Abstract
The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice.
Highlights
We identified significantly differentially expressed probe sets and genes in mouse metabolic reaction (MMR), from here on referred as metabolic genes, by comparing gene expression profiles of tissues obtained from conventionally raised (CONV-R) versus GF mice (Fig 1B, Dataset EV1)
Comparing the differentially expressed metabolic genes between duodenum, jejunum, ileum, colon, and liver tissues of CONV-R and GF mice (Fig 1C), we found that the expression of the nicotinamide nucleotide transhydrogenase (Nnt) gene is higher and ectonucleoside triphosphate diphosphohydrolase 4 (Entpd4) is lower in all five tissues of CONV-R mice compared with GF mice (Fig 1D)
We found that the expression of Alas1 involved in glycine metabolism, Slc2a1 known as Glut1 and involved in glucose transportation, Slc16a12 involved in creatine transportation, and Hmgcr involved in cholesterol synthesis as well as Cyp7a1 and Akr1d1 involved in bile acid synthesis were significantly lower in the liver tissue of CONV-R mice compared to GF mice (Fig 5A)
Summary
The human gut harbors a vast ensemble of bacteria that have profound effects on host physiology (Huttenhower et al, 2012). Larsson et al (2012) studied the response of the host induced by microbiota along the length of the gut in CONV-R and GF C57Bl6/J mice and provided a detailed description for tissue-specific host transcriptional responses. GEMs include the known metabolism-related reactions and associated genes in a particular cell and tissue and serve as an excellent scaffold for the integration of omics data (e.g. proteomics, transcriptomics, and metabolomics) for increasing our understanding of the relationship between genotype and phenotype (Mardinoglu et al, 2013b). We investigated the metabolic differences between CONV-R and GF mice using global gene expression profiling of the host tissues and the network topology provided by the tissue GEMs, and validated our predictions by generating metabolomics data for these two sets of mice. We revealed the metabolic differences between the small intestine of CONV-R and GF mice accounting for the content of the chow diet as well as the relative gene expression differences using relative metabolic differences (RMetD) method
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