Short Chain Fatty Acid Metabolism in Relation to Gut Microbiota and Genetic Variability

Abstract

It is widely accepted that the gut microbiota plays a significant role in modulating inflammatory and immune responses of their host. In recent years, the host-microbiota interface has gained relevance in understanding the development of many non-communicable chronic conditions, including cardiovascular disease, cancer, autoimmunity and neurodegeneration. Importantly, dietary fibre (DF) and associated compounds digested by the microbiota and their resulting metabolites, especially short-chain fatty acids (SCFA), were significantly associated with health beneficial effects, such as via proposed anti-inflammatory mechanisms. However, SCFA metabolic pathways are not fully understood. Major steps include production of SCFA by microbiota, uptake in the colonic epithelium, first-pass effects at the liver, followed by biodistribution and metabolism at the host's cellular level. As dietary patterns do not affect all individuals equally, the host genetic makeup may play a role in the metabolic fate of these metabolites, in addition to other factors that might influence the microbiota, such as age, birth through caesarean, medication intake, alcohol and tobacco consumption, pathogen exposure and physical activity. In this article, we review the metabolic pathways of DF, from intake to the intracellular metabolism of fibre-derived products, and identify possible sources of inter-individual variability related to genetic variation. Such variability may be indicative of the phenotypic flexibility in response to diet, and may be predictive of long-term adaptations to dietary factors, including maladaptation and tissue damage, which may develop into disease in individuals with specific predispositions, thus allowing for a better prediction of potential health effects following personalized intervention with DF.

Keywords: SNPs; dietary fibre; holobiont; microbiome; nutrigenetics; nutrigenomics; short chain fatty acids; sustainable development; synergies; translational research.

Figure 1

Host-driven variability in SCFA metabolism and distribution may lead to different disease outcomes. ADME (sub-) steps may explain the variability in SCFA effects. The enterotype influences the amount of SCFA produced, while human digestive enzymatic activity may regulate microbial communities; (1) Absorption: SNPs in mucin, MCTs or tight junction function could impair SCFA bioavailability. Butyrate is the main energy source for colonocytes. (2) In the portal circulation SCFA undergo first-pass effects, where a majority of propionate is metabolized via GPR109A, GPR43 and GPR41, having gluconeogenic or lipogenic effects. Distribution In the systemic circulation: although at present at low concentrations, butyrate and propionate are still detectable; acetate is now the most abundant SCFA. (3) Acetate inhibits lipolysis at the adipose tissue level. (4) Acetate can cross the “blood-brain-barrier” (BBB). Metabolism: SCFA have showed to be effective against microglial oxidative stress responses. SCFA may also have cellular signalling properties, as evidenced by its control of centrally released insulin (6) or its impact on the hypothalamic-pituitary-adrenal axis in leptin and cortisol responses, which may ultimately lead into maladaptive health conditions across the body (7). Finally, gluconeogenic, lipogenic and insulinogenic signals impact ghrelin, leptin and peptide YY release, leading to appetite suppression and satiety (8), improved insulin sensitivity and glucose metabolism, as well as reduction of serum lipids. (9) Excretion: in the kidney, SCFA can be re-absorbed by MCT1. Note: the intracellular effect of SCFA e.g., on HDAC or NF-κB are not displayed. Created with BioRender.com.

Figure 2

SCFA-producing microbiota. Different bacterial taxa are associated with the production of different SCFA. Of note, the Clostridium family is not associated with a particular SCFA. This may reflect the abundance of different species of the Clostridia genus in the human gut. Adapted from Macfarlane and Macfarlane [129].

Figure 3

Pleotropism of SCFA, acetate and butyrate. Each SCFA seem to have some organ specificity; butyrate is mainly used for energy generation at the colonic level. In the liver, propionate is principally metabolized, where pleotropic action is found, being lipogenic or gluconeogenic based on its concentration. Acetate is found to affect the hypophysis-adrenal gland axis. However, the same SCFA may impact different organs through different receptors, as receptors show preference but are not restricted to a single SCFA, possibly leading to synergistic effects. Created with BioRender.com.