Beyond metabolic endotoxemia paradigm: The circulating lipopolysaccharidome as a determinant of low-grade inflammation and immunomodulation

Abstract

Metabolic endotoxemia refers to the translocation of lipopolysaccharides (LPS) from gut-resident Gram-negative bacteria into the bloodstream, a process associated with low-grade chronic inflammation in several pathologies. Although elevated LPS and pro-inflammatory cytokine levels have been documented in affected patients, LPS is also detectable in healthy individuals without eliciting inflammatory responses. Most studies assume that any circulating LPS invariably activates TLR4 and triggers inflammation, overlooking the structural variability of LPS across bacterial species, which may function as either agonists or antagonists. Moreover, repeated exposure to agonistic LPS can induce endotoxin tolerance (ET), a regulatory phenomenon that suppresses subsequent inflammatory signaling. Thus, it is necessary to move beyond the simplistic view that modest elevations in LPS invariably drive inflammation and instead examine the structural diversity of LPS translocated into the bloodstream and their ability to modulate immune responses. This requires the isolation, purification, and comprehensive chemical and immunological characterization of circulating LPS. Therefore, the authors propose the term “circulating lipopolysaccharidome” to describe the heterogeneous pool of LPS molecules present in the bloodstream and their distinct immunomodulatory roles. Recognizing this diversity offers a conceptual framework to better understand how LPS-TLR4 interactions shape host immunity, providing new insight into the mechanisms linking low-grade chronic inflammation with a broad spectrum of associated diseases.