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Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids

ABSTRACT: Acetate, propionate and butyrate are the main short-chain fatty acids (SCFAs) that arise from the fermentation of fibers by the colonic microbiota. While many studies focus on the regulatory role of SCFAs, their quantitative role as a catabolic or anabolic substrate for the host has received relatively little attention. To investigate this aspect, we infused conscious mice with physiological quantities of stable isotopes [1-13C]acetate, [2-13C]propionate or [2,4-13C2]butyrate directly into the cecum, which is the natural production site in mice, and analyzed their interconversion by the microbiota as well as their metabolism by the host. Cecal interconversion - pointing to microbial cross-feeding - was high between acetate and butyrate, low between butyrate and propionate and almost absent between acetate and propionate. As much as 62% of infused propionate was used in whole-body glucose production, in line with its role as gluconeogenic substrate. Conversely, glucose synthesis from propionate accounted for 69% of total glucose production. The synthesis of palmitate and cholesterol in the liver was high from cecal acetate (2.8% and 0.7%, respectively) and butyrate (2.7% and 0.9%, respectively) as substrates, but low or absent from propionate (0.6% and 0.0%, respectively). Label incorporation due to chain elongation of stearate was approximately 8-fold higher than de novo synthesis of stearate. Microarray data suggested that SCFAs exert only a mild regulatory effect on the expression of genes involved in hepatic metabolic pathways during the 6h infusion period. Altogether, gut-derived acetate, propionate and butyrate play important roles as substrates for glucose, cholesterol and lipid metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE45926 | GEO | 2013/10/21

SECONDARY ACCESSION(S): PRJNA196648

REPOSITORIES: GEO

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Project description:Background: Acetate, propionate, and butyrate are the main short-chain fatty acids (SCFA) produced in the colon as a result of microbial fermentation of dietary fibers. An increasing amount of evidence suggests that these SCFA have major health benefits. The composition of the microbiota is altered by dietary fat, and this is believed to impact SCFA production. Currently it is unknown whether host gene expression responses to SCFA are modulated by fat content of the diet. The aim of this study was to compare the changes in colonic gene expression profiles after acetate, propionate and butyrate infusions between a low fat and high fat diet. Methods: Male C57BL/6J mice were fed semi-synthetic low fat (10 energy%) or high fat (45 E%) diets starting 2 weeks before the SCFA treatment period. During treatment, mice received a rectal infusion of either an acetate, propionate, butyrate, or a saline (control) solution for 6 consecutive days, after which colon was subjected to gene expression profiling. Unsupervised visualization of the dataset was performed using Independent Principal Component Analysis. For each SCFA, similarities of its effects on a low fat and a high fat diet were assessed using Rank-Rank Hypergeometric Overlap. In addition, differentially expressed genes were identified, and gene set enrichment analysis was performed to determine functional implications of the regulated genes. Results: Taking into account the complete dataset, we observed that more variation in gene expression profiles was explained by fat content of the diet than by SCFA treatment. Gene expression responses to acetate and butyrate were similar on the low fat versus high fat diet, but were opposite for propionate. Functionally the expression changes reflected differential modulation of several metabolic processes; genes involved in oxidative phosphorylation, lipid catabolism, lipoprotein metabolism and cholesterol transport were suppressed by acetate and butyrate treatment, whereas propionate treatment resulted in changes in fatty acid and sterol biosynthesis, and in amino acid and carbohydrate metabolism. Conclusions: We demonstrated that dietary fat content impacts the colonic gene expression response to propionate, and to a lesser extent to acetate and butyrate. The study demonstrates that knowledge on diet composition is essential when studying effects of SCFAs on metabolism.

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Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids

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