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. 2015 Apr 21;6(2):e00300-15.
doi: 10.1128/mBio.00300-15.

"V体育官网入口" Identification of metabolic signatures linked to anti-inflammatory effects of Faecalibacterium prausnitzii

Sylvie Miquel, Marion Leclerc, Rebeca Martin, Florian Chain, Marion Lenoir, Sébastien Raguideau, Sylvie Hudault, Chantal Bridonneau, Trent Northen  1 , Benjamin Bowen  1 , Luis G Bermúdez-Humarán, Harry Sokol, Muriel Thomas, Philippe Langella  2
Affiliations

Identification of metabolic signatures linked to anti-inflammatory effects of Faecalibacterium prausnitzii

Sylvie Miquel et al. mBio. .

Abstract

Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified on the basis of human clinical data. The mechanisms underlying its beneficial effects are still unknown. Gnotobiotic mice harboring F. prausnitzii (A2-165) and Escherichia coli (K-12 JM105) were subjected to 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis VSports手机版. The inflammatory colitis scores and a gas chromatography-time of flight (GC/TOF) mass spectrometry-based metabolomic profile were monitored in blood, ileum, cecum, colon, and feces in gnotobiotic mice. The potential anti-inflammatory metabolites were tested in vitro. We obtained stable E. coli and F. prausnitzii-diassociated mice in which E. coli primed the gastrointestinal tract (GIT), allowing a durable and stable establishment of F. prausnitzii. The disease activity index, histological scores, myeloperoxidase (MPO) activity, and serum cytokine levels were significantly lower in the presence of F. prausnitzii after TNBS challenge. The protective effect of F. prausnitzii against colitis was correlated to its implantation level and was linked to overrepresented metabolites along the GIT and in serum. Among 983 metabolites in GIT samples and serum, 279 were assigned to known chemical reactions. Some of them, belonging to the ammonia (α-ketoglutarate), osmoprotective (raffinose), and phenolic (including anti-inflammatory shikimic and salicylic acids) pathways, were associated with a protective effect of F. prausnitzii, and the functional link was established in vitro for salicylic acid. We show for the first time that F. prausnitzii is a highly active commensal bacterium involved in reduction of colitis through in vivo modulation of metabolites along the GIT and in the peripheral blood. .

Importance: Inflammatory bowel diseases (IBD) are characterized by low proportions of F. prausnitzii in the gut microbiome. This commensal bacterium exhibits anti-inflammatory effects through still unknown mechanisms. Stable monoassociated rodents are actually not a reproducible model to decipher F. prausnitzii protective effects. We propose a new gnotobiotic rodent model providing mechanistic clues. In this model, F. prausnitzii exhibits protective effects against an acute colitis and a protective metabolic profile is linked to its presence along the digestive tract. We identified a molecule, salicylic acid, directly involved in the protective effect of F. prausnitzii. Targeting its metabolic pathways could be an attractive therapeutic strategy in IBD V体育安卓版. .

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Figures

FIG 1
FIG 1
Setup of the E. coli/F. prausnitzii-diassociated mouse gnotobiotic model. (A and B) Inoculation of F. prausnitzii without E. coli. (A) Enumeration in feces of F. prausnitzii after gavage in germfree mice (n = 18 inoculations). (B) Scanning electron microscopy images from cecum of F. prausnitzii-infected mice. (C, D, and E) Inoculation of F. prausnitzii with E. coli. (C) Establishment of E. coli (open circles) and F. prausnitzii (solid squares) in the GIT of mice (n = 29) was monitored weekly by enumeration in the feces; arrows represent the various inoculations with F. prausnitzii before successful colonization. (D) Scanning electron microscopy images of E. coli (thick arrow) and F. prausnitzii (thin arrow) in the cecum of E. coli/F. prausnitzii-diassociated mice. (E) Representation along the GIT of E. coli (white bar) and F. prausnitzii (black bars) in CFU/g of content in diassociated mice.
FIG 2
FIG 2
Experimental design of TNBS-induced colitis and metabolomic profiling. (A) Protocol of TNBS induction of colitis in E. coli-monoassociated and E. coli/F. prausnitzii-diassociated BALB/c mice. Different readouts are indicated in the box. (B) Numbers and comparison, using a stringent 3-fold-intensity criterion, of metabolites in the GIT segments and in the serum of E. coli-monoassociated and E. coli/F. prausnitzii-diassociated mice after a TNBS-induced colitis, identified by mass spectrometric and biological metadata.
FIG 3
FIG 3
Analysis of colonic responses to a TNBS-induced colitis. (A) Disease activity index (DAI), (B) Wallace macroscopic score, (C) Ameho histologic score, (D) representative hematoxylin-eosin-safran staining of colonic tissue sections from E. coli-monoassociated (white bars) (n = 16 and 12) and E. coli/F. prausnitzii-diassociated (gray bars) (n = 18 and 11) mice with or without colitis, respectively. (E) Metabolomic analysis of E. coli-monoassociated (n = 8) compared to E. coli/F. prausnitzii-diassociated (n = 9) mouse colon content after TNBS treatment. The values are expressed as box-and-whisker plots with interquartile range, with the top portion of the box representing the 75th percentile and the bottom portion representing the 25th percentile. The horizontal bar within the box represents the median, with the mean shown as “+.” Asterisks indicate significant differences: **, P ≤ 0.01; ***, P ≤ 0.001. Metabolomics results are expressed as log intensities of metabolites with KEGG ID (t test, red and green, P ≤ 0.05).
FIG 4
FIG 4
Analysis of serum immune response after TNBS-induced colitis. (A) MPO activity from E. coli-monoassociated (white bars) (n = 16 and 12) and E. coli/F. prausnitzii-diassociated (gray bars) (n = 18 and 11) mice with or without colitis, respectively. (B) Blood cytokine levels (IL-1α, IL-2, and IL-5) from E. coli-monoassociated (n = 9 and 8) and E. coli/F. prausnitzii-diassociated (n = 10 and 8) mice with or without colitis, respectively. (C) Venn diagram depicting common metabolites between gut contents (cecum, colon, ileum, and feces) and serum (serum, colon, ileum, and feces). (D) Serum metabolites from E. coli-monoassociated (n = 8) compared to E. coli/F. prausnitzii-diassociated (n = 10) mice after TNBS treatment. Values are expressed as the mean ± SEM. Asterisks indicate significant differences: *, P ≤ 0.05; **, P ≤ 0.01. Metabolomic data are expressed as log intensities of metabolites with KEGG ID (t test, red and green, P ≤ 0.05).
FIG 5
FIG 5
Immunomodulation capacities of F. prausnitzii supernatant and identified molecules in vitro. IL-8 production in TNF-α-stimulated HT-29 cells is shown. Experiments were done in triplicate. Results are expressed as picograms of IL-8 per milligram of protein and have been normalized with the IL-8 produced after the coincubation with PBS or LYBHI medium. SN, F. prausnitzii supernatant (20%). ***, P ≤ 0.001.
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