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-(13)C]acetate, [2-(13)C]propionate, or [2,4-(13)C2]butyrate directly in 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 eightfold higher than de novo synthesis of stearate. Microarray data suggested that SCFAs exert a mild regulatory effect on the expression of genes involved in hepatic metabolic pathways during the 6-h infusion period. Altogether, gut-derived acetate, propionate, and butyrate play important roles as substrates for glucose, cholesterol, and lipid metabolism.

Dietary Mannan Oligosaccharides Modulate Gut Microbiota, Increase Fecal Bile Acid Excretion, and Decrease Plasma Cholesterol and Atherosclerosis Development

“…In a previous study performed in mice, cecal infusion of butyrate increased hepatic cholesterol synthesis, suggesting that butyrate might elevate plasma cholesterol 49. However, in another study performed in rats, hepatic cholesterol synthesis was reduced after ingestion of butyrate, albeit butyrate was given in combination with other SCFAs 50.…”

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

“…Once SCFAs are transported to the liver, acetate and to a lesser extend butyrate are used as substrates in cholesterol synthesis and lipogenesis [33]. As mentioned earlier, through the activation of AMPK, SCFAs also regulate lipid-and cholesterol synthesis [42][43][44][45][46].…”

“…For instance, it was shown that co-colonization of germ-free mice with the methanogenic archaeon Methanobrevibacter smithii as well as the saccharolytic bacterium Bacteroides thetaiotaomicron resulted in a significant increase in host adiposity, compared to mono-colonization with either one [32]. Moreover, after SCFAs have been formed, they are subjected to a high intracolonic interconversion due to microbial crossfeeding [33]. This shows that interventional studies with only one type of SCFA should be interpreted with caution as the observed effects might be due to other SCFAs after conversion in the gut.…”

“…Propionate, specifically, is a substrate for intestinal [40] and hepatic [33] gluconeogenesis and accounts for 69% of total body glucose production in mice [33]. Furthermore, SCFAs can regulate glucose metabolism by acting as signaling molecules.…”

Short-Chain Fatty Acids Protect Against High-Fat Diet–Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation

“…The main products of intestinal fermentation of dietary fibers are short-chain fatty acids (SCFAs), of which acetate, propionate, and butyrate are the most abundant (6). Although these three SCFAs are rapidly assimilated into host carbohydrates and lipids-providing ;10% of our daily energy requirements (7)-there are clear differences in the way each is metabolized: propionate is primarily a precursor for gluconeogenesis, whereas acetate and butyrate are rather incorporated into fatty acids and cholesterol (8). Besides serving as an energy source, SCFAs also regulate metabolism by inhibition of histone deacetylases and chain-length-dependent activation of the endogenous G-protein-coupled receptor (GPR) 41 and 43 (9)(10)(11).…”