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. 2007:3:112.
doi: 10.1038/msb4100153. Epub 2007 May 22.

A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model

François-Pierre J Martin  1 , Marc-Emmanuel Dumas, Yulan Wang, Cristina Legido-Quigley, Ivan K S Yap, Huiru Tang, Séverine Zirah, Gerard M Murphy, Olivier Cloarec, John C Lindon, Norbert Sprenger, Laurent B Fay, Sunil Kochhar, Peter van Bladeren, Elaine Holmes, Jeremy K Nicholson
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"V体育官网入口" A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model

François-Pierre J Martin et al. Mol Syst Biol. 2007.

Abstract

Symbiotic gut microorganisms (microbiome) interact closely with the mammalian host's metabolism and are important determinants of human health. Here, we decipher the complex metabolic effects of microbial manipulation, by comparing germfree mice colonized by a human baby flora (HBF) or a normal flora to conventional mice. We perform parallel microbiological profiling, metabolic profiling by (1)H nuclear magnetic resonance of liver, plasma, urine and ileal flushes, and targeted profiling of bile acids by ultra performance liquid chromatography-mass spectrometry and short-chain fatty acids in cecum by GC-FID. Top-down multivariate analysis of metabolic profiles reveals a significant association of specific metabotypes with the resident microbiome. We derive a transgenomic graph model showing that HBF flora has a remarkably simple microbiome/metabolome correlation network, impacting directly on the host's ability to metabolize lipids: HBF mice present higher ileal concentrations of tauro-conjugated bile acids, reduced plasma levels of lipoproteins but higher hepatic triglyceride content associated with depletion of glutathione VSports手机版. These data indicate that the microbiome modulates absorption, storage and the energy harvest from the diet at the systems level. .

