Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome
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Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against colitis. SCFAs binding to the ‘metabolite-sensing’ receptors GPR43 and GPR109A in non-haematopoietic cells mediate these protective effects. The inflammasome pathway has hitherto been reported as a principal pathway promoting gut epithelial integrity. SCFAs binding to GPR43 on colonic epithelial cells stimulates K+ efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. Dietary fibre also shapes gut bacterial ecology, resulting in bacterial species that are more effective for inflammasome activation. SCFAs and metabolite receptors thus explain health benefits of dietary fibre, and how metabolite signals feed through to a major pathway for gut homeostasis. Dietary fibre is metabolized into short-chain fatty acids by gut bacteria. Here the authors show that these metabolites activate the NLRP3 inflammasome in gut epithelial cells and protect mice from injury-induced colitis, suggesting a mechanism for the benefits of a high-fibre diet.
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SCFAs support the integrity of the intestinal mucosa in vitro and in vivo.
“which have been shown in vitro and in vivo to support the integrity of the intestinal mucosa in a variety of ways (Fukuda et al., 2011; Gaudier et al., 2004; Macia et al., 2015; Willemsen et al., 2003; Wrzosek et al., 2013).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Macia et al., 2015
Inflammasome activation has an essential role in the progression of several neurological disorders like MS, AD, PPD, and NPS.
“In the CNS, inflammasome activation has been mainly linked to neuroinflammatory conditions. As example, it has an essential role in the progression of several neurological disorders like MS, AD, PPD, and NPS (132, 193–197).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [193]
Released IL-18 importantly contributes to maintaining homeostasis in the gut.
“It has been shown that released IL-18 importantly contributes to maintaining homeostasis in the gut (193).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [193]
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“The control of the intestinal mucosa is thus exerted by the epithelial cells, which are able to integrate and respond to various stimuli coming through their PPRs, such as Toll-like receptors (TLRs) [15], Nod-like receptors (NLRs) [16] and short-chain fatty-acid receptors (SCFARs) [17], to establish the so-called “dem…”
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- Authors
- Macia, L., Tan, J., Vieira, A. T., Leach, K., Stanley, D., Luong, S., Maruya, M., Ian McKenzie, C., Hijikata, A., Wong, C., Binge, L., Thorburn, A. N., Chevalier, N., Ang, C., Marino, E., Robert, R., Offermanns, S., Teixeira, M. M., Moore, R. J., Flavell, R. A., Fagarasan, S., & Mackay, C. R.
- Affiliations
- Monash University (AU)
- Universidade Federal de Minas Gerais (BR)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- RIKEN (JP)
- Max Planck Institute for Heart and Lung Research (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mackay, Charles R.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-04-01
- Volume
- 6
- Issue
- 1
- Pages
- 6734-6734
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2078455937
- Cited by
- 1,439
- References
- 49
- Citations by year
- 2026: 132 · 2025: 148 · 2024: 157 · 2023: 150 · 2022: 183 · 2021: 203 · 2020: 125 · 2019: 103 · 2018: 73 · 2017: 81 · 2016: 67 · 2015: 15
- FWCI
- 33.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Acquire (CQUniversity) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Figshare (submittedVersion, cc-by)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais
- Medical Research Council
- National Health and Medical Research Council
- RIKEN
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- dietary fiber, short-chain fatty acids, GPR43, GPR109A, NLRP3 inflammasome, colitis, intestinal homeostasis, gut microbiota, acetate, colonic epithelial cells, potassium efflux, hyperpolarization, high-fiber diet, intestinal barrier integrity
- MeSH terms
- Gastrointestinal Microbiome, NLR Family, Pyrin Domain-Containing 3 Protein, Acetates, Animals, Butyrates, Carrier Proteins, Colitis, Colon, Dietary Fiber, Fatty Acids, Volatile, Fermentation, Homeostasis, Receptors, Nicotinic, Mice, Knockout, Receptors, G-Protein-Coupled, Mice, Inflammasomes
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