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. 2014 Aug 12;5(4):e01438-14.
doi: 10.1128/mBio.01438-14.

Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids

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Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids

Sabina Lukovac et al. mBio. .

Abstract

The gut microbiota is essential for numerous aspects of human health. However, the underlying mechanisms of many host-microbiota interactions remain unclear. The aim of this study was to characterize effects of the microbiota on host epithelium using a novel ex vivo model based on mouse ileal organoids. We have explored the transcriptional response of organoids upon exposure to short-chain fatty acids (SCFAs) and products generated by two abundant microbiota constituents, Akkermansia muciniphila and Faecalibacterium prausnitzii. We observed that A. muciniphila metabolites affect various transcription factors and genes involved in cellular lipid metabolism and growth, supporting previous in vivo findings. Contrastingly, F. prausnitzii products exerted only weak effects on host transcription. Additionally, A. muciniphila and its metabolite propionate modulated expression of Fiaf, Gpr43, histone deacetylases (HDACs), and peroxisome proliferator-activated receptor gamma (Pparγ), important regulators of transcription factor regulation, cell cycle control, lipolysis, and satiety. This work illustrates that specific bacteria and their metabolites differentially modulate epithelial transcription in mouse organoids. We demonstrate that intestinal organoids provide a novel and powerful ex vivo model for host-microbiome interaction studies.

Importance: We investigated the influence of the gut microbiota and microbially produced short-chain fatty acids (SCFAs) on gut functioning. Many commensal bacteria in the gut produce SCFAs, particularly butyrate, acetate, and propionate, which have been demonstrated to reduce the risk of gastrointestinal disorders. Organoids-small crypt-villus structures grown from ileal intestinal stem cells-were exposed to SCFAs and two specific gut bacteria. Akkermansia muciniphila, found in the intestinal mucus, was recently shown to have a favorable effect on the disrupted metabolism associated with obesity. Faecalibacterium prausnitzii is a commensal gut bacterium, the absence of which may be associated with Crohn's disease. We showed that in our model, A. muciniphila induces stronger effects on the host than F. prausnitzii. We observed that A. muciniphila and propionate affect the expression of genes involved in host lipid metabolism and epigenetic activation or silencing of gene expression. We demonstrated that organoids provide a powerful tool for host-microbe interaction studies.

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Figures

FIG 1
FIG 1
Bright-field images of mouse small-intestinal organoids cultured in Matrigel for 1 (A), 3 (B), and 7 (C) days after splitting.
FIG 2
FIG 2
Distinct transcriptome signatures in intestinal organoids upon stimulation with bacterial monocultures and SCFAs. (A) Heat map and hierarchical clustering representing the array correlation plot of microarray data from all replicates. (B) PCA plot of the microarray data showing the distribution of different experimental treatment groups. Clusters represent samples exposed to A. muciniphila culturing medium (Am−), A. muciniphila-conditioned medium (Am+), F. prausnitzii culturing medium (Fp−), F. prausnitzii-conditioned medium (Fp+), acetate (Ace), butyrate (But), propionate (Pro), and standard organoid culturing medium (Con). (C) Venn diagrams representing the number of genes up- and downregulated by exposure of organoids to A. muciniphila-conditioned medium relative to their respective controls (unconditioned microbial culture medium) compared to exposure to the SCFAs butyrate, propionate, and acetate. (D) Venn diagrams representing the number of genes up- and downregulated by exposure to F. prausnitzii-conditioned medium relative to the respective controls compared to exposure to butyrate, propionate, and acetate.
FIG 3
FIG 3
A. muciniphila regulates the expression of many host transcription factors and genes involved in cellular metabolic function. (A) Network representation of transcription factors affected by A. muciniphila, F. prausnitzii, and SCFAs. (B) Transcription factors affected in organoids after exposure to both A. muciniphila and its metabolite propionate. (C) IPA network demonstrating the effect of A. muciniphila on expression of genes involved in lipid metabolism. Nodes in green and red correspond to down- and upregulated genes, respectively. Noncolored nodes are proposed by IPA and suggest potential targets functionally coordinated with the differential genes.
FIG 4
FIG 4
Many metabolic processes are affected in organoids after exposure to A. muciniphila and propionate. Pie charts show the distribution of affected genes in relation to A. muciniphila (A), F. prausnitzii (B), butyrate (C), propionate (D), and acetate (E) based on their annotations in biological functions (Gene Ontology).
FIG 5
FIG 5
Effects of A. muciniphila, propionate, and butyrate on expression of metabolic genes coding for Fiaf, Gpr43, Hdac3, and Hdac4 in intestinal organoids. (A) Log fold change of gene expression after exposure to F. prausnitzii and A. muciniphila relative to control conditions (A) and after exposure to butyrate, propionate, and acetate relative to control conditions (B) (mean fold change ± standard deviation [SD]; P < 0.01; n = 4).

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