Metabolic endotoxemia in metabolic and neurodegenerative diseases

Metabolic diseases, which include obesity, type 2 diabetes, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease (MASLD), are significant global health challenges. Patients with these conditions frequently exhibit gut dysbiosis and compromised gut barrier integrity, which lead to excessive translocation of Gram-negative bacterial lipopolysaccharide (LPS or endotoxin) from the gut lumen into the systemic circulation. This results in chronically elevated systemic LPS levels, a condition termed "metabolic endotoxemia". Gut-derived LPS may stimulate inflammatory responses and oxidative stress when it translocates and is recognized by host Toll-like receptor 4 (TLR4) and caspase-4/-5/-11. Metabolic endotoxemia is a primary trigger for the low-grade inflammation that promotes the development of metabolic diseases. Emerging evidence also indicates that metabolic endotoxemia acts as a key driver in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease, by promoting chronic neuroinflammation. In this review, we discuss: (1) the molecular structure of LPS that determines its bioactivity and its recognition by host cells, (2) host regulation of its bioactivity, (3) its translocation from the gut lumen into the systemic circulation, and (4) how metabolic endotoxemia contributes to obesity, type 2 diabetes, atherosclerosis, MASLD, and Alzheimer's disease. We conclude by exploring potential interventions aimed at preventing or mitigating metabolic endotoxemia by promoting LPS degradation and inactivation.