Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections

The human intestinal microbiome substantially affects human health and resistance to infections in its dynamic composition and varying release of microbial-derived metabolites. Short-chain fatty acids (SCFA) produced by commensal bacteria through fermentation of indigestible fibres are considered key regulators in orchestrating the host immune response to microbial colonization by regulating phagocytosis, chemokine and central signalling pathways of cell growth and apoptosis, thereby shaping the composition and functionality of the intestinal epithelial barrier. Although research of the last decades provided valuable insight into the pleiotropic functions of SCFAs and their capability to maintain human health, mechanistic details on how SCFAs act across different cell types and other organs are not fully understood. In this review, we provide an overview of the various functions of SCFAs in regulating cellular metabolism, emphasizing the orchestration of the immune response along the gut-brain, the gut-lung and the gut-liver axes. We discuss their potential pharmacological use in inflammatory diseases and infections and highlight new options of relevant human three-dimensional organ models to investigate and validate their biological functions in more detail.

Automated summary

The human intestinal microbiome has a significant impact on human health and resistance to infections through the dynamic composition and release of microbial-derived metabolites. Short-chain fatty acids (SCFA), which are produced by commensal bacteria through fermentation of indigestible fibers, play a key role in regulating the host immune response to microbial colonization by influencing various cellular processes. While the pleiotropic functions of SCFAs and their importance in maintaining human health have been studied, there is still a need for a better understanding of their mechanisms of action across different cell types and organs. This review provides an overview of the functions of SCFAs in cellular metabolism, with a focus on their role in orchestrating the immune response along different axes. It also discusses their potential use in treating inflammatory diseases and infections, as well as the use of human three-dimensional organ models for further research.