Why Your Brain Fog Won't Lift: The Six Mechanisms of Cognitive Dysfunction in Chronic Illness, and Why Standard Interventions Keep Failing — Mechanism Two: Neuroinflammation and the Endotoxin to Microglia Pathway

The second mechanism is the inflammatory signaling that crosses from the gut and the systemic circulation into the central nervous system, where it activates the resident immune cells of the brain (microglia) and changes the local biochemical environment of neurons. Lipopolysaccharide (LPS), the principal component of the outer membrane of gram negative bacteria, is continuously generated in the gut. When the gut barrier is intact, LPS exposure to the systemic circulation is minimal. When the gut barrier is compromised, LPS translocates into the lamina propria, enters the portal circulation, and can reach systemic circulation in significant quantities. LPS is a potent activator of toll like receptor 4 (TLR4), which is expressed widely including on microglia, astrocytes, and endothelial cells of the cerebral vasculature. Activated microglia change their phenotype. They release pro inflammatory cytokines (IL 1 beta, TNF alpha, IL 6), produce reactive oxygen species, alter synaptic pruning behavior, and impair the local glymphatic clearance that normally removes metabolic waste from the brain. Neurons in this environment perform less well. Synaptic function is reduced. Memory consolidation is compromised. Working memory becomes effortful. The subjective experience is brain fog. LPS is one mechanism. Other inflammatory mediators do similar work. Circulating IL 6 crosses the blood b