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Panorganismal metabolic response modeling of an experimental Echinostoma caproni infection in the mouse.

Saric J, Li JV, Wang Y, Keiser J, Veselkov K, Dirnhofer S, Yap IK, Nicholson JK, Holmes E, Utzinger J - J. Proteome Res. (2009)

Bottom Line: Furthermore, altered gut microbial activity or composition was reflected by increased levels of trimethylamine in the colon.Our modeling approach facilitated in-depth appraisal of the covariation of the metabolic profiles of different biological matrices and found that urine and plasma most closely reflected changes in ileal compartments.In conclusion, an E. caproni infection not only results in direct localized (ileum and jejenum) effects, but also causes remote metabolic changes (colon and several peripheral organs), and therefore describes the panorganismal metabolic response of the infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Public Health and Epidemiology, Swiss Tropical Institute, Basel, Switzerland.

ABSTRACT
Metabolic profiling of host tissues and biofluids during parasitic infections can reveal new biomarker information and aid the elucidation of mechanisms of disease. The multicompartmental metabolic effects of an experimental Echinostoma caproni infection have been characterized in 12 outbred female mice infected orally with 30 E. caproni metacercariae each, using a further 12 uninfected animals as a control group. Mice were killed 36 days postinfection and brain, intestine (colon, ileum, jejeunum), kidney, liver, and spleen were removed. Metabolic profiles of tissue samples were measured using high-resolution magic angle spinning (1)H NMR spectroscopy and biofluids measured by applying conventional (1)H NMR spectroscopy. Spectral data were analyzed via principal component analysis, partial least-squares-derived methods and hierarchical projection analyses. Infection-induced metabolic changes in the tissues were correlated with altered metabolite concentrations in the biofluids (urine, plasma, fecal water) using hierarchical modeling and correlation analyses. Metabolic descriptors of infection were identified in liver, renal cortex, intestinal tissues but not in spleen, brain or renal medulla. The main physiological change observed in the mouse was malabsorption in the small intestine, which was evidenced by decreased levels of various amino acids in the ileum, for example, alanine, taurine, glutamine, and branched chain amino acids. Furthermore, altered gut microbial activity or composition was reflected by increased levels of trimethylamine in the colon. Our modeling approach facilitated in-depth appraisal of the covariation of the metabolic profiles of different biological matrices and found that urine and plasma most closely reflected changes in ileal compartments. In conclusion, an E. caproni infection not only results in direct localized (ileum and jejenum) effects, but also causes remote metabolic changes (colon and several peripheral organs), and therefore describes the panorganismal metabolic response of the infection.

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Hierarchical-PCA scores plot, assessing the weight of the different biological matrices due to an E. caproni infection. Initially, separate PCAs have been performed for all the biological matrices, and subsequently the PCs were extracted from those models with positive Q2X and/or R2cumX and which showed a visual separation in the scores plot (i.e., liver, renal cortex, ileum, colon, spleen, plasma, and urine). Two or 3 extracted PCs from each chosen compartment formed the sublevel of the hierarchical analysis. Only the closest time point to the dissection was chosen for the biofluids (i.e., day 33 postinfection), in order to minimize time-dependent variation compared to the time point of tissue-removal (i.e., day 36 postinfection). The loadings plot shows the distribution of the biomatrices in relation to the 2 groups in the corresponding scores plot, whereby ‘t’ indicates E. caproni-infected animals and ‘c’ the uninfected control mice. Of note, two uninfected control mice (c4 and c10) were excluded from the global hierarchical analysis due to unsatisfactory water suppression in the 1D spectra of ileum and urine, respectively. The H-PCA loadings are composed of the tissues (C, colon; I, ileum; K, renal cortex; L, liver; P, plasma; U, urine) and the corresponding pulse program that has been applied for 1H NMR data acquisition (c, CPMG; d, DOESY; n, 1D pulse sequence).
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fig4: Hierarchical-PCA scores plot, assessing the weight of the different biological matrices due to an E. caproni infection. Initially, separate PCAs have been performed for all the biological matrices, and subsequently the PCs were extracted from those models with positive Q2X and/or R2cumX and which showed a visual separation in the scores plot (i.e., liver, renal cortex, ileum, colon, spleen, plasma, and urine). Two or 3 extracted PCs from each chosen compartment formed the sublevel of the hierarchical analysis. Only the closest time point to the dissection was chosen for the biofluids (i.e., day 33 postinfection), in order to minimize time-dependent variation compared to the time point of tissue-removal (i.e., day 36 postinfection). The loadings plot shows the distribution of the biomatrices in relation to the 2 groups in the corresponding scores plot, whereby ‘t’ indicates E. caproni-infected animals and ‘c’ the uninfected control mice. Of note, two uninfected control mice (c4 and c10) were excluded from the global hierarchical analysis due to unsatisfactory water suppression in the 1D spectra of ileum and urine, respectively. The H-PCA loadings are composed of the tissues (C, colon; I, ileum; K, renal cortex; L, liver; P, plasma; U, urine) and the corresponding pulse program that has been applied for 1H NMR data acquisition (c, CPMG; d, DOESY; n, 1D pulse sequence).

