Ornithine lipids from <i>Akkermansia muciniphila</i> are dynamically modulated in colitis and shape macrophage inflammatory responses
Habiba Selmi, Alesia Walker, Laurence Balas, Marianna Lucio, Markus Klotz, Aicha Jeridi, Anna Burrichter, Devon E. Conti, Lorenzo Chaffringeon, Brice Beinsteiner, Marion Jasnin, Nicolas Vanthuyne, Thierry Durand, Ali Önder Yildirim, Bärbel Stecher, Laurent Debarbieux, Philippe Schmitt‐Kopplin
Abstract
The gut microbiota is a key modulator of host immunity, in part through the production of structurally diverse and largely still uncharacterized bacterial lipids and metabolites with potential immunoregulatory properties. Using a gnotobiotic Oligo-Mouse-Microbiota (OMM12) mouse model infected with the Citrobacter rodentium pathogen, we investigated metabolomic changes associated with colitis. Untargeted metabolomics revealed an accumulation of host-derived lipids in the inflamed colon, while several bacterial lipid classes, including sphingolipids, glycerophospholipids, and fatty acyls were depleted. Among the bacterial lipids, ornithine-containing lipids (OLs) produced by Akkermansia muciniphila were significantly reduced during inflammation. Isolation, structural characterization, and chemical synthesis revealed OL 16:0/15:0 as a membrane-associated lipid from A. muciniphila. This lipid contains an L-ornithine head group, with its α-amino group forming an amide bond with 3(R)-hydroxypalmitic acid, while the 3(R)-hydroxyl position is esterified with pentadecanoic acid. Functional studies showed that macrophages internalize and partially metabolize OL 16:0/15:0 into Nα-(3-hydroxypalmitoyl)-L-ornithine and 3(R)-hydroxypalmitic acid. In LPS-stimulated macrophages, a 1:1 mixture of OL diastereomers (3R,S + 3S,S) reduced Il6 and Il1b gene expression and decreased IL-6 secretion, without triggering IL-1β release. Interestingly, this diastereomeric mixture exhibited an opposite effect to the natural (3R,S)-epimer, which selectively promoted IL-1β secretion in LPS-primed macrophages. These results uncover a possible stereoselective modulation of IL-1β production by bacterial OLs. Overall, OL 16:0/15:0 is dynamically regulated during inflammation and may play a role in the immunomodulation of host–microbiota interactions.