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Shifts in the gut microbiota composition, called dysbiosis, have been directly associated with acute and chronic diseases. However, the underlying biological systems connecting gut dysbiosis to systemic inflammatory pathologies are not well understood. Phospholipids (PLs) act as precursors of both, bioactive inflammatory and resolving mediators. Their dysregulation is associated with chronic diseases including cancer. Gut microbial-derived lipids are structurally unique and capable of modulating host’s immunity.  Lactobacillus johnsonii  N6.2 is a Gram-positive gut symbiont with probiotic characteristics.  L. johnsonii  N6.2 reduces the incidence of autoimmunity in animal models of Type 1 Diabetes and improves general wellness in healthy volunteers by promoting, in part, local and systemic anti-inflammatory responses. By utilizing bioassay-guided fractionation methods with bone marrow-derived dendritic cells (BMDCs), we report here that  L. johnsonii  N6.2 purified lipids induce a transcriptional signature that resembles that of migratory (mig) DCs. RNAseq-based analysis showed that BMDCs stimulated with  L. johnsonii N6.2  total lipids upregulate maturation-mig related genes  Cd86 ,  Cd40 ,  Ccr7 ,  Icam1  along with immunoregulatory genes including  Itgb8 ,  Nfkbiz ,  Jag1 ,  Adora2a ,  IL2ra ,  Arg1 , and  Cd274 . Quantitative reverse transcription (qRT)-PCR analysis indicated that PLs are the bioactive lipids triggering the BMDCs response. Antibody-blocking of surface Toll-like receptor (TLR)2 resulted in boosted PL-mediated upregulation of pro-inflammatory  Il6 . Chemical inhibition of the IKKα kinase from the non-canonical NF-κB pathway specifically restricted upregulation of  Il6  and  Tnf . Phenotypically, PL-stimulated BMDCs displayed an immature like-phenotype with significantly increased surface ICAM-1. This study provides insight into the immunoregulatory capacity of Gram-positive, gut microbial-derived phospholipids on innate immune responses.

Lactobacillus johnsonii N6.2 phospholipids induce immature-like dendritic cells with a migratory-regulatory-like transcriptional signature