PT  - JOURNAL ARTICLE
AU  - Thibaut Duparc
AU  - Hubert Plovier
AU  - Vannina G Marrachelli
AU  - Matthias Van Hul
AU  - Ahmed Essaghir
AU  - Marcus Ståhlman
AU  - Sébastien Matamoros
AU  - Lucie Geurts
AU  - Mercedes M Pardo-Tendero
AU  - Céline Druart
AU  - Nathalie M Delzenne
AU  - Jean-Baptiste Demoulin
AU  - Schalk W van der Merwe
AU  - Jos van Pelt
AU  - Fredrik Bäckhed
AU  - Daniel Monleon
AU  - Amandine Everard
AU  - Patrice D Cani
TI  - Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism
AID  - 10.1136/gutjnl-2015-310904
DP  - 2017 Apr 01
TA  - Gut
PG  - 620--632
VI  - 66
IP  - 4
4099  - http://gut.bmj.com/content/66/4/620.short
4100  - http://gut.bmj.com/content/66/4/620.full
SO  - Gut2017 Apr 01; 66
AB  - Objective To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.Design To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).Results Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.Conclusions Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.