Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. C URRENT O PINION Gut nutrient sensing and microbiota function in the control of energy homeostasis Gilles Mithieux a,b,c Purpose of review To analyze the respective roles of macronutrient-derived moieties, of a gut mucosal function [intestinal gluconeogenesis (IGN)] and its capacity of influencing the brain control of energy homeostasis, and of the microbiota ‘function’ versus ‘genomic composition’ in the control of host metabolism. Recent findings Small products deriving from protein digestion (peptides) or from fermentation by the gut microbiota (short- chain fatty acids and succinate) activate IGN, a mucosal function sensed by the peripheral gut nervous system, which intitiates metabolic benefits deriving from brain control of energy homeostasis. The microbiota function (fermentation) rather than its genomic composition is a key in these processes. Summary Short-chain fatty acids and succinate produced from the fermentation of macronutrients by the gut microbiota positively influence the brain’s control of energy homeostasis via the activation of IGN. The microbiota function rather than genomic composition is a key in these processes. Keywords gut microbiota, intestinal gluconeogenesis, nutrient sensing, short chain fatty acids INTRODUCTION The maintenance of plasma glucose concentration at around 1 g/l is a critical requirement for the body, as most mammals including humans are incapable of tolerating hypoglycemic episodes for more than a few minutes. Endogenous glucose production (EGP) is thus a crucial function for survival, especially when food is lacking (between the meals or during the night and of course during fasting). Since Claude Bernard, we know that the liver is a crucial organ to produce glucose in blood. After the identification of the key enzyme operating the final reaction of hydrolysis of glucose-6 phosphate (glucose-6 phos- phatase (G6Pase)), the gluconeogenic role of the kidney was evidenced. Compared with the liver and kidney, the intestine expresses weaker-specific G6Pase activity. In addition, it is merged with a high alkaline phosphatase activity. This explains why the expression of specific G6Pase remained for a long time a matter of debate. After the identification of the gene of G6Pase in the 1990s, the presence of its mRNA in the small intestine and its modulation by fasting and diabetes allowed us to firmly assert that G6Pase is actually expressed in the intestine in rats and humans. The demonstration of the gluconeo- genic capacity of the intestine was published soon later. As fasting settles, the intestinal contribution to EGP increases from 5–10% to about 20–25% of the total (for a review, see [1 && ]). Interestingly, previous studies suggested that the delivery of glucose directly in the portal vein in fasting rats could curb their subsequent food intake, whether they were reefed,whereas the glu- cose infusion was maintained. Indeed, glucose may be sensed by specific neurons in the nerves sur- rounding the portal vein walls, which is the first step of a gut to brain neural signalling process activating the main hypothalamic nuclei control- ling energy homeostasis [1 && ]. As intestinal gluco- neogenesis (IGN) delivers glucose just upstream of the site of glucose sensing, this led to the hypothesis that IGN could have the capacity to control food intake, would it be induced between the meals and/ a Institut National de la Sante ´ et de la Recherche Me ´dicale, b Universite ´ de Lyon, Lyon and c Universite ´ Lyon I, Villeurbanne, France Correspondence to Gilles Mithieux, PhD, Inserm U1213, Universite ´ Lyon 1, Laennec, 7 rue Guillaume Paradin, 69372 Lyon Cedex 08, France. Tel: +33 4 78 77 8788; fax: +33 4 7877 87 62; e-mail: gilles.mithieux@inserm.fr Curr Opin Clin Nutr Metab Care 2018, 21:273–276 DOI:10.1097/MCO.0000000000000478 1363-1950 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-clinicalnutrition.com REVIEW