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

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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.

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Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

Zobair Younossi, Aaron Koenig, Dinan Abdelatif … (2016)

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver-related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random-effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (95% CI: 22.10-28.65) with highest prevalence in the Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity (51.34%; 95% CI: 41.38-61.20), type 2 diabetes (22.51%; 95% CI: 17.92-27.89), hyperlipidemia (69.16%; 95% CI: 49.91-83.46%), hypertension (39.34%; 95% CI: 33.15-45.88), and metabolic syndrome (42.54%; 95% CI: 30.06-56.05). Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69-47.13) and 0.09 (95% CI: 0.06-0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person-years (range, 0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33-1.77) and 11.77 per 1,000 person-years (range, 7.10-19.53) and 15.44 per 1,000 (range, 11.72-20.34) and 25.56 per 1,000 person-years (range, 6.29-103.80). Incidence risk ratios for liver-specific and overall mortality for NAFLD were 1.94 (range, 1.28-2.92) and 1.05 (range, 0.70-1.56).

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The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Patrick M. Smith, Michael R. Howitt, Nicolai Panikov … (2013)

Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda … (2013)

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

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Author and article information

Contributors

Lisa-Marie Ney:

ORCID: http://orcid.org/0009-0001-0005-3693

Role: InvestigationRole: Writing – original draftRole: Writing – review & editing

Maximilian Wipplinger:

ORCID: http://orcid.org/0009-0008-2693-5564

Role: InvestigationRole: Writing – original draftRole: Writing – review & editing

Martha Grossmann: Role: InvestigationRole: Writing – original draftRole: Writing – review & editing

Nicole Engert:

ORCID: http://orcid.org/0009-0000-3114-1963

Role: Writing – original draftRole: Writing – review & editing

Valentin D. Wegner:

ORCID: http://orcid.org/0009-0003-7570-9575

Role: Writing – original draftRole: Writing – review & editing

Alexander S. Mosig:

ORCID: http://orcid.org/0000-0002-5687-2444

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Journal

Journal ID (nlm-ta): Open Biol

Journal ID (iso-abbrev): Open Biol

Journal ID (publisher-id): RSOB

Journal ID (hwp): royopenbio

Title: Open Biology

Publisher: The Royal Society

ISSN (Electronic): 2046-2441

Publication date (Electronic, pub): March 29, 2023

Publication date (Electronic, collection): March 2023

Publication date PMC-release: March 29, 2023

Volume: 13

Issue: 3

Electronic Location Identifier: 230014

Affiliations

[ ¹ ] Institute of Biochemistry II, Jena University Hospital, , Kastanienallee 1, 07747 Jena, Germany

[ ² ] Center for Sepsis Control and Care, Jena University Hospital, , Am Klinikum 1, 07747 Jena, Germany

Author notes

[ † ]

Contributed equally

Author information

Lisa-Marie Ney http://orcid.org/0009-0001-0005-3693

Maximilian Wipplinger http://orcid.org/0009-0008-2693-5564

Nicole Engert http://orcid.org/0009-0000-3114-1963

Valentin D. Wegner http://orcid.org/0009-0003-7570-9575

Alexander S. Mosig http://orcid.org/0000-0002-5687-2444

Article

Publisher ID: rsob230014

DOI: 10.1098/rsob.230014

PMC ID: 10049789

PubMed ID: 36977462

SO-VID: 197da06f-b399-4fc3-8ab7-f7a9ce6890c3

License:

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

History

Date received : January 14, 2023

Date accepted : Feburary 21, 2023

Funding

Funded by: Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Jena;

Funded by: Deutsche Forschungsgemeinschaft, http://dx.doi.org/10.13039/501100001659;

Award ID: EXC 2051 – Project-ID 690 390713860

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

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Biomarkers for Inflammatory Lung Disease

Most cited references 191

Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

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Cited by 30

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