title: The acetate switch of an intestinal pathogen disrupts host insulin signaling and lipid metabolism.
abstract: Vibrio cholerae is lethal to the model host Drosophila melanogaster through mechanisms not solely attributable to cholera toxin. To examine additional virulence determinants, we performed a genetic screen in V. cholerae-infected Drosophila and identified the two-component system CrbRS. CrbRS controls transcriptional activation of acetyl-CoA synthase-1 (ACS-1) and thus regulates the acetate switch, in which bacteria transition from excretion to assimilation of environmental acetate. The resultant loss of intestinal acetate leads to deactivation of host insulin signaling and lipid accumulation in enterocytes, resulting in host lethality. These metabolic effects are not observed upon infection with &#916;crbS or &#916;acs1 V. cholerae mutants. Additionally, uninfected flies lacking intestinal commensals, which supply short chain fatty acids (SCFAs) such as acetate, also exhibit altered insulin signaling and intestinal steatosis, which is reversed upon acetate supplementation. Thus, acetate consumption by V. cholerae alters host metabolism, and dietary acetate supplementation may ameliorate some sequelae of cholera.
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Saiyu
authors.initials: S
authors.lastname: Hang
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Purdy
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Robins
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Molecular Biology and Biotechnology, Tezpur University, Assam 784 028, India.
authors.forename: Manabendra
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mekalanos
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: paula.watnick@childrens.harvard.edu.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Watnick
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002772:Cholera Toxin / Q000633:toxicity; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism / Q000382:microbiology; D020895:Enterocytes / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D061385:Insulins / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology*; D050356:Lipid Metabolism; D064307:Microbiota; D015398:Signal Transduction; D014734:Vibrio cholerae / Q000472:pathogenicity*; D037521:Virulence Factors
chemical_list: D000085:Acetates; D001426:Bacterial Proteins; D061385:Insulins; D037521:Virulence Factors; D002772:Cholera Toxin; D003066:Coenzyme A Ligases; C561832:Acsl1 protein, rat