Short-Chain Fatty Acids in Immune Modulation

Short-chain fatty acids (SCFAs) are small organic acids—primarily acetate, propionate and butyrate—generated by bacterial fermentation of dietary fibre in the gut. Once produced, these metabolites engage cell-surface sensors and penetrate host cells to influence energy metabolism, barrier integrity and gene expression. SCFAs orchestrate both innate and adaptive immune responses by modulating the function of epithelial cells, macrophages, dendritic cells, T lymphocytes and innate lymphoid cells. Mechanisms include activation of G-protein coupled receptors, inhibition of histone deacetylases and induction of metabolic reprogramming. Collectively, these pathways contribute to maintenance of mucosal homeostasis, limitation of excessive inflammation and regulation of systemic immunity. Growing evidence underscores the global significance of SCFAs in preventing inflammatory and autoimmune disorders, shaping responses to infection and offering new avenues for therapeutic intervention.

Research from Nature Portfolio

Early-life interactions between the gut microbiota and liver-resident natural killer cells have been shown to depend on butyrate-driven interleukin-18 production. Antibiotic-induced dysbiosis in neonates lowers hepatic butyrate levels, impairs IL-18 synthesis by Kupffer cells and hepatocytes, and disrupts natural killer cell maturation. Dietary supplementation with butyrate-producing bacteria restores IL-18 signalling and NK cell function. SCFAs have been demonstrated to enhance interleukin-22 production by both CD4+ T cells and innate lymphoid cells. This effect is mediated through GPR41 activation and histone deacetylase inhibition, leading to upregulation of aryl hydrocarbon receptor and hypoxia-inducible factor 1α. The resulting increase in IL-22 fortifies intestinal barrier integrity and dampens inflammation. Gut microbiota-derived SCFAs also promote interleukin-10 secretion by antigen-specific Th1 cells via GPR43 engagement. Activation of mTOR and STAT3 pathways induces the transcription factor Blimp-1, which drives IL-10 expression and limits colitis severity in experimental models.

Short-Chain Fatty Acids in Immune Modulation publication trend

The graph below shows the total number of articles in short-chain fatty acids in immune modulation across all publications each year (not limited to Nature Index journals).

Technical terms

Short-chain fatty acids (SCFAs): Saturated aliphatic fatty acids with two to six carbons, produced by microbial fermentation of dietary fibre.

G-protein coupled receptors (GPRs): Seven-transmembrane cell-surface receptors that sense extracellular SCFAs and trigger intracellular signalling cascades.

Histone deacetylases (HDACs): Enzymes that remove acetyl groups from histone proteins, altering chromatin structure and regulating gene transcription.

Innate lymphoid cells (ILCs): Innate immune cells that mirror T helper subsets in cytokine production and contribute to tissue homeostasis.

Type 3 immunity: Immune responses characterised by interleukin-22 and interleukin-17 production, essential for mucosal barrier defence.

Interleukin-22 (IL-22): A cytokine produced by ILCs and T cells that promotes epithelial regeneration and antimicrobial peptide expression.

References

1. Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis. Nature Communications (2023).
2. Gut Microbiota‐Derived Hyocholic Acid Enhances Type 3 Immunity and Protects Against Salmonella enterica Serovar Typhimurium in Neonatal Rats. Advanced Science (2024).
3. Regulation of immune cell function by short‐chain fatty acids. Clinical & Translational Immunology (2016).
4. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nature Communications (2020).
5. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nature Communications (2018).
6. Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate. Scientific Reports (2018).
7. Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids. Cellular & Molecular Immunology (2021).