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Abstract
Butyrate is considered the primary energy source of colonocytes and has received wide attention due to its unique health benefits. Insight into the mechanistic effects of butyrate on cellular and metabolic function relies mainly on research in in-vitro-cultured cells. However, cells in culture differ from those in vivo in terms of metabolic phenotype and nutrient availability. For translation, it is therefore important to understand the impact of different nutrients on the effects of butyrate. We investigated the metabolic consequences of butyrate exposure under various culturing conditions, with a focus on the interaction between butyrate and glucose. To investigate whether the effects of butyrate were different between cells with high and low mitochondrial capacity, we cultured HT29 cells under either low- (0.5 mM) or high- (25 mM) glucose conditions. Low-glucose culturing increased the mitochondrial capacity of HT29 cells compared to high-glucose (25 mM) cultured HT29 cells. Long-term exposure to butyrate did not alter mitochondrial bioenergetics, but it decreased glycolytic function, regardless of glucose availability. In addition, both high- and low-glucose-grown HT29 cells showed increased lipid droplet accumulation following long-term butyrate exposure. Acute exposure of cultured cells (HT29 and Caco-2) to butyrate increased their oxygen consumption rate (OCR). A simultaneous decrease in extracellular acidification rate (ECAR) was observed. Furthermore, in the absence of glucose, OCR did not increase in response to butyrate. These results lead us to believe that butyrate itself was not responsible for the observed increase in OCR, but, instead, butyrate stimulated pyruvate flux into mitochondria. Indeed, blocking of the mitochondrial pyruvate carrier prevented a butyrate-induced increase in oxygen consumption. Taken together, our results indicate that butyrate itself is not oxidized in cultured cells but instead alters pyruvate flux and induces lipid accumulation.
Highlights
Butyrate is a short-chain fatty acid (SCFA) that, in humans, is mostly produced through fiber fermentation by microbiota in the colon
2.1 mpH/min/1 × 105 area, p = 0.0012) as compared to cells cultured in 25 mM glucose, which indicated that our low-glucose-cultured HT29 cells relied more on mitochondrial metabolism than high-glucose cultured HT29 cells (Figure 1)
Since butyrate is a short-chain fatty acid that can be converted to acetyl-CoA in the mitochondria, we expected that long-term butyrate exposure would affect mitochondrial parameters
Summary
Butyrate is a short-chain fatty acid (SCFA) that, in humans, is mostly produced through fiber fermentation by microbiota in the colon. Butyrate is mainly known as the primary source of energy for healthy colon cells [1] and has been found to have beneficial health effects. Because butyrate catabolism in mitochondria utilizes oxygen for oxidation in colonocytes, it lowers oxygen levels, which prevents vascular oxygen from leaking into the anoxic colonic lumen [10]. In some diseases, such as IBD, butyrate oxidation is decreased, especially during phases of active disease [11,12,13]. The mechanistic explanation for the decrease in butyrate oxidation is likely the ongoing inflammation, which alters the ability of colonocytes to take up and metabolize butyrate [14], highlighting that butyrate metabolism is central to many of its physiological functions
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