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Short-chain fatty acids: linking diet, the microbiome and immunity

Abstract

The short-chain fatty acids (SCFAs) butyrate, propionate and acetate are microbial metabolites and their availability in the gut and other organs is determined by environmental factors, such as diet and use of antibiotics, that shape the diversity and metabolism of the microbiota. SCFAs regulate epithelial barrier function as well as mucosal and systemic immunity via evolutionary conserved processes that involve G protein-coupled receptor signalling or histone deacetylase activity. Indicatively, the anti-inflammatory role of butyrate is mediated through direct effects on the differentiation of intestinal epithelial cells, phagocytes, B cells and plasma cells, and regulatory and effector T cells. Intestinally derived SCFAs also directly and indirectly affect immunity at extra-intestinal sites, such as the liver, the lungs, the reproductive tract and the brain, and have been implicated in a range of disorders, including infections, intestinal inflammation, autoimmunity, food allergies, asthma and responses to cancer therapies. An ecological understanding of microbial communities and their interrelated metabolic states, as well as the engineering of butyrogenic bacteria may support SCFA-focused interventions for the prevention and treatment of immune-mediated diseases.

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Fig. 1: Environmental factors drive microbial metabolism and diversity with effects on short-chain fatty acid production and inflammation.
Fig. 2: Effects of short-chain fatty acids on G protein-coupled receptor-mediated signalling and histone deacetylases.
Fig. 3: The role of butyrate in intestinal mucosal immunity.
Fig. 4: The role of butyrate in lung mucosal immunity.

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Acknowledgements

E.R.M. is supported by the Wellcome Trust and the Royal Society (206206/Z/17/Z). H.H.U. is supported by the National Institute for Health Research Biomedical Research Centre Oxford, and The Leona M. and Harry B. Helmsley Charitable Trust. The authors thank A. Mowat and A. Cavounidis for critical comments on the manuscript. In light of the large field covered, the authors express their sincere apologies for any literature omissions in the Review due to limitations in the number of references.

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H.H.U. has received research support or consultancy fees from Janssen, UCB Pharma, Eli Lilly, GSK, Celgene/BMS and AbbVie. There is no direct link between any funding and the subject reviewed. All other authors declare no competing interests.

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Glossary

Antimicrobial peptides

Peptides that are essential for the defence of intestinal barrier surfaces against invading bacteria.

Colonization resistance

The ability of the intestinal microbiota to prevent expansion of new microorganisms.

Cross-feeding

An exchange of metabolites among different species or strains of microorganisms as energy or metabolic source.

Faecal microbiota transplantation

The transfer of microorganisms from the stool of one individual to another.

First-pass effect

The reduction of the concentration of a metabolite owing to metabolism at a specific location in the body (such as the liver) before reaching the systemic circulation.

Genetically modified bacteria

Bacteria that have been engineered to express specific genes to modify the bacterial ecosystem, to produce metabolites or proteins, and to modify host function.

Histone deacetylase

(HDAC). An enzyme that mediates protein deacetylation, in particular histone deacetylation, to modify histone function, DNA accessibility and gene transcription.

Holobiont

An ecological unit of a host and other species including commensal bacteria, viruses and fungi residing in the intestine or skin.

Kupffer cells

Liver-resident specialized mononuclear phagocytes that line the hepatic sinusoids.

Microglia

Brain-resident phagocytes that protect the cerebral microenvironment.

Prebiotics

Substances such as carbohydrates that stimulate the growth of probiotic bacteria.

Probiotic bacteria

Bacteria that provide health benefits when consumed.

Resistant starch

Starch that is resistant to digestion in the small intestine.

Short-chain fatty acids

(SCFAs). Comprise fatty acids with a carbon backbone of 1–6 carbons: formate (C1), acetate (C2), propionate (C3), butyrate (C4) and valerate (C5).

T follicular helper cells

Specialized CD4+ T cells that support B cell responses.

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Mann, E.R., Lam, Y.K. & Uhlig, H.H. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01014-8

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