Abstract
Fermentation of dietary fibre in the gut yields large amounts of short chain fatty acids (SCFAs). SCFAs can impart biological responses in cells through their engagement of ‘metabolite-sensing’ G protein-coupled receptors (GPCRs). One of the main SCFA receptors, GPR43, is highly expressed by neutrophils, which suggests that the actions of GPR43 and dietary fibre intake may affect neutrophil recruitment during inflammatory responses in vivo. Using intravital imaging of the small intestine, we found greater intravascular neutrophil rolling and adhesion in Gpr43−/−mice in response to LPS at 1 h. After 4 h of LPS challenge, the intravascular rolling velocity of GPR43-deficient neutrophils was reduced significantly and increased numbers of neutrophils were found in the lamina propria of Gpr43−/−mice. Additionally, GPR43-deficient leukocytes demonstrated exacerbated migration into the peritoneal cavity following fMLP challenge. The fMLP-induced neutrophil migration was significantly suppressed in wildtype mice that were treated with acetate, but not in Gpr43−/−mice, strongly suggesting a role for SCFAs in modulating neutrophil migration via GPR43. Indeed, neutrophils of no fibre-fed wildtype mice exhibited elevated migratory behaviour compared to normal chow-fed wildtype mice. Interestingly, this elevated migration could also be reproduced through simple transfer of a no fibre microbiota into germ-free mice, suggesting that the composition and function of microbiota stemming from a no fibre diet mediated the changes in neutrophil migration. Therefore, GPR43 and a microbiota composition that allows for SCFA production function to modulate neutrophil recruitment during inflammatory responses.
Highlights
Microbes in the gut were once considered harmful or pathogenic, it is recognized that commensal bacteria and their metabolites are critical in regulating the PLOS ONE | DOI:10.1371/journal.pone.0163750 September 22, 2016GPR43 and Neutrophil Recruitment preparation of the manuscript
Despite recent research revealing a role for dietary fibre or short chain fatty acids (SCFAs) in immune modulation of chronic diseases such as colitis, arthritis and asthma [9,14,15,16], the impact that fibre and its metabolites have on the initial events of neutrophil recruitment during intestinal inflammation in vivo remains unclear
We found no differences in the number of circulating leukocytes and neutrophils in the peripheral blood (Fig 1A and 1B) and in the bone marrow (Fig 1C and 1D) between wildtype and Gpr43−/−mice
Summary
Microbes in the gut were once considered harmful or pathogenic, it is recognized that commensal bacteria and their metabolites are critical in regulating the PLOS ONE | DOI:10.1371/journal.pone.0163750 September 22, 2016. One of the major obstacles to unraveling the function of SCFAs and GPR43 in vivo is the sheer complexity of the cells and mechanisms that contribute to gut homeostasis and immune regulation. Despite recent research revealing a role for dietary fibre or SCFA in immune modulation of chronic diseases such as colitis, arthritis and asthma [9,14,15,16], the impact that fibre and its metabolites have on the initial events of neutrophil recruitment during intestinal inflammation in vivo remains unclear. Using intravital microscopy of the small intestine and in vitro transwell chemotactic assays, we demonstrated that the absence of GPR43 or a fibre-deficient diet results in exacerbated neutrophil recruitment and migration in response to inflammation
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