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. 2022 Dec 30;12(1):22585.
doi: 10.1038/s41598-022-26322-8.

Metabolomic profiling in dogs with dilated cardiomyopathy eating non-traditional or traditional diets and in healthy controls

Caren E Smith  1 , Laurence D Parnell  2 , Chao-Qiang Lai  2 , John E Rush  3 , Darcy B Adin  4 , José M Ordovás  1 , Lisa M Freeman  5
Affiliations

Metabolomic profiling in dogs with dilated cardiomyopathy eating non-traditional or traditional diets and in healthy controls

Caren E Smith et al. Sci Rep. .

Abstract

Dilated cardiomyopathy (DCM), caused by genetic and environmental factors, usually progresses to heart failure, a major cause of death in elderly people. A diet-associated form of DCM was recently identified in pet dogs eating non-traditional (NT) diets. To identify potential dietary causes, we analyzed metabolomic signatures and gene set/pathway enrichment in (1) all dogs based on disease, diet, and their interactions and (2) dogs with DCM based on diet. Metabolomic analysis was performed in 38 dogs with DCM eating NT diets (DCM-NT), 8 dogs with DCM eating traditional diets, 12 healthy controls eating NT diets, and 17 healthy controls eating traditional diets. Overall, 153 and 63 metabolites differed significantly between dogs with DCM versus healthy controls and dogs eating NT versus traditional diets, respectively, with 12 metabolites overlapping both analyses. Protein-protein interaction networks and gene set enrichment analysis identified 105 significant pathways and gene sets including aging-related pathways (e.g., nuclear factor-kappa B, oxidative damage, inflammation). Seventeen metabolites differed significantly in dogs with DCM eating NT versus traditional diets (e.g., fatty acids, amino acids, legume biomarkers), suggesting different mechanisms for primary versus diet-associated DCM. Our multifaceted metabolomic assessment of DCM in dogs highlighted diet's role in some forms of DCM.

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Conflict of interest statement

In the last 3 years, Dr. Freeman has received research funding from, given sponsored lectures for, and/or provided professional services to Aratana Therapeutics, Elanco, Guiding Stars LLC, Nestlé Purina PetCare, P&G Pet Care (now Mars), and Royal Canin. In the last 3 years, Dr. Rush has received research funding from, given sponsored lectures for, and/or provided professional services to Aratana Therapeutics, Boehringer Ingelheim, Elanco, IDEXX, Nestlé Purina PetCare, and Royal Canin. Dr. Adin acknowledges research support from Nestle Purina PetCare and is a consultant and sponsored lecturer for Ceva Animal Health and Boehringer Ingelheim. None of the other authors has any competing interests to declare.

Figures

Figure 1
Figure 1
Random forest machine learning analysis was used to evaluate the 12 metabolites that overlapped between disease and diet comparisons at baseline in 75 dogs for their relative contribution in the biochemical importance plot. The super pathway for each metabolite is indicated by color as defined by the legend on the right. (A) Comparison based on disease (DCM vs. healthy controls). These metabolites had a predictive accuracy of 86%, (B) Comparison based on diet. These metabolites had a predictive accuracy of 87%. Key: 2-MeO-HQ sulfate, 2-methoxyhydroquinone sulfate (1); 3-MeO-catechol sulfate, 3-methoxycatechol sulfate (2).
Figure 2
Figure 2
Illustration of metabolites that were significantly different between groups at baseline in 46 dogs with dilated cardiomyopathy (DCM): 38 dogs with DCM eating non-traditional diets (DCM-NT) and 8 dogs with DCM eating traditional diets (DCM-T) at baseline. Metabolites plotted in gray have P values above the cutoff of 9.78E-05 and are considered not statistically significantly different between disease groups, whereas metabolites in colors were statistically significant with a P value < 9.78E-05. The beta values, where a negative value denotes higher levels in the DCM-NT diet group, are plotted against the negative of log10(P value).
Figure 3
Figure 3
Tile plot showing pathway enrichments for the comparison of dogs by disease (dogs with DCM eating non-traditional diets [DCM-NT] + dogs with DCM eating traditional diets [DCM-T]) vs. (healthy controls eating non-traditional diets [C-NT] + healthy controls eating traditional diets [C-T]) and by diet (DCM-NT vs. DCM-T). Color reflects the corrected P value of enrichment, and white indicates the pathway was not significant in that comparison. The pathways that were enriched in the comparison by disease were almost completely different from the pathways enriched in the comparison by diet in dogs with DCM. Of 160 pathways, only three (choline, food nutraceutical, and quaternary ammonium salt) pathways were shared between these two comparisons.
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