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Review
. 2023 Mar;13(3):230014.
doi: 10.1098/rsob.230014. Epub 2023 Mar 29.

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

Lisa-Marie Ney  1 , Maximilian Wipplinger  1 , Martha Grossmann  1 , Nicole Engert  1 , Valentin D Wegner  1 , Alexander S Mosig  1   2
Affiliations
Review

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

Lisa-Marie Ney et al. Open Biol. 2023 Mar.

Abstract

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.

Keywords: SCFA; gut–brain axis; gut–liver axis; gut–lung axis; immune metabolism; organ-on-chip.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
SCFAs are central modulators of the mucosal immune response. They are produced by fermenting commensal bacteria in the intestine and could passively diffuse or be actively transported by MCT-1 or SMCT-1 through the intestinal barrier. SCFAs could act as an energy source for intestinal epithelial cells, contribute to maintaining intestinal barrier function by upregulating Claudin-1 expression, stimulate mucus secretion and induce M2 macrophage polarization with increased LC3-phagocytosis to protect from invading pathogens. Their effects on peripheral immune cells include stimulation of Treg differentiation, boosting neutrophil migration to sites of inflammation, and induction of B cell antibody class switch and antibody secretion against toxins (i.e. from C. diff.). Created with BioRender.com.
Figure 2.
Figure 2.
SCFAs produced and released from the gut are distributed via the bloodstream, eventually reaching the liver, the lung and the CNS. SCFAs can be metabolized via FAO or in the TCA cycle. They can mediate anti-inflammatory effects, contribute to tissue homeostasis, protect from blood barrier breakdown, and alleviate symptoms of inflammatory diseases and neural disorders. HCC, hepatocellular carcinoma; AHR, airway hyperreactivity; NASH, non-alcoholic steatohepatitis. Created with BioRender.com.
Figure 3.
Figure 3.
Organ-on-chip models for studying SCFA function in the gut and along the gut–liver axis. (a) Annotated schematic illustration of the key features of the HuMiX platform. A microporous membrane serves as a cell culture substrate for epithelial cells that can be perfused in the chip. A nanoporous membrane separates a living microbiota cocultured in the chip from direct interaction with epithelial cells but allows diffusion of microbiota-derived metabolites. The cell culture system allows the generation of oxygen gradients to mimic physiologically relevant culture conditions. Optodes are used to monitor the oxygen saturation of the perfused cell culture medium. Integrated electrodes measure transepithelial electrical resistance (TEER) to quantify the permeability of the epithelial cell layer modulated by microbiota-derived metabolites (with permission from Elsevier, [178]). (b) Schematic illustration of a human microphysiological system integrating organ models of the gut, the liver, and circulating Treg and Th17 cells. In the multi-organ model, disease conditions of ulcerative colitis (UC) were simulated. SCFAs were shown to improve or worsen UC severity, depending on the involvement of effector CD4+ T cells (with permission from Elsevier [179]).
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