Cell
Volume 156, Issues 1–2, 16 January 2014, Pages 84-96
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Article
Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits

https://doi.org/10.1016/j.cell.2013.12.016Get rights and content
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Highlights

  • Propionate directly initiates portal-brain neural communication

  • Butyrate and propionate induce intestinal gluconeogenesis via different mechanisms

  • Intestinal gluconeogenesis provides a causal link for benefits of dietary fiber

  • Propionate and butyrate positively influence the host metabolism

Summary

Soluble dietary fibers promote metabolic benefits on body weight and glucose control, but underlying mechanisms are poorly understood. Recent evidence indicates that intestinal gluconeogenesis (IGN) has beneficial effects on glucose and energy homeostasis. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate, which are generated by fermentation of soluble fiber by the gut microbiota, activate IGN via complementary mechanisms. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit involving the fatty acid receptor FFAR3. The metabolic benefits on body weight and glucose control induced by SCFAs or dietary fiber in normal mice are absent in mice deficient for IGN, despite similar modifications in gut microbiota composition. Thus, the regulation of IGN is necessary for the metabolic benefits associated with SCFAs and soluble fiber.

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