Oral Administration of Lipopolysaccharides in Immune Modulation

The oral administration of lipopolysaccharides (LPS) has emerged as a novel strategy in immune modulation, diverging from the pro-inflammatory profiles observed with systemic endotoxin exposure. LPS, a constituent of Gram-negative bacterial outer membranes, interacts with mucosal immune receptors to promote homeostasis and protective responses across several physiological systems. Orally delivered LPS appears to traverse the gut epithelium in sub-inflammatory concentrations, engaging pattern recognition receptors on intestinal immune cells and peripheral leukocytes. This engagement triggers signalling cascades that enhance barrier integrity, regulate cytokine production and shift resident macrophage and microglial populations towards regulatory or neuroprotective phenotypes. Experimental models have demonstrated benefits ranging from improved metabolic profiles and lipid regulation to prevention of neurodegenerative pathology and facilitation of wound healing. While dosage and source of LPS are critical determinants of outcome, current evidence points to a dose-dependent bifurcation: low-dose regimens support immunoregulatory and reparative pathways, whereas high-dose exposure retains classical inflammatory effects. The global significance of this approach lies in its potential to apply a safe, inexpensive microbial-derived compound to mitigate lifestyle-related diseases, neuroinflammation and age-associated cognitive decline.

Research from Nature Portfolio

Recent analyses of herbal extracts have revealed that certain botanicals contain microgram-to-milligram levels of LPS capable of activating macrophages without overt inflammation. By systematically quantifying LPS content across hundreds of samples, researchers have identified specific root and leaf extracts that enhance phagocytic activity and nitric oxide production in innate immune cells, suggesting a natural reservoir of oral LPS immunomodulators. Separately, foundational studies on repetitive low-dose LPS exposure in microglial cell lines have uncovered a hybrid activation state characterised by simultaneous upregulation of pro- and anti-inflammatory mediators alongside enhanced phagocytic capacity. These findings highlight the nuanced capacity of low-level LPS stimuli to reprogramme brain-resident macrophages towards phenotypes supportive of neuroprotection and debris clearance, offering mechanistic insight into oral LPS-driven central immune benefits.

Oral Administration of Lipopolysaccharides in Immune Modulation publication trend

The graph below shows the total number of articles in oral administration of lipopolysaccharides in immune modulation across all publications each year (not limited to Nature Index journals).

Technical terms

Lipopolysaccharide (LPS): A complex glycolipid component of Gram-negative bacterial outer membranes that triggers immune signalling.

Pattern recognition receptor: A host receptor, such as Toll-like receptor 4, that detects microbial molecules and initiates immune responses.

Microglia: Resident macrophage-like immune cells in the central nervous system involved in debris clearance and neuroprotection.

Cytokines: Signalling proteins secreted by immune cells that mediate inflammation and cell communication.

Colony stimulating factor 1 (CSF1): A growth factor that binds to its receptor on macrophages and microglia, promoting survival and functional differentiation.

References

1. Oral route lipopolysaccharide as a potential dementia preventive agent inducing neuroprotective microglia. Frontiers in Immunology (2023).
2. Utility of In Vitro Cellular Models of Low-Dose Lipopolysaccharide in Elucidating the Mechanisms of Anti-Inflammatory and Wound-Healing-Promoting Effects of Lipopolysaccharide Administration In Vivo. International Journal of Molecular Sciences (2023).
3. Baseline data collections of lipopolysaccharide content in 414 herbal extracts and its role in innate immune activation. Scientific Reports (2024).
4. A unique hybrid characteristic having both pro- and anti-inflammatory phenotype transformed by repetitive low-dose lipopolysaccharide in C8-B4 microglia. Scientific Reports (2020).
5. Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents development of atherosclerosis in high-fat diet-fed apoE-deficient mice via ameliorating hyperlipidemia, pro-inflammatory mediators and oxidative responses. PLOS ONE (2018).
6. Prevention of Diabetes-Associated Cognitive Dysfunction Through Oral Administration of Lipopolysaccharide Derived From Pantoea agglomerans. Frontiers in Immunology (2021).