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The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation
Etienne Doré, … , Arnaud Droit, Eric Boilard
Etienne Doré, … , Arnaud Droit, Eric Boilard
Published January 25, 2022
Citation Information: JCI Insight. 2022;7(2):e152638. https://doi.org/10.1172/jci.insight.152638.
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Research Article Inflammation Microbiology

The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation

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Abstract

Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.

Authors

Etienne Doré, Charles Joly-Beauparlant, Satoshi Morozumi, Alban Mathieu, Tania Lévesque, Isabelle Allaeys, Anne-Claire Duchez, Nathalie Cloutier, Mickaël Leclercq, Antoine Bodein, Christine Payré, Cyril Martin, Agnes Petit-Paitel, Michael H. Gelb, Manu Rangachari, Makoto Murakami, Laetitia Davidovic, Nicolas Flamand, Makoto Arita, Gérard Lambeau, Arnaud Droit, Eric Boilard

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Figure 6

Mice with enhanced arthritis susceptibility present limited microbiota alterations.

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Mice with enhanced arthritis susceptibility present limited microbiota a...
The fecal microbiota of donor and recipient mice involved in the fecal microbiota transplantation was sequenced at 3 different time points: before the transplantation (D0), 10 days following the transplantation (D21), and 8 days following the induction of arthritis (D29). (A) α-Diversity (Shannon index) of the microbiome of each mouse group at every time point (n = 5–7). (B) Principal component analysis based on the Bray Curtis dissimilarity comparing the flora from all mouse groups. (C and D) Groups were organized into 2 categories depending on their susceptibility to induced arthritis: sPLA2-IIATGN donors and sPLA2-IIATGN mice receiving the flora from sPLA2-IIATGN donors were classified as “Prone to inflammation,” and WT donors, WT recipients, and sPLA2-IIATGN mice receiving the WT flora were labeled “Less susceptible to inflammation.” (C) Distribution of amplicon sequence variants (ASV) differentially modulated between categories. (D) Distribution of differentially enriched ASVs found only in WT donors and their recipient mouse groups within every mouse. Bacterial species with highest percentage of identity for each differentially enriched ASV are as follows: ASV 52, Ruminococcus bromii (99%); ASV 48, Vallitalea promyensis (87%); ASV 99, Anaerobacterium chartisolvens (88%); ASVs 24, 34, and 35, uncultured Muribaculum species (100%); ASV 17, Muribaculum intestinale (91%); ASV 71, Pseudoflafonifractor phocaeensis (89%); ASV 67, Uncultured Muribaculum specie (96%); and ASV 28, Muribaculum intestinale (92 %). Data are presented as boxes representing the median and quartiles, with whiskers extending up to 1.5 interquartile range. Statistical analysis included Welch’s t test with P value corrected by Benjamini-Hochberg FDR procedure. Percentage of identity represent the percentage of similarity to the closest known sequence (Blastn using RefSeq NT). *P < 0.05, **P < 0.01.

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