lipid-a and Colitis

Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the 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

Topics: Animals; Biomarkers; CD11c Antigen; Colitis; Disease Models, Animal; Gastrointestinal Microbiome; Homeostasis; Humans; Immunity, Mucosal; Inflammatory Bowel Diseases; Intestinal Mucosa; Lipid A; Lipopolysaccharides; Mice; Mice, Knockout; Positron-Emission Tomography

Resilience to host inflammation and other perturbations is a fundamental property of gut microbial communities, yet the underlying mechanisms are not well understood. We have found that human gut microbes from all dominant phyla are resistant to high levels of inflammation-associated antimicrobial peptides (AMPs) and have identified a mechanism for lipopolysaccharide (LPS) modification in the phylum Bacteroidetes that increases AMP resistance by four orders of magnitude. Bacteroides thetaiotaomicron mutants that fail to remove a single phosphate group from their LPS were displaced from the microbiota during inflammation triggered by pathogen infection. These findings establish a mechanism that determines the stability of prominent members of a healthy microbiota during perturbation.

Topics: Animals; Antimicrobial Cationic Peptides; Bacteroides; Colitis; Drug Resistance, Bacterial; Escherichia coli; Gastrointestinal Tract; Germ-Free Life; Humans; Lipid A; Mice; Microbiota; Phosphoric Monoester Hydrolases; Polymyxin B; Symbiosis

Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-alpha release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caproates; Cells, Cultured; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Glucosamine; HeLa Cells; Humans; Inflammatory Bowel Diseases; Lipid A; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Monocytes; Receptors, Immunologic; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Topics: Antibody Formation; Colitis; Colitis, Ulcerative; Crohn Disease; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Intestinal Mucosa; Lipid A