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Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease

Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease
Published: 
Jan 2016
Publisher: 
Cell Host Microbe
Author: 
William R. DePaolo, Ph.D.

Kamdar K1, Khakpour S2, Chen J3, Leone V2, Brulc J4, Mangatu T5, Antonopoulos DA6, Chang EB2, Kahn SA5, Kirschner BS5, Young G7, DePaolo RW8.

Author information

  • 1Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA.
  • 2Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA.
  • 3College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Department of Food Science and Technology, University of California, Davis, Davis, CA 95616, USA.
  • 4Argonne National Laboratory, Argonne, IL 60439, USA.
  • 5Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA.
  • 6Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Argonne National Laboratory, Argonne, IL 60439, USA.
  • 7Department of Food Science and Technology, University of California, Davis, Davis, CA 95616, USA.
  • 8Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: william.depaolo@med.usc.edu.

Abstract

Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.