Bacteria with a cell wall structure containing an outer membrane with lipopolysaccharide (LPS), which does not retain crystal violet stain in Gram staining. The LPS component is a potent endotoxin recognized as a danger signal by the innate immune system.
The outer membrane contains LPS composed of lipid A (toxic component), core polysaccharide, and O-antigen. When released (bacterial death, division, or membrane shedding), LPS binds to LBP (LPS-binding protein), then CD14 and TLR4 on immune cells, triggering NF-κB activation and pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6).
Gram-negative bacteria in the gut are the primary source of LPS driving metabolic endotoxemia and low-grade inflammation when gut barrier integrity is compromised. Dysbiosis with gram-negative overgrowth (Escherichia, Klebsiella, Enterobacter) contributes to chronic inflammatory conditions, insulin resistance, and neuroinflammation through LPS translocation.
- LPS is lipid A + core polysaccharide + O-antigen in outer membrane
- LPS recognized by TLR4 via CD14 and MD-2 complex
- LPS triggers potent pro-inflammatory cascade (TNF-α, IL-1β, IL-6)
- Gram-negative overgrowth associated with dysbiosis and inflammation
- Common genera: Escherichia, Klebsiella, Enterobacter, Salmonella, Pseudomonas
- LPS crosses leaky gut barriers causing metabolic endotoxemia
- Postprandial lipemia increases LPS absorption
- Lactoferrin has bacteriostatic/bactericidal effects through iron deprivation
- LPS — gram-negative bacteria are the source of endotoxic LPS
- TLR4 — LPS from gram-negative bacteria activates TLR4 signaling
- endotoxemia — gram-negative LPS causes metabolic endotoxemia when translocated
- Low-Grade Inflammation — chronic LPS exposure drives systemic low-grade inflammation
- dysbiosis — gram-negative overgrowth is hallmark of intestinal dysbiosis
- gut barrier — compromised barrier allows gram-negative LPS translocation
- tight junctions — LPS disrupts tight junctions increasing permeability
- zonulin — LPS triggers zonulin release opening tight junctions
- bacterial translocation — gram-negative bacteria can translocate across damaged epithelium
- NF-κB — LPS-TLR4 activation triggers NF-κB inflammatory pathway
- TNF-α — LPS induces TNF-α production by macrophages
- IL-6 — gram-negative LPS is potent IL-6 inducer
- insulin resistance — LPS from gram-negative bacteria drives insulin resistance
- lactoferrin — iron-binding protein with bacteriostatic effect on gram-negative bacteria
- Escherichia coli — archetypal gram-negative bacterium, can be pathogenic or commensal
- Klebsiella — gram-negative genus associated with dysbiosis and inflammation
- SIBO — gram-negative overgrowth common in small intestinal bacterial overgrowth
- postprandial immune response — high-fat meals increase LPS absorption from gram-negative bacteria
- neuroinflammation — translocated LPS from gram-negative bacteria drives brain inflammation
- CD14 — co-receptor essential for LPS recognition from gram-negative bacteria
- Module 4
- Module 5
- Module 6