title: Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut.
abstract: Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the key microbial functions influencing host energy metabolism and adiposity remain to be determined. Despite an increased understanding of the genetic content of the gastrointestinal microbiome, functional analyses of common microbial gene sets are required. We established a controlled expression system for the parallel functional analysis of microbial alleles in the murine gut. Using this approach we show that bacterial bile salt hydrolase (BSH) mediates a microbe-host dialogue that functionally regulates host lipid metabolism and plays a profound role in cholesterol metabolism and weight gain in the host. Expression of cloned BSH enzymes in the gastrointestinal tract of gnotobiotic or conventionally raised mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (Pparγ, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIγ), and circadian rhythm (Dbp, Per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in a significant reduction in host weight gain, plasma cholesterol, and liver triglycerides, demonstrating the overall impact of elevated BSH activity on host physiology. In addition, BSH activity in vivo varied according to BSH allele group, indicating that subtle differences in activity can have significant effects on the host. In summary, we demonstrate that bacterial BSH activity significantly impacts the systemic metabolic processes and adiposity in the host and represents a key mechanistic target for the control of obesity and hypercholesterolemia.
authors.affiliation: Alimentary Pharmabiotic Centre and Schools ofMedicine.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Joyce
authors.affiliation: Alimentary Pharmabiotic Centre and Schools ofMedicine,Microbiology.
authors.forename: John
authors.initials: J
authors.lastname: MacSharry
authors.affiliation: Alimentary Pharmabiotic Centre and Schools ofMicrobiology.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Casey
authors.affiliation: Nutrition, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Kinsella
authors.affiliation: Alimentary Pharmabiotic Centre and Schools ofAlimentary Health Ltd., Cork, Ireland.
authors.forename: Eileen F
authors.initials: EF
authors.lastname: Murphy
authors.affiliation: Alimentary Pharmabiotic Centre and Schools of.
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.affiliation: Alimentary Pharmabiotic Centre and Schools ofMicrobiology.
authors.forename: Colin
authors.initials: C
authors.lastname: Hill
authors.affiliation: Alimentary Pharmabiotic Centre and Schools ofMicrobiology,Pharmacy, University College Cork, Cork, Ireland; and c.gahan@ucc.ie.
authors.forename: Cormac G M
authors.initials: CG
authors.lastname: Gahan
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D002940:Circadian Rhythm; D004926:Escherichia coli / Q000235:genetics; D041981:Gastrointestinal Tract / Q000382:microbiology*; D005856:Germ-Free Life; D006868:Hydrolysis; D007778:Lactobacillus / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D014158:Transcription, Genetic; D015430:Weight Gain / Q000235:genetics*
chemical_list: D052242:Adiponectin; D001647:Bile Acids and Salts
keywords: FXR; Lactobacillus salivarius; adiponectin; barrier function; host response