The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism

Abstract

Short-chain fatty acids (SCFAs), the end products of fermentation of dietary fibers by the anaerobic intestinal microbiota, have been shown to exert multiple beneficial effects on mammalian energy metabolism. The mechanisms underlying these effects are the subject of intensive research and encompass the complex interplay between diet, gut microbiota, and host energy metabolism. This review summarizes the role of SCFAs in host energy metabolism, starting from the production by the gut microbiota to the uptake by the host and ending with the effects on host metabolism. There are interesting leads on the underlying molecular mechanisms, but there are also many apparently contradictory results. A coherent understanding of the multilevel network in which SCFAs exert their effects is hampered by the lack of quantitative data on actual fluxes of SCFAs and metabolic processes regulated by SCFAs. In this review we address questions that, when answered, will bring us a great step forward in elucidating the role of SCFAs in mammalian energy metabolism.

Keywords: bacterial short-chain fatty acid metabolism; nutritional fiber; short-chain fatty acid fluxes and concentrations.

Fig. 1.

Schematic overview of the three pathways that gut microbes use to get rid of excess reducing equivalents A: Pyruvate reduced to lactate thereby reducing NADH (1), pyruvate:ferredoxin oxidoreductase and hydrogenase (2a) or NADH:ferredoxin oxidoreductase and hydrogenase to sink reducing equivalents into molecular H₂ (2b), and primitive anaerobic electron transport chain for reducing NADH (3). B, C: Schematic overview of the production of acetate, propionate, and butyrate from carbohydrates. B: Acetate is either formed directly from acetyl CoA or via the Wood-Ljungdahl pathway using formate. Propionate can be formed from PEP through the succinate decarboxylation pathway or through the acrylate pathway in which lactate is reduced to propionate. C: Condensation of two molecules of acetyl CoA results in butyrate by the enzyme butyrate-kinase or by utilizing exogenously derived acetate using the enzyme butyryl-CoA:acetate-CoA-transferase.

Fig. 2.

Schematic overview of the proposed transport mechanisms of SCFAs in colonocytes. Across the apical membrane the major part of SCFAs is transported in the dissociated form by an HCO₃⁻ exchanger of unknown identity (?) or by one of the known symporters, MCT1 or SMCT1. A small part may be transported via passive diffusion (spiral). The part of SCFAs that is not oxidized by the colonocytes is transported across the basolateral membrane. The basolateral transport can be mediated by an unknown HCO₃⁻ exchanger, MCT4, or MCT5.

Fig. 3.

Schematic overview of the proposed mechanisms by which SCFAs increase fatty acid oxidation in liver, muscle, and brown adipose tissue. In muscle and liver, SCFAs phosphorylate and activate AMPK (pAMPK) directly by increasing the AMP/ATP ratio and indirectly via the Ffar2-leptin pathway in white adipose tissue. In white adipose tissue, SCFAs decrease insulin sensitivity via Ffar2 and thereby decrease fat storage. In addition, binding of SCFAs to Ffar2 leads to the release of the G_i/o protein, the subsequent inhibition of adenylate cyclase (AC), and an increase of the ATP/cAMP ratio. This, in turn, leads to the inhibition of PKA and the subsequent inhibition of HSL, leading to a decreased lipolysis and reduced plasma free fatty acids.

Fig. 4.

Schematic overview of the proposed mechanisms by which SCFAs effect glucose metabolism. In the colon SCFAs can increase PYY and GLP-1 expression via Ffar2 and Ffar3. PYY has been shown to increase glucose uptake in muscle and adipose tissue, whereas GLP-1 increases insulin and decreases glucagon production in the pancreas. In addition, SCFAs have been shown to decrease hepatic gluconeogenesis by increasing the AMPK phosphorylation and activity.