Mentions: Among the multivariate statistical models for the biofluids, PCA models of the plasma and urine obtained at the ultimate sampling time point (i.e., day 33 postinfection) acquired by the standard 1D pulse sequence showed good separation in the scores plots and, additionally, the CPMG-acquired spectra for plasma were included in the hierarchical model. H-PLS-DA analyses were based on the new 34-descriptor template and were optimally modeled by 2 PCs (PLS-DA: R2X = 0.35, Q2Y = 0.76). In the H-PLS loadings plot (Figure 4), the main source of variation corresponding to the 2 separate classes (infected and noninfected control) in the scores plot lay in differentiation of the pulse programs rather than the biological compartments (Figure 4). Thus, the 1D and diffusion-edited experiments for all biological compartments (with the exception of the 1D plasma and urine and the diffusion-edited ileum spectral information) co-mapped with the control animals, whereas the spectra acquired by the CPMG pulse sequence predominantly influenced the animals infected with E. caproni, again indicating the relatively greater contribution of the low molecular weight components to the characterization of E. caproni infection.


Panorganismal metabolic response modeling of an experimental Echinostoma caproni infection in the mouse.

Saric J, Li JV, Wang Y, Keiser J, Veselkov K, Dirnhofer S, Yap IK, Nicholson JK, Holmes E, Utzinger J - J. Proteome Res. (2009)

Hierarchical-PCA scores plot, assessing the weight of the different biological matrices due to an E. caproni infection. Initially, separate PCAs have been performed for all the biological matrices, and subsequently the PCs were extracted from those models with positive Q2X and/or R2cumX and which showed a visual separation in the scores plot (i.e., liver, renal cortex, ileum, colon, spleen, plasma, and urine). Two or 3 extracted PCs from each chosen compartment formed the sublevel of the hierarchical analysis. Only the closest time point to the dissection was chosen for the biofluids (i.e., day 33 postinfection), in order to minimize time-dependent variation compared to the time point of tissue-removal (i.e., day 36 postinfection). The loadings plot shows the distribution of the biomatrices in relation to the 2 groups in the corresponding scores plot, whereby ‘t’ indicates E. caproni-infected animals and ‘c’ the uninfected control mice. Of note, two uninfected control mice (c4 and c10) were excluded from the global hierarchical analysis due to unsatisfactory water suppression in the 1D spectra of ileum and urine, respectively. The H-PCA loadings are composed of the tissues (C, colon; I, ileum; K, renal cortex; L, liver; P, plasma; U, urine) and the corresponding pulse program that has been applied for 1H NMR data acquisition (c, CPMG; d, DOESY; n, 1D pulse sequence).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724024&req=5

