The lipooligosaccharide of the gut symbiont Akkermansia muciniphila exhibits a remarkable structure and TLR signaling capacity

• Published in: Nature communications Vol. 15; no. 1; pp. 8411 - 12
• Main Authors: Garcia-Vello, Pilar, Tytgat, Hanne L. P., Elzinga, Janneke, Van Hul, Matthias, Plovier, Hubert, Tiemblo-Martin, Marta, Cani, Patrice D., Nicolardi, Simone, Fragai, Marco, De Castro, Cristina, Di Lorenzo, Flaviana, Silipo, Alba, Molinaro, Antonio, de Vos, Willem M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 631/250/347; 631/326/41/2533; 631/45/72/1205; 64/60; 82/58; 96/106; 96/95; Akkermansia; Akkermansia muciniphila; Animals; Bacteria; Chain branching; Digestive system; Female; Gastrointestinal Microbiome; Gastrointestinal tract; Gene expression; Glycan; Gram-negative bacteria; Humanities and Social Sciences; Humans; Immune system; Inflammation; Inflammatory response; Innate immunity; Interleukin-10 - metabolism; Lipid A; Lipid A - chemistry; Lipid A - metabolism; Lipids; Lipooligosaccharides; Lipopolysaccharides; Liver - metabolism; Liver - microbiology; Mice; Mice, Inbred C57BL; Mucosal immunity; multidisciplinary; Polysaccharides; Proteins; Receptor mechanisms; Science; Science (multidisciplinary); Signal Transduction; Symbiosis; TLR2 protein; TLR4 protein; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - metabolism; Toll-like receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52683-x

The cell-envelope of Gram-negative bacteria contains endotoxic lipopolysaccharides (LPS) that are recognized by the innate immune system via Toll-Like Receptors (TLRs). The intestinal mucosal symbiont Akkermansia muciniphila is known to confer beneficial effects on the host and has a Gram-negative architecture. Here we show that A. muciniphila LPS lacks the O-polysaccharide repeating unit, with the resulting lipooligosaccharide (LOS) having unprecedented structural and signaling properties. The LOS consists of a complex glycan chain bearing two distinct undeca- and hexadecasaccharide units each containing three 2-keto-3-deoxy-D- manno -octulosonic acid (Kdo) residues. The lipid A moiety appears as a mixture of differently phosphorylated and acylated species and carries either linear or branched acyl moieties. Peritoneal injection of the LOS in mice increased higher gene expression of liver TLR2 than TLR4 (100-fold) and induced high IL-10 gene expression. A. muciniphila LOS was found to signal both through TLR4 and TLR2, whereas lipid A only induced TLR2 in a human cell line. We propose that the unique structure of the A. muciniphila LOS allows interaction with TLR2, thus generating an anti-inflammatory response as to compensate for the canonical inflammatory signaling associated with LOS and TLR4, rationalizing its beneficial host interaction. Here, the authors characterize the structure of the Lipooligosaccharide of the gut symbiont Akkermansia muciniphila showing unique features and TLR4 and TLR2 signaling capacity, which underscore the beneficial properties of this bacterium.