Our intestine is host to a complex microbial community, the gut microbiota, which is dominated by obligate anaerobic bacteria belonging to the classes Clostridia and Bacteroidia. It is well established that a disruption of the gut microbiota by antibiotic treatment leads to an expansion of facultative anaerobic Enterobacteriaceae, including pathogens, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), however, the underlying mechanisms are just beginning to be worked out. Importantly, it is not known whether S. Typhimurium expands and/or triggers changes in the microbiota composition in the absence of antibiotic treatment. Our long-range goal is to elucidate molecular mechanisms that control the balance between the pathogen, the host and its gut microbiota. The objectives of this application are to study the mechanisms that enable the pathogen to gain an edge over competing bacteria during intestinal inflammation. Our central hypothesis is that in the absence of antibiotic treatment, S. Typhimurium virulence factors trigger host responses that lead to a depletion of butyrate-producing Clostridia from the gut-associated microbial community, which in turn increases oxygenation of colonocytes, thereby driving a cytochrome bd-II oxidase- dependent pathogen expansion in the gut lumen. We will test different aspects of our hypothesis and accomplish the objectives of this application using the logical and innovative approach outlined in the following specific aims:
Specific Aim 1 : Determine how S. Typhimurium depletes Clostridia during colitis.
Specific Aim 2 : Determine how Clostridia depletion drives S. Typhimurium growth during colitis.
Specific Aim 3 : Determine whether respiration drives S. Typhimurium transmission. It is our expectation that successful completion of the proposed experiments will usher in important conceptual advances in understanding the mechanisms underlying pathogen expansion during S. Typhimurium-induced gastroenteritis. This paradigm-shifting work will be significant because it will have wide appeal among researchers interested in microbial pathogenesis and the contribution of host-associated microbial communities to health and disease.

Public Health Relevance

Non-typhoidal Salmonella serotypes are the single most common cause of death from diarrheal disease associated with viruses, parasites or bacteria and the leading cause of foodborne disease outbreaks in the United States, producing between $0.5 billion to $2.3 billion in annual costs for medical care and lost productivity. The most common human clinical isolate is Salmonella enterica serotypes Typhimurium (S. Typhimurium). Research proposed in this application will support pioneering studies on molecular mechanisms that control the balance between the pathogen, the host and its microbiota. The proposed studies will drive knowledge about Salmonella gastroenteritis to a higher level by providing critical new insights into pathogenesis and by facilitating the development of new intervention strategies through science.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI096528-09
Application #
9687659
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
2011-05-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Litvak, Yael; Byndloss, Mariana X; Bäumler, Andreas J (2018) Colonocyte metabolism shapes the gut microbiota. Science 362:
Hiyoshi, Hirotaka; Wangdi, Tamding; Lock, Gabriel et al. (2018) Mechanisms to Evade the Phagocyte Respiratory Burst Arose by Convergent Evolution in Typhoidal Salmonella Serovars. Cell Rep 22:1787-1797
Byndloss, Mariana X; Olsan, Erin E; Rivera-Chávez, Fabian et al. (2017) Microbiota-activated PPAR-? signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357:570-575
Faber, Franziska; Thiennimitr, Parameth; Spiga, Luisella et al. (2017) Respiration of Microbiota-Derived 1,2-propanediol Drives Salmonella Expansion during Colitis. PLoS Pathog 13:e1006129
Velazquez, Eric M; Rivera-Chávez, Fabian; Bäumler, Andreas J (2017) Spore Preparation Protocol for Enrichment of Clostridia from Murine Intestine. Bio Protoc 7:
Bäumler, Andreas J; Sperandio, Vanessa (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85-93
Faber, Franziska; Tran, Lisa; Byndloss, Mariana X et al. (2016) Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature 534:697-9
Rivera-Chávez, Fabian; Zhang, Lillian F; Faber, Franziska et al. (2016) Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella. Cell Host Microbe 19:443-54
Rivera-Chávez, Fabian; Lopez, Christopher A; Zhang, Lillian F et al. (2016) Energy Taxis toward Host-Derived Nitrate Supports a Salmonella Pathogenicity Island 1-Independent Mechanism of Invasion. MBio 7:
Lopez, Christopher A; Miller, Brittany M; Rivera-Chávez, Fabian et al. (2016) Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration. Science 353:1249-53

Showing the most recent 10 out of 29 publications