Weak Agonistic LPS Restores Intestinal Immune Homeostasis

Alex Steimle, Lena Michaelis, Flaviana Di Lorenzo, Thorsten Kliem, Tobias Münzner, Jan Kevin Maerz, Andrea Schäfer, Anna Lange, Raphael Parusel, Kerstin Gronbach, Kerstin Fuchs, Alba Silipo, Hasan Halit Öz, Bernd J. Pichler, Ingo B. Autenrieth, Antonio Molinaro, Julia Stefanie Frick*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

41 Citations (Scopus)

Abstract

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+ 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.

Original languageEnglish
Pages (from-to)1974-1991
Number of pages18
JournalMolecular Therapy
Volume27
Issue number11
DOIs
Publication statusPublished - 6 Nov 2019
Externally publishedYes

Keywords

  • inflammatory bowel disease
  • intestinal immune homeostasis
  • lipopolysaccharide

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