fig4: Hierarchical-PCA scores plot, assessing the weight of the different biological matrices due to an E. caproni infection. Initially, separate PCAs have been performed for all the biological matrices, and subsequently the PCs were extracted from those models with positive Q2X and/or R2cumX and which showed a visual separation in the scores plot (i.e., liver, renal cortex, ileum, colon, spleen, plasma, and urine). Two or 3 extracted PCs from each chosen compartment formed the sublevel of the hierarchical analysis. Only the closest time point to the dissection was chosen for the biofluids (i.e., day 33 postinfection), in order to minimize time-dependent variation compared to the time point of tissue-removal (i.e., day 36 postinfection). The loadings plot shows the distribution of the biomatrices in relation to the 2 groups in the corresponding scores plot, whereby ‘t’ indicates E. caproni-infected animals and ‘c’ the uninfected control mice. Of note, two uninfected control mice (c4 and c10) were excluded from the global hierarchical analysis due to unsatisfactory water suppression in the 1D spectra of ileum and urine, respectively. The H-PCA loadings are composed of the tissues (C, colon; I, ileum; K, renal cortex; L, liver; P, plasma; U, urine) and the corresponding pulse program that has been applied for 1H NMR data acquisition (c, CPMG; d, DOESY; n, 1D pulse sequence).
Mentions: Among the multivariate statistical models for the biofluids, PCA models of the plasma and urine obtained at the ultimate sampling time point (i.e., day 33 postinfection) acquired by the standard 1D pulse sequence showed good separation in the scores plots and, additionally, the CPMG-acquired spectra for plasma were included in the hierarchical model. H-PLS-DA analyses were based on the new 34-descriptor template and were optimally modeled by 2 PCs (PLS-DA: R2X = 0.35, Q2Y = 0.76). In the H-PLS loadings plot (Figure 4), the main source of variation corresponding to the 2 separate classes (infected and noninfected control) in the scores plot lay in differentiation of the pulse programs rather than the biological compartments (Figure 4). Thus, the 1D and diffusion-edited experiments for all biological compartments (with the exception of the 1D plasma and urine and the diffusion-edited ileum spectral information) co-mapped with the control animals, whereas the spectra acquired by the CPMG pulse sequence predominantly influenced the animals infected with E. caproni, again indicating the relatively greater contribution of the low molecular weight components to the characterization of E. caproni infection.

Bottom Line: Furthermore, altered gut microbial activity or composition was reflected by increased levels of trimethylamine in the colon.Our modeling approach facilitated in-depth appraisal of the covariation of the metabolic profiles of different biological matrices and found that urine and plasma most closely reflected changes in ileal compartments.In conclusion, an E. caproni infection not only results in direct localized (ileum and jejenum) effects, but also causes remote metabolic changes (colon and several peripheral organs), and therefore describes the panorganismal metabolic response of the infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Public Health and Epidemiology, Swiss Tropical Institute, Basel, Switzerland.

ABSTRACT
Metabolic profiling of host tissues and biofluids during parasitic infections can reveal new biomarker information and aid the elucidation of mechanisms of disease. The multicompartmental metabolic effects of an experimental Echinostoma caproni infection have been characterized in 12 outbred female mice infected orally with 30 E. caproni metacercariae each, using a further 12 uninfected animals as a control group. Mice were killed 36 days postinfection and brain, intestine (colon, ileum, jejeunum), kidney, liver, and spleen were removed. Metabolic profiles of tissue samples were measured using high-resolution magic angle spinning (1)H NMR spectroscopy and biofluids measured by applying conventional (1)H NMR spectroscopy. Spectral data were analyzed via principal component analysis, partial least-squares-derived methods and hierarchical projection analyses. Infection-induced metabolic changes in the tissues were correlated with altered metabolite concentrations in the biofluids (urine, plasma, fecal water) using hierarchical modeling and correlation analyses. Metabolic descriptors of infection were identified in liver, renal cortex, intestinal tissues but not in spleen, brain or renal medulla. The main physiological change observed in the mouse was malabsorption in the small intestine, which was evidenced by decreased levels of various amino acids in the ileum, for example, alanine, taurine, glutamine, and branched chain amino acids. Furthermore, altered gut microbial activity or composition was reflected by increased levels of trimethylamine in the colon. Our modeling approach facilitated in-depth appraisal of the covariation of the metabolic profiles of different biological matrices and found that urine and plasma most closely reflected changes in ileal compartments. In conclusion, an E. caproni infection not only results in direct localized (ileum and jejenum) effects, but also causes remote metabolic changes (colon and several peripheral organs), and therefore describes the panorganismal metabolic response of the infection.

Show MeSH
Related in: MedlinePlus