, detergents, and host immune compounds. The layer makes the bacteria resistant to certain antimicrobial drugs and protective proteins produced by the host immune system, like complement proteins. This protective function is an essential component for the viability and survival of most Gram-negative bacteria.
LPS as an Endotoxin and Immune Trigger
When a Gram-negative bacterial infection is fought off, either by the immune system or by antibiotics, large amounts of LPS can be shed into the host’s bloodstream. The immune system recognizes the Lipid A component as a danger signal, leading to a rapid inflammatory reaction.
This recognition triggers the release of immune signaling molecules, known as pro-inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-6 (IL-6). While a localized release of these molecules helps clear an infection, their systemic release in high concentrations causes widespread inflammation and fever. An overwhelming systemic response to high levels of circulating LPS leads to the severe clinical condition known as septic shock.
In septic shock, the inflammatory response damages the endothelial lining of blood vessels, leading to blood clotting issues and fluid leakage. The resulting drop in blood pressure and reduced blood flow can quickly lead to multiorgan dysfunction syndrome (MODS) and acute organ failure in the kidneys, lungs, and heart.
Detecting and Neutralizing LPS in the Body
The body possesses a highly specific mechanism to recognize the Lipid A component of LPS through the Toll-like Receptor 4 (TLR4) pathway. TLR4 is a pattern recognition receptor found on immune cells that works in complex with co-receptors like CD14 and MD-2 to detect the presence of LPS, initiating the entire inflammatory cascade.
The gut is a major source of LPS, as it is home to trillions of Gram-negative bacteria, but the intestinal lining normally prevents significant amounts from entering the bloodstream. However, increased intestinal permeability, often referred to as “leaky gut,” allows small, persistent levels of LPS to cross the barrier and enter systemic circulation. This low-level, chronic exposure, called endotoxemia, is increasingly associated with chronic inflammatory conditions, including certain metabolic, cardiovascular, and autoimmune disorders.
Given the severe consequences of high LPS exposure, much research focuses on ways to neutralize the molecule to treat or prevent septic shock. One strategy involves the use of host defense peptides, which bind directly to the Lipid A portion of LPS and block its ability to activate TLR4. Other methods include using advanced filtration devices to physically remove circulating LPS from the blood during sepsis.