Short-Chain Fatty Acids and Human Health: From Metabolic Pathways to Current Therapeutic Implications

Abstract

The gastrointestinal tract is home to trillions of diverse microorganisms collectively known as the gut microbiota, which play a pivotal role in breaking down undigested foods, such as dietary fibers. Through the fermentation of these food components, short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are produced, offering numerous health benefits to the host. The production and absorption of these SCFAs occur through various mechanisms within the human intestine, contingent upon the types of dietary fibers reaching the gut and the specific microorganisms engaged in fermentation. Medical literature extensively documents the supplementation of SCFAs, particularly butyrate, in the treatment of gastrointestinal, metabolic, cardiovascular, and gut-brain-related disorders. This review seeks to provide an overview of the dynamics involved in the production and absorption of acetate, propionate, and butyrate within the human gut. Additionally, it will focus on the pivotal roles these SCFAs play in promoting gastrointestinal and metabolic health, as well as their current therapeutic implications.

Keywords: dietary fiber fermentation; gastrointestinal and metabolic health; intestinal microbiota; short-chain fatty acids (SCFAs); therapeutic implications.

Figure 1

Production, absorption, transport and potential effects of the SCFAs acetate, propionate and butyrate in the human gut. Dietary fibers lead to a higher production of propionate and acetate, while butyrate is primarily obtained through cross-feeding and transformation of other SCFAs. Butyrate, acetate and propionate share some common transporters and are predominantly absorbed through a facilitated process. GPR43 refers to G-protein-coupled-receptors 43, GPR41 to G-protein-coupled-receptors 41, GPR109a refers to G-protein-coupled-receptors 109a, MCT1 to monocarboxylate transporters 1, MCT4 to monocarboxylate transporters 4.

Figure 2

Mechanisms by which SCFAs exert their effects on target cells. SCFAs enter cells via MCT and transporters located on the cell membrane. Once inside the cell nucleus, they inhibit HDAC and activate HAT, facilitating histone acetylation. This process gradually relaxes compacted chromosomes, ultimately resulting in increased gene expression. Additionally, upon entering colonocytes, SCFAs may undergo beta-oxidation and enter the mitochondria, where the citric acid cycle (also known as the Krebs cycle) generates energy for the cell. Another mechanism involves SCFAs binding to GPCR, such as GPR43, GPR41, or GPR109A, on the cell membrane of both colonocytes and immune cells. This interaction inhibits downstream signaling pathways, including NF-κB, Akt, MAPK, and mTOR, while activating the 5’ adenosine monophosphate-activated protein kinase (AMPK) pathway. Consequently, this regulates gene transcription and translation, leading to inflammation mitigation, oxidative stress reduction, and autophagy enhancement. AKT refers to the activation of a serine/threonine kinase; NF-κB to nuclear factor-κB; AMPK to adenosine 5′-monophosphate (AMP)-activated protein kinase; MAPK to mitogen-activated protein kinase; NLRP3 to nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing proteins (NLR); mTOR to mammalian target of rapamycin. The figure was created using BioRender.com (accessed on 25 March 2024).