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

Macia, Laurence; Tan, Jian; Vieira, Angélica T.; Leach, Katie; Stanley, Dragana; Luong, Suzanne; Maruya, Mikako; McKenzie, Craig; Hijikata, Atsushi; Wong, Connie Hoi Yee; Binge, Lauren Clare; Thorburn, Alison N.; Chevalier, Nina; Ang, Caroline; Mariño, Eliana; Robert, Rémy; Offermanns, Stefan; Teixeira, Mauro Martins; Moore, Robert J.; Flavell, Richard A.; Fagarasan, Sidonia; Mackay, Charles R.

doi:10.1038/ncomms7734

Cited by 1,101 publications

(973 citation statements)

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“…13,39,40 Activation of GPR43 by acetate leads to colonic epithelial hyperpolarization, which was accompanied by a reduction in apoptosis. 11 We found, however, that Gpr43 and other metabolite-sensing G proteincoupled receptors previously associated with SCFAs such as the olfactory receptor (Olfr78) 41 were not expressed in the kidney or heart (data not shown). Gpr43 mRNA was also downregulated in the gut with mineralocorticoid excess independently of the treatment group (data not shown).…”

Section: Cardiac Transcriptomementioning

confidence: 64%

“…Consumption of a diet high in fiber increases gut microbiota populations that generate short-chain fatty acids (SCFAs) such as acetate. [9][10][11] Gut microbiota dysbiosis has been recently associated with high BP in animal and human hypertension. 12 In the present study, we aimed to investigate whether dietary fiber or acetate supplementation, through changes in the gut microbiota, prevents the development of hypertension and associated renal and cardiac fibrosis in the deoxycorticosterone acetate (DOCA)-salt model.…”

Section: Fibre Contentmentioning

confidence: 99%

“…10,11 To determine whether fiber would increase SCFAs, major genera were classified according to their primary fermentation product as acetate or butyrate according to previously published work. 16 …”

Section: Clinical Perspectivementioning

confidence: 99%

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High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

et al. 2017

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Background: Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here, we evaluated the effect of a high-fiber diet and supplementation with the short-chain fatty acid acetate on the gut microbiota and the prevention of cardiovascular disease. Methods: Gut microbiome, cardiorenal structure/function, and blood pressure were examined in sham and mineralocorticoid excess–treated mice with a control diet, high-fiber diet, or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets. Results: We found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria independently of mineralocorticoid excess. Both fiber and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of Bacteroides acidifaciens . Compared with mineralocorticoid-excess mice fed a control diet, both high-fiber diet and acetate supplementation significantly reduced systolic and diastolic blood pressures, cardiac fibrosis, and left ventricular hypertrophy. Acetate had similar effects and markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fiber and acetate were accompanied by the downregulation of cardiac and renal Egr1 , a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation. We also observed the upregulation of a network of genes involved in circadian rhythm in both tissues and downregulation of the renin-angiotensin system in the kidney and mitogen-activated protein kinase signaling in the heart. Conclusions: A diet high in fiber led to changes in the gut microbiota that played a protective role in the development of cardiovascular disease. The favorable effects of fiber may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.

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Section: Cardiac Transcriptomementioning

confidence: 64%

Section: Fibre Contentmentioning

confidence: 99%

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High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

et al. 2017

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“…Dietary fibre is fermented by colonic commensal bacteria to short-chain fatty acids (SCFAs). SCFAs are anti-inflammatory 24 , promote gut homeostasis 30 and epithelial integrity 4,29 , and regulate the size and function of the colonic Treg pool [25][26][27] . A recent study reported that dietary fibre and the SCFA propionate protected against allergic airway disease (AAD) in mice 6 .…”

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confidence: 99%

Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites

et al. 2015

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“…In general, the activation of GPR41 (or FFAR3) and GPR43 (or FFAR2) releases peptide YY and glucagon-like peptide-1 (GLP-1), which affect host satiety and intestinal gluconeogenesis. Besides, SCFAs signalling through GPR109A exerts antiinflammatory and anti-tumorigenic responses (Macia et al 2015). Butyrate and propionate to a lesser extent, can also be involved in the epigenetic regulation of host gene expression by inhibiting histone deacetylase (HDAC) (Fellows et al 2018).…”

Section: Comparative Genomics Reveal Thatmentioning

confidence: 99%

Cross-feeding interactions of gut symbionts driven by human milk oligosaccharidesand mucins

Chia¹

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Chapter 4Microbial metabolic networks at the mucus layer lead to dietindependent butyrate and vitamin B12 production by intestinal symbionts 71 Chapter 5Deciphering trophic interaction between Akkermansia muciniphila and the butyrogenic gut commensal Anaerostipes caccae using a metatranscriptomic approach 97 Chapter 6General discussion 123 Chapter 7 Thesis summary & Nederlandse samenvatting 143 Appendices References 153Co-author affiliations 179Acknowledgements 183About the author 184List of publications 185 VLAG training activities 186Chapter 1 General introduction and thesis outlineChapter 1 2 General introductionHumans can be considered holobionts, consisting of cells from the host and an even larger number of microorganisms (Postler and Ghosh 2017). The majority of microbes are residing in the gut (Sender et al 2016). The human gut microbiota is a complex ecosystem consisting of bacteria, archaea, microeukaryotes and viruses (Clemente et al 2012). Over 2000 species-level phylotypes (prokaryotes including bacteria and archaea) have been detected for the gut microbiota, with each individual estimated to host at least 160 species (Qin et al 2010, Zoetendal et al 2008. The gut microbiota may impact the well-being of human and susceptibility for diseases by interacting with our metabolic, immune and neurological system (Honda and Littman 2016, Koh et al 2016, Rogers et al 2016. Furthermore, the gut microbiota contributes to a variety of metabolic functions and can be seen as an essential part of our digestive system (El Kaoutari et al 2013). Bacterial symbionts allow the human hosts to utilise inaccessible nutrients by converting complex substrates to short chain fatty acid (SCFA) and vitamins (Fisher et al 2017). Bacterial-derived SCFAs are estimated to contribute about 10% of our daily caloric requirement (Bergman 1990). While all SCFAs are vital for maintaining gut homeostasis, butyrate is of particular interest because it has been attributed to a range of health-promoting functions. Butyrate is the primary energy source for colonic epithelial cells and is associated with the enhancement of colonic barrier function, increase of satiety, pain relief, anti-inflammatory responses, and protection against colorectal cancer (Banasiewicz et al 2013, Bolognini et al 2016, Donohoe et al 2011, Furusawa et al 2013, Goncalves and Martel 2013.Considering the physiological benefits of butyrate to human health, this thesis investigates the microbial interaction of gut symbionts that support butyrate production driven primarily by the host produced glycans in human milk and mucus. Glycans are compounds consisting of an array of glycosidically linked monosaccharides (monosaccharides and disaccharides are collectively termed sugars) such as human milk oligosaccharides (HMOS) and mucins (Varki and Kornfeld 2017). HMOS present in mother milk are the major compositional and functional driver of the infant gut microbiota (Backhed et al 2015). Mucin glycans covering the intestinal lining create a stable niche for bacterial coloni...

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

Cited by 1,101 publications

References 48 publications

High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites

Cross-feeding interactions of gut symbionts driven by human milk oligosaccharidesand mucins

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