Immunomodulatory potential of gut microbiome-derived short-chain fatty acids (SCFAs)

Abstract

Intestinal microbiota is an element of the bacterial ecosystem in all mammalian organisms. These microorganisms play a very important part in the development, functioning, and modulation of the immune system from the moment of birth. In recent years, owing to the use of modern sequencing techniques, the microbiome composition in healthy people has been identified based on bacterial 16S rRNA analysis. Currently, more and more attention is being given to the influence of microorganisms on the host’s cellular metabolism. Analysis of microbial metabolites, among them short-chain fatty acids (SCFAs), and disruption of intestinal microbiota homeostasis in terms of their effects on molecular regulatory mechanisms of immune reactions will surely improve the understanding of the etiology of many common diseases. SCFAs, mainly butyrate, propionate, and acetate, occur in specific amounts, and their proportions can change, depending on the diet, age and diseases. The levels of SCFAs are substantially influenced by the ratio of commensal intestinal bacteria, the disturbance of which (dysbiosis) can lead to a disproportion between the SCFAs produced. SCFAs are regarded as mediators in the communication between the intestinal microbiome and the immune system. The signal they produce is transferred, among others, in immune cells via free fatty acid receptors (FFARs), which belong to the family of G protein-coupled receptors (GPCRs). It has been also confirmed that SCFAs inhibit the activity of histone deacetylase (HDAC) – an enzyme involved in post-translational modifications, namely the process of deacetylation and, what is new, the process of histone crotonylation. These properties of SCFAs have an effect on their immunomodulatory potential i.e. maintaining the anti/pro-inflammatory balance. SCFAs act not only locally in the intestines colonized by commensal bacteria, but also influence the intestinal immune cells, and modulate immune response by multi-protein inflammasome complexes. SCFAs have been confirmed to contribute to the maintenance of the immune homeostasis of the urinary system (kidneys), respiratory system (lungs), central nervous system, and the sight organ.

Identification of Potential Biomarkers in the Cervicovaginal Fluid by Metabolic Profiling for Preterm Birth

“…[ 6 ]. Acetate and succinate exhibit deleterious immunomodulatory function, and studies reveal that high acetate and low succinate in CVF associated with PTB [ 23 , 24 ], by disturbing the vaginal pH, induce pro-inflammatory markers (e.g., IL-1B, IL-6, TNF-a, and IL-8) through toll-like receptor (TLR) interaction [ 17 , 18 , 19 , 20 ]. Unfortunately, we did not observe the promising predictive value of acetate and succinate in PTB subjects in this cohort, and this result may be due to the presence of acetate/succinate producing microbiota (Bacteriodetes/Proteobacteria), and different ethnicity [ 19 , 20 ].…”

Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators

“…Genetic models of obesity, the ob/ob mice, have increased levels of butyrate and acetate in the cecal portion of the gut compared to their lean counterparts [37]. These data need to be investigated further in the light of the reported anorexigenic action of acetate in lean mice [3] and the insulin-sensitizing actions of SCFAs in adipocytes and peripheral organs [38], along with their immunomodulatory and anti-inflammatory properties, which participate in the development of the immune system [39]. Germ-free (GF) mice are a critical tool to uncover the causal relationship between the microbiome and disease and to determine the mechanistic basis through which microbes influence the host.…”

The Effect of Probiotics on the Production of Short-Chain Fatty Acids by Human Intestinal Microbiome

“…In addition, SCFAs influence AIM2 and NLRP3 inflammasomes activation which then affects production of interleukin-18 (IL-18) and enhanced epithelial barrier function. Moreover, NLRP6 inflammasome activation and secretion of IL-18 regulate the production of intestinal antimicrobial peptides (AMPs)[54,55]. Abbreviations: FOXP3-forkhead box P3; TGF-β-transforming growth factor β.…”