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"V体育官网入口" Figures

Figure 1
Figure 1
Metabolism and synthesis of the major bile acids in mouse. Key: Color denotes family of bile acids, that is, primary bile acids synthesized in liver in black, secondary bile acids synthesized in liver and processed by microflora in green and tertiary bile acids synthesized in liver, processed by microflora and re-metabolized in liver through enterohepatic recirculation in orange. Conjugation with taurine and glycine is colored in blue and red respectively. Key intermediates in the pathway are colored in gray.
Figure 2
Figure 2
Typical 600 MHz 1H NMR spectra. 1H CPMG NMR spectra of plasma (A) and intact liver tissue (B), and 1H NMR spectrum of urine (C) from an HBF mouse, and 1H NMR spectra of ileal flushes from HBF (D) and conventional mice (E). The spectra of the urine and ileal flushes were magnified 6 and 10 times respectively in the aromatic region (δ 5.2–8.5) compared to the aliphatic region (δ 0.7–4.5). The liver regions δ 5.2–5.4 and 5.4–8.5 were magnified 4 and 8 times respectively. The plasma regions δ 5.2–5.4 and 5.4–8.5 were magnified 4 and 10 times respectively. Keys to the figures are given in Table III.
Figure 3
Figure 3
O-PLS-DA coefficient plots derived from 1H NMR spectra. O-PLS-DA coefficient plots derived from 1H NMR CPMG spectra of plasma (A), 1H MAS NMR CPMG spectra of liver (B) and 1H NMR spectra of urine (C) and ileal flushes (D) indicating discrimination between conventional (negative) and HBF-colonized mice (positive). The O-PLS-DA coefficient plots are presented using a back-scaling transformation, as described previously (Cloarec et al, 2005b), which allows each variable to be plotted with a color code that relates to the significance of class discrimination as calculated from the correlation matrix. Arg, arginine; Asp, aspartate; Asn, asparagine; CA, cholic acid; Gln, glutamine; Gsh, glutathione; GPC, glycerophosphorylcholine; IAG, indoleacetylglycine; Lys, lysine; Nac, N-acetyl-glycoproteins; PAG, phenylacetylglycine; TCA, taurocholic acid; TβMCA, Tauro β muricholic acid; TUDCA, tauroursodeoxycholic acid.
Figure 4
Figure 4
Structural and functional study of bile acids. Structures of bile acids and cholesterol (A), as characterized in this study. Color denotes family of bile acids, that is, primary (black), secondary (green) and tertiary (orange). Conjugation with taurine and glycine is colored in blue and red respectively. Key intermediates in the pathway are colored in gray. Typical negative ion mass chromatograms from the UPLC–MS analysis (B) for the ions detected at the given m/z for the ileal flush from a conventional mouse with sample injections of 10 μl (1 μl for m/z=514.2). Numbers under the m/z ratios are the total ion counts for that chromatogram.
Figure 5
Figure 5
O-PLS-DA coefficient plots derived from the UPLC–MS bile acid composition. O-PLS-DA coefficient plots derived from the bile acid composition obtained by UPLC–MS analysis of ileal flushes, indicating discrimination between conventional (positive) and HBF colonized mice (negative) (A), and partial discrimination between conventional (positive) and re-conventionalized mice (negative) (B). The color code corresponds to the correlation coefficients of the variables. One predictive and one orthogonal components were calculated, and the respective (Q2Y, R2X) are (89.1%, 80%) and (51.4%, 62%). The O-PLS-DA coefficient plots are presented using a back-scaling transformation, as described previously (Cloarec et al, 2005b), which allows each variable to be plotted with a color code that relates to the significance of class discrimination as calculated from the correlation matrix.
Figure 6
Figure 6
Effect of major bile acids on organ-specific metabolic profiles. O-PLS coefficient plots describing correlation between 1H NMR spectra of 1H MAS NMR CPMG spectra of liver (A, C) and ileal flushes (B, D) and ileal concentrations of cholic acid (A, B) and taurocholic acid (C, D), as measured using UPLC–MS. The O-PLS coefficients plots are presented using a back-scaling transformation, as described previously (Cloarec et al, 2005b), which allows each variable to be plotted with a color code that relates to the significance of correlation as calculated from the correlation matrix. One predictive and two orthogonal components were calculated; the respective (Q2Y, R2X) are (55%, 39%), (47%, 37%), (36%, 44%) and (21%, 41%). CA, cholic acid; TCA, taurocholic acid.
Figure 7
Figure 7
Integration of bile acid and fecal flora correlations. The bipartite graphs were derived from correlations between fecal flora and bile acids in each group: conventional (A) or HBF (B). G=(N,E) specifies a graph G with N denoting the node set (bile acids) and E the edge set (correlation between bile acids, above a defined cutoff, that is, ∣r∣>0.5), which was defined using network degree statistics (C). Bile acids and fecal bacteria correspond to blue ellipse nodes and green rectangle nodes respectively. Edges are coded according to correlation value: positive and negative correlations are respectively displayed in blue and orange. aMA, α-muricholic acid; Ba, Bacteroides; Bf, Bifidobacteria; bMA, β-muricholic acid; CA, cholic acid; CDCA, chenodeoxycholic acid; Cp, Clostridium perfringens; DCA, deoxycholic acid; Eb, Enterobacteria; GCA, glycocholic acid; HCA, hyocholic acid; Lb, Lactobacillus; OMA, ω-muricholic acid; Sc, Staphylococcus; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TMCA, tauro-β-muricholic acid; TUDCA, tauroursocholic acid; UDCA, ursocholic acid.
Figure 8
Figure 8
Microbe–mammalian metabolic interactions related to bile acid and lipid metabolism. The bacterial reprocessing of the bile acid pool and regulation of bile acid metabolism by bacterial SCFAs affect significantly the enterohepatic recirculation and the systemic lipid metabolism, that is, emulsification, absorption, transport of dietary fats. The gut bacterial-induced regulation of enterohepatic recirculation also led to a physiological regulation of oxidative stress (glutathione), reprocessing of fatty acids (deposition, apoprotein and VLDL synthesis) and VLDL secretion from the liver, which result in controlling the influx and efflux of fatty acids in the liver. BA, bile acids; CA, cholic acid; GPC, glycerophosphorylcholine; GSH, glutathione; HBF, human baby flora; LDL, low-density Lipoproteins; βMCA, β-muricholic acid; SCFAs, short-chain fatty acids; TβMCA, tauro-β-muricholic acid; TCA, taurocholic acid; VLDL, very low-density lipoproteins.
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