title: Microbiota prevents cholesterol loss from the body by regulating host gene expression in mice.
abstract: We have previously observed that knockout of Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol transporter essential for intestinal cholesterol absorption, reduces the output of dry stool in mice. As the food intake remains unaltered in NPC1L1-knockout (L1-KO) mice, we hypothesized that NPC1L1 deficiency may alter the gut microbiome to reduce stool output. Consistently, here we demonstrate that the phyla of fecal microbiota differ substantially between L1-KO mice and their wild-type controls. Germ-free (GF) mice have reduced stool output. Inhibition of NPC1L1 by its inhibitor ezetimibe reduces stool output in specific pathogen-free (SPF), but not GF mice. In addition, we show that GF versus SPF mice have reduced intestinal absorption and increased fecal excretion of cholesterol, particularly after treatment with ezetimibe. This negative balance of cholesterol in GF mice is associated with reduced plasma and hepatic cholesterol, and likely caused by reduced expression of NPC1L1 and increased expression of ABCG5 and ABCG8 in small intestine. Expression levels of other genes in intestine and liver largely reflect a state of cholesterol depletion and a decrease in intestinal sensing of bile acids. Altogether, our findings reveal a broad role of microbiota in regulating whole-body cholesterol homeostasis and its response to a cholesterol-lowering drug, ezetimibe.
authors.affiliation: 1] Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China [2] Department of Animal and Avian Sciences, University of Maryland, 20746, USA.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Zhong
authors.affiliation: Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Sun
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, 20746, USA.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, 20746, USA.
authors.forename: Hongling
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Ben-Hua
authors.initials: BH
authors.lastname: Zeng
authors.affiliation: 1] Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China [2] Department of Animal and Avian Sciences, University of Maryland, 20746, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Wen-Xia
authors.initials: WX
authors.lastname: Li
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, 20746, USA.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, 20746, USA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China.
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Song
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001419:Bacteria / Q000235:genetics / Q000302:isolation & purification*; D001647:Bile Acids and Salts / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000072474:Cytochrome P450 Family 7; D059305:Diet, High-Fat; D000069438:Ezetimibe / Q000494:pharmacology; D005243:Feces / Q000382:microbiology; D005786:Gene Expression Regulation; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism / Q000382:microbiology*; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D012336:RNA, Ribosomal, 16S / Q000737:chemistry / Q000235:genetics; D013250:Steroid Hydroxylases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D008055:Lipids; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D012336:RNA, Ribosomal, 16S; D002784:Cholesterol; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse; D000069438:Ezetimibe