Weak agonistic LPS restores intestinal immune homeostasis

Abstract Generated by Gram negative bacteria, lipopolysaccharides (LPS) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host MD-2/TLR4 receptor complex results in NFκB activation followed by robust induction of pro-inflammatory immune responses. Here, we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk, which provides only weak agonistic activity. This weak agonistic activity leads to amelioration of inflammatory immune responses in a mouse model for experimental colitis and was in sharp contrast to strong agonists and antagonists. In this context, administration of Bacteroides vulgatus mpk LPS into mice suffering from severe intestinal inflammation re-established intestinal immune homeostasis within only two weeks resulting in clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c + cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g. in Inflammatory Bowel Diseases.