Review
Butyrate in Energy Metabolism: There Is Still More to Learn

https://doi.org/10.1016/j.tem.2020.12.003Get rights and content

Highlights

  • Butyrate is a vital mediator between gut microbiota and host metabolic health.

  • Butyrate has regulatory effects on body weight, body composition, and glucose homeostasis.

  • Butyrate is absorbed and metabolized by tissues and cells beyond the colon and has regulatory effects on their metabolic functions.

  • The metabolic effects of butyrate are subject to multiple regulatory mechanisms.

Butyrate, a main product of gut microbial fermentation, has been recognized as an important mediator of gut microbiota regulation in whole body energy homeostasis. However, the mechanisms of butyrate metabolic control remain unclear. This review summarizes studies that directly examined the effects of butyrate on metabolic health. The effects of butyrate on metabolic functions, including thermogenesis, lipid and glucose metabolism, appetite, inflammation, and influence on gut microbiota, are described. The effects of butyrate on cellular systems via G protein-coupled receptors (GPRs), as a histone deacetylase inhibitor, and as a substrate that is metabolized intercellularly, are also discussed. Hopefully, a better understanding of butyrate metabolic regulation may provide new perspectives for the nutritional prevention and treatment of metabolic diseases.

Introduction

The link between gut microbiota and metabolic health has been continuously demonstrated. However, the mechanisms of microbial metabolic regulation are less well understood because of the complexity of microbiota. Short-chain fatty acids (SCFAs), which constitute the most abundant metabolites of microbial fermentation from undigested dietary carbohydrates, are vital mediators between microbiota and host physiology. Decreased SCFA production is associated with metabolic diseases [1,2]. There is evidence that dietary fiber intervention has beneficial effects in type 2 diabetes patients via the promotion of SCFA producers [3]. However, SCFAs produced by gut microbiota are also important energy substrates for the host [4] and increased SCFA production promotes energy harvest and host obesity [5., 6., 7.]. Perry et al. found that the most abundant SCFA acetate promoted the development of metabolic syndrome via the gut microbiota–brain–β-cell axis [8]. Therefore, it is critical to understand exactly how each SCFA affects host energy homeostasis to improve the clinical efficacy of microbiota regulation on metabolic health.

Among the SCFAs, emerging evidence suggests that butyrate is a key regulator in mediating microbiota metabolic control [9., 10., 11., 12., 13., 14., 15., 16., 17., 18.]. Butyrate was first identified as a principal energy source for the intestines [19] and up to 95% of microbial-produced butyrate has been estimated to be consumed by the colon, where butyrate plays an important regulatory role in intestinal barrier function and inflammation via interactions with G protein-coupled receptors (GPRs) and the inhibition of histone deacetylases (HDACs) [20]. Butyrate also plays a role in colorectal cancer [21]. Recent evidence suggests that butyrate is distributed beyond the intestines to the central nerve system and peripheral tissues, such as liver, brown adipose tissue (BAT), and white adipose tissue (WAT), and it regulates tissue function to affect whole body energy homeostasis. Besides interactions with GPRs and HDACs, evidence shows that butyrate is absorbed and metabolized intercellularly in multiple tissues to directly affect function. This review discusses recent advances in our understanding of butyrate production, absorption, and metabolism and its role in metabolic regulation.

Section snippets

Butyrate Production

Butyrate is a natural nutrient in certain foods, such as butter and milk, but most of the butyrate in the human body comes from gut microbiota fermentation of undigested carbohydrates. There are two metabolic pathways for butyrate biosynthesis: one pathway is via butyryl-CoA/acetate CoA transferase, which requires one molecule of acetate, and the other pathway is the phosphotransbutyrylase-butyrate kinase pathway [22]. Gut microbiota produce approximately 500–600 mmol of SCFAs and butyrate is

Butyrate Absorption

Gut microbiota-produced butyrate is rapidly absorbed across the apical membrane of intestinal epithelial cells via the Na+-coupled transporter SLC5A8 and the H+-coupled transporter SLC16A1 [29]. Notably, these transporters have widespread expression, from the central nerve system to peripheral tissues, including the liver, adipose, heart, and kidney tissues [29]. Up to 95% of butyrate is considered to be absorbed and used in colonocytes and only a very small part is absorbed into the

Butyrate Metabolism

The absorbed butyrate can act as a signaling molecule via the ligand–receptor action of the GPRs GPR43, GPR41, and GPR109a, which are widely expressed in the central nervous system and peripheral tissues [36]. Previous studies suggested GPR-mediated SCFA effects on metabolic control in multiple tissues [37., 38., 39.], but studies in GPR43 and GPR41 knockout mice yielded conflicting results and did not eliminate all of the metabolic effects of SCFAs [40,41], which indicates that other

Effects of Butyrate on Body Weight and Fat Mass

The direct physiological effects of butyrate on body weight and fat mass were studied recently in animal models (Table 1). Most evidence suggests that chronic 5% sodium butyrate (wt/wt) supplementation in food reduces HFD-induced body weight gain in mice compared with HFD only [9,11,12,14,39,41]. Most of these studies also reported reduced fat mass [9,11., 12., 13., 14.], which suggests that butyrate prevents diet-induced obesity (DIO). Notably, butyrate also has effects in the treatment of DIO

Effects on Thermogenesis

When studying the physiological effects of butyrate, some results showed that butyrate increased energy expenditure to counteract HFD-induced obesity and no significant alterations in food intake or physical activities were observed [9,11,13,14,16]. One important mechanism for butyrate to increase energy expenditure is via the activation of thermogenesis, which is a function of adipose tissues to dissipate chemical energy in the form of heat via uncoupling protein 1 (UCP1) to regulate body

Concluding Remarks and Future Perspectives

Studies support a role of butyrate as an important mediator of microbiota in host metabolic control. However, the effects of butyrate remain controversial and the mechanisms of butyrate regulation are not clear. Important questions should be elucidated, such as the production and absorption of microbial butyrate under different metabolic conditions, the regulatory effects of butyrate in different animals and humans, and the mechanisms of butyrate regulation on cellular systems in different

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 32072744, 31802068, 31790411) to L.Z. and Q.Y.J., Key Research Program of Frontier Sciences, CAS (No. QYZDY-SSW-SMC008) and the Earmarked Fund of China Agriculture Research System (No. CARS-35) to Y.L.Y., as well as the Natural Science Foundation of Guangdong Province (No. 2018A030310145) to L.Z.

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