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. 2018 Aug 29;13(8):e0202587.
doi: 10.1371/journal.pone.0202587. eCollection 2018.

Inter-kingdom effect on epithelial cells of the N-Acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota

Cécilia Landman  1 , Jean-Pierre Grill  1 , Jean-Maurice Mallet  1 , Philippe Marteau  1 , Lydie Humbert  1 , Eric Le Balc'h  1 , Marie-Anne Maubert  1 , Kevin Perez  1 , Wahiba Chaara  2 , Loic Brot  1 , Laurent Beaugerie  1 , Harry Sokol  1 , Sophie Thenet  3 , Dominique Rainteau  1 , Philippe Seksik  1 , Elodie Quévrain  1 ; Saint Antoine IBD Network
Affiliations

Inter-kingdom effect on epithelial cells of the N-Acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota

Cécilia Landman et al. PLoS One. .

Abstract

Background and aims: N-acyl homoserine lactones (AHLs), which are autoinducer quorum-sensing molecules involved in the bacterial communication network, also interact with eukaryotic cells. Searching for these molecules in the context of inflammatory bowel disease (IBD) is appealing. The aims of our study were to look for AHL molecules in faecal samples from healthy subjects (HS) and IBD patients to correlate AHL profiles with the microbiome and investigate the effect of AHLs of interest on epithelial cells.

Methods: Using mass spectrometry, we characterised AHL profiles in faecal samples from HS (n = 26) and IBD patients in remission (n = 24) and in flare (n = 25) and correlated the presence of AHLs of interest with gut microbiota composition obtained by real-time qPCR and 16S sequencing. We synthesised AHLs of interest to test the inflammatory response after IL1β stimulation and paracellular permeability on Caco-2 cells.

Results: We observed 14 different AHLs, among which one was prominent. This AHL corresponded to 3-oxo-C12:2 and was found significantly less frequently in IBD patients in flare (16%) and in remission (37.5%) versus HS (65.4%) (p = 0.001). The presence of 3-oxo-C12:2 was associated with significantly higher counts of Firmicutes, especially Faecalbacterium prausnitzii, and lower counts of Escherichia coli. In vitro, 3-oxo-C12:2 exerted an anti-inflammatory effect on Caco-2 cells. Interestingly, although 3-oxo-C12, the well-known AHL from Pseudomonas aeruginosa, increased paracellular permeability, 3-oxo-C12:2 did not.

Conclusions: We identified AHLs in the human gut microbiota and discovered a new and prominent AHL, 3-oxo-C12:2, which correlates with normobiosis and exerts a protective effect on gut epithelial cells.

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Conflict of interest statement

Dr Landman has received personal fees from Abbvie and Hospira and travel support from Abbvie, Hospira, Mayoly Spindler, Biocodex and Takeda. Professor Marteau has received lecture fees from Abbvie, Astellas, Biocodex, Danone, Hospira-Pfizer, Janssen, Merck-MSD, Ferring Pharmaceuticals and Takeda. Professor Beaugerie has received consulting fees from Janssen; lecture fees from Abbvie, Janssen, MSD, Ferring Pharmaceuticals and Takeda; and research support from Abbvie, Ferring Pharmaceuticals, Hospira-Pfizer, Janssen and Takeda. Professor Sokol has received personal fees from Danone, MSD, Takeda, Abbvie, Astellas, BMS and Novartis; options from Enterome and Maat; and grants from Biocodex. Professor Seksik has received personal fees from Takeda, Merck MSD, Biocodex and Abbvie and non-financial support from Takeda. The remaining authors disclose no conflict. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Heatmap of the results of the AHL profile in IBD patients and healthy controls.
AHLs are designated by their m/z. The grey colour bar indicates AHL m/z concentrations from none (white) to highest concentration (black). HS: healthy subject, R-IBD: inflammatory bowel disease patients in remission, A-IBD: inflammatory bowel disease patients in flare, UC: ulcerative colitis, CD: Crohn’s disease.
Fig 2
Fig 2. Full scan (80–100) of the fraction containing AHLs at m/z 294.2 using high-resolution mass spectrometry (LTQ-Orbitrap XL) in infusion mode with its precise mass and deducted formula.
Fig 3
Fig 3. Bar graph of AHL 3-oxo-C12:2 distribution and concentration among healthy subjects (HS) and IBD in remission (R-IBD) and in flare (A-IBD).
A: proportion of samples with AHL 3-oxo-C12:2. B: mean 3-oxo-C12:2 faecal concentration. * p < 0.05 **p < 0.005 ***p < 0.0005.
Fig 4
Fig 4
Bacterial diversity and composition among healthy subjects (HS), IBD in remission (R-IBD) and in flare (A-IBD): alpha diversity Shannon index (A) and Chao 1 index (B) and composition at a phyla scale (C) and at family scale (D).
Fig 5
Fig 5. Beta diversity according to Bray Curtis index between healthy subjects (HS) and IBD in remission (R-IBD) and in flare (A-IBD).
Fig 6
Fig 6. Bacterial composition among faecal samples according to AHL 3-oxo-C12:2 detection (3-oxo-C12:2 [+] group) or AHL 3-oxo-C12:2 absence (3-oxo-C12:2 [–] group).
A: Beta diversity according to Bray Curtis index between the two groups. B: Bacterial taxa that were differentially represented in the 3-oxo-C12:2 (+) group with statistical levels of significance according to linear discriminant analysis (LDA score > 2). Taxa were identified at the order, family, gender or species level and colour-coded according to their phylum.
Fig 7
Fig 7. Relative quantification (2^-DDCT) of gut microbiota principal bacterial groups and species.
* p < 0.05 **p < 0.005 *** p < 0.001.
Fig 8
Fig 8. IL-8 (normalized ratio) secretion by Caco-2/TC7 cells before and after IL1β stimulation with increasing concentrations of AHLs 3-oxo-C12 and 3-oxo-C12:2 compared to control (DMSO 0.1%).
*p < 0.05 ***p < 0.001.
Fig 9
Fig 9. Proportion of FD4-FITC in the basal medium after 4 hours on Caco-2/TC7 cells cultured in transwell.
Cells were pre-exposed with AHLs 3-oxo-C12 and 3-oxo-C12:2 at 200 μM for 4 and 20 hours. *p < 0.05 **p < 0.01.
See this image and copyright information in PMC

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