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Review
. 2016 Apr 22;5(4):e73.
doi: 10.1038/cti.2016.17. eCollection 2016 Apr.

Regulation of immune cell function by short-chain fatty acids

Renan Corrêa-Oliveira  1 , José Luís Fachi  1 , Aline Vieira  1 , Fabio Takeo Sato  1 , Marco Aurélio R Vinolo  1
Affiliations
Review

Regulation of immune cell function by short-chain fatty acids

Renan Corrêa-Oliveira et al. Clin Transl Immunology. .

Abstract

Short-chain fatty acids (SCFAs) are bacterial fermentation products, which are chemically composed by a carboxylic acid moiety and a small hydrocarbon chain. Among them, acetic, propionic and butyric acids are the most studied, presenting, respectively, two, three and four carbons in their chemical structure. These metabolites are found in high concentrations in the intestinal tract, from where they are uptaken by intestinal epithelial cells (IECs). The SCFAs are partially used as a source of ATP by these cells. In addition, these molecules act as a link between the microbiota and the immune system by modulating different aspects of IECs and leukocytes development, survival and function through activation of G protein coupled receptors (FFAR2, FFAR3, GPR109a and Olfr78) and by modulation of the activity of enzymes and transcription factors including the histone acetyltransferase and deacetylase and the hypoxia-inducible factor. Considering that, it is not a surprise, the fact that these molecules and/or their targets are suggested to have an important role in the maintenance of intestinal homeostasis and that changes in components of this system are associated with pathological conditions including inflammatory bowel disease, obesity and others. The aim of this review is to present a clear and updated description of the effects of the SCFAs derived from bacteria on host immune system, as well as the molecular mechanisms involved on them.

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Figures

Figure 1
Figure 1
Cellular signaling pathways activated by the short-chain fatty acids. These bacterial metabolites activate membrane receptors called GPCRs (as FFAR2, FFAR3, GPR109a and Olfr78). They are also able to reach the cytoplasm of the cells through transporters (Slc16a1 and Slc5a8) or passive diffusion across the plasma membrane (mainly, the non-ionized form) and they modulate the activity of several enzymes and transcription factors including the HIF, HDACs and histone acetyltransferase (HAT). SCFAs modify several cellular processes including gene expression, chemotaxis, differentiation, proliferation and apoptosis through these mechanisms.
Figure 2
Figure 2
The SCFAs are bacterial fermentation products found in high concentrations in the intestine. These metabolites act as a link between the microbiota and the immune system. IECs uptake SCFAs through passive (mainly, the non-ionized form) and active mechanisms. Once inside the cells, they are partially used as a source of energy (1). In addition, these SCFAs increase the expression of antimicrobial peptides secreted to the external surface by epithelial cells (2) and modulate their production of immune mediators including IL-18, a key cytokine for the repair and maintenance of epithelial integrity, and others cytokines and chemokines (3). SCFAs can also regulate the differentiation, recruitment and activation of immune cells: including neutrophil (4), DCs (5), macrophages (6) and T lymphocytes (7). In this context, SCFAs interact with neutrophils and modulate their recruitment, effector function and survival at the tissues (4). In general, these bacterial metabolites present anti-inflammatory effects including reduction of some pro-inflammatory cytokines such as TNF-α and IL-12 production by macrophages and DCs, and change their capacity to capture antigens and stimulate T cells. In addition, the SCFAs also modulate the proliferation and differentiation of T lymphocytes through direct effects on these cells (for example, inducing the generation of Tregs) (7).
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