Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

By L. Macia, Jian Tan, A. T. Vieira, K. Leach, D. Stanley, S. Luong, M. Maruya, Craig Ian McKenzie, A. Hijikata, Connie H. Y. Wong and 12 more. Nature Communications, 2015

1,244 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/88f7e3307d2686b50412c0129a4cf81a7e7a5145

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In Molecular Biology

1. S. Ghosh
2. E. Canfora
3. Ellen E. Blaak
4. A. Valdes
5. E. Verdin
6. Ana Nogal
7. Albert K. Groen
8. M. De Angelis

In Surgery

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Citations in the corpus

• β-Hydroxybutyrate (2017, positive): “Activation of HCAR2 in the gut epithelium by short-chain fatty acids produced by bacterial fermentation of dietary fiber activates the NLRP3 inflammasome and maintains gut membrane integrity (79).”
• Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis (2022, background): “Acetate in the gut epithelial cells of the animal model directly activates the nucleotidebinding oligomerization domain 3 (NLRP3) inflammasome, which increases the release of IL-18 [46], engaging the epithelial IL-18 receptor and promoting intestinal barrier integrity [47].”
• Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis (2019, background): “As mentioned above, SCFAs activate inflammasome through GPR-dependent mechanisms to conduct suppressive functions in colitis [21], and the GPR-inflammasome reactions are also responsible for SCFA-induced differentiation of suppressive Tregs [67, 68].”
• Understanding the Holobiont: How microbial metabolites affect human health and shape the immune system (2017, background): “Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”
• Short chain fatty acids in human gut and metabolic health. (2020, positive): “Activated caspase-1 in turn converts pro-IL-18 into IL-18, which promotes epithelial repair (Macia et al. , 2015).”
• Butyrate: A Double-Edged Sword for Health? (2018, background): “The secretion of IL-18 is also increased in intestinal epithelial cells via butyrate-stimulated signaling ofGPR109A (45).”
• Homeostatic immunity and the microbiota (2017, positive): “, 2011) and short chain fatty acid receptors (Macia et al., 2015).”
• The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “homeostasis.(148,149) Increased protein acetylation and production of TGFβ1 in IEC by butyrate lead to a decrease of IL-8 production in IEC(150) and a promotion of anti-inflammatory regulatory T cells (Treg),(151) respectively.”
• Microbiota metabolite short chain fatty acids, GCPR, and inflammatory bowel diseases (2016, background): “GPR43 on intestinal epithelial cells activates the NLRP3 inflammasome and enhances the production of IL-18, which is critical for maintaining epithelial integrity and intestinal homeostasis [19].”