LPS / metabolic endotoxemia

Lipopolysaccharide (LPS) is a structural component of the outer membrane of Gram-negative bacteria; when shed by bacteria at cell death or division, it is the most potent ligand for Toll-like receptor 4 (TLR4) and a primary driver of the inflammatory cascade in sepsis. In metabolic endotoxemia — a term coined by Cani and colleagues in a 2007 Cell Metabolism paper — low but chronically elevated circulating LPS levels (2- to 3-fold above fasting baseline) arise from impaired intestinal barrier function and increased chylomicron-mediated translocation of LPS after high-fat feeding. The resulting low-grade TLR4 activation on hepatocytes, adipocytes and macrophages promotes insulin resistance, adipose tissue inflammation and hepatic steatosis in rodent models. The phrase 'leaky gut' is a popular shorthand for increased intestinal permeability, but it is informal and mechanistically imprecise; barrier function is controlled by tight junction proteins (occludin, claudins, ZO-1) whose downregulation, along with reduced mucus layer thickness, is demonstrably altered by certain dietary patterns and dysbiosis. Human evidence for a causal metabolic endotoxemia–disease pathway is supportive but not conclusive, and circulating LPS is technically difficult to measure accurately.