My past research experiences have spanned the fields of molecular microbiology, protein biochemistry, microbial ecology, and bacterial pathogenesis. This multi-disciplinary training has fostered an ability to think outside the box in developing new approaches to understand mechanisms of bacterial pathogenesis. As an undergraduate researcher at the University of Georgia I studied the presence and absence of Desulfovibrio in the intestinal tracts of primates exposed to elemental mercury. After graduating from UGA, I went to work at the Centers for Disease Control and Prevention in Atlanta, Georgia. At CDC I was able to work with NARMS, the National Antimicrobial Resistance Monitoring System, and work on a collection of clinical enteric pathogen isolates from around the United States. My graduate work was a departure from working with intestinal pathogens and was focused on characterizing metalloproteases in Archaeal organisms. During my graduate career at North Carolina State University, I worked closely with the Army Research Office to engineer proteins from Pyrococcus species for stable and long term detoxification of nerve agents. The training in biochemistry and protein structure has been valuable in my current research, analyzing the structure and function of the gastrointestinal tract and its role in Clostridium difficile pathogenesis.
To build upon my prior research training and to contribute to public health research, I went to the University of Michigan to complete my postdoctoral training with Dr. Vincent Young, a leader in the field of microbial ecology and bacterial pathogenesis. My research is multidisciplinary and collaborative, bridging basic research with translational research. My postdoctoral research training has focused on exploring the interplay between the gastrointestinal tract microbiota and the pathogen C. difficile, a significant and re-emerging public health problem. C. difficile infection (CDI) is the leading cause of antibiotic-associated colitis, and is responsible for significant morbidity, mortality, and increased healthcare costs. My research has shown that antibiotics disrupt the indigenous gut microbiota reducing resistance to C. difficile colonization. My broad research career goal is to understand the complex interactions among the gastrointestinal microbiota, pathogens, and the host. I am currently focused on characterizing these mechanisms with respect to antibiotic usage. To accomplish my research goals I integrate data obtained from high-throughput methods that analyze the gastrointestinal microbiome, metabolome and host immune responses in animal models and human biological specimens to model these interactions.
B.S. Environmental Health Science The University of Georgia
Ph.D Microbiology North Carolina State University
Area(s) of Expertise
COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, GASTROENTEROLOGY, GLOBAL HEALTH, INFECTIOUS DISEASES
• Identifying the role of the gastrointestinal tract microbiome and metabolome in shaping colonization resistance against Clostridium difficile
• Clostridium difficile physiology and pathogenesis
• Metabolism of bile acids by the indigenous gastrointestinal microbiota
- Bile acid distributions, sex-specificity, and prognosis in colorectal cancer , BIOLOGY OF SEX DIFFERENCES (2022)
- Prolonged oral antimicrobial administration prevents doxorubicin-induced loss of active intestinal stem cells , GUT MICROBES (2022)
- Tauroursodeoxycholic Acid Inhibits Clostridioides difficile Toxin-Induced Apoptosis , INFECTION AND IMMUNITY (2022)
- The Stickland Reaction Precursor trans-4-Hydroxy-l-Proline Differentially Impacts the Metabolism of Clostridioides difficile and Commensal Clostridia , MSPHERE (2022)
- Clostridioides difficile exploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota , NATURE COMMUNICATIONS (2021)
- Contribution of Inhibitory Metabolites and Competition for Nutrients to Colonization Resistance against Clostridioides difficile by Commensal Clostridium , MICROORGANISMS (2021)
- Lactobacillus bile salt hydrolase substrate specificity governs bacterial fitness and host colonization , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)
- Mechanisms of Colonization Resistance Against Clostridioides difficile , JOURNAL OF INFECTIOUS DISEASES (2021)
- Secondary bile acid ursodeoxycholic acid alters weight, the gut microbiota, and the bile acid pool in conventional mice , PLOS ONE (2021)
- Clostridioides difficile carriage in animals and the associated changes in the host fecal microbiota , ANAEROBE (2020)
Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated colitis and is responsible for significant morbidity, mortality and increased healthcare costs. Antibiotics disrupt the indigenous gut microbiota, reducing resistance to C. difficile colonization. Our knowledge of the mechanism(s) by which the gut microbiota confers resistance to CDI is incomplete, presenting a significant roadblock to improving preventative and therapeutic approaches against this pathogen. My long-term goal is to understand how the gastrointestinal tract microbiota mediates colonization resistance against enteric pathogens, including C. difficile. The overall objective of this application is to define members of the gut microbiota that are able to alter bile acids and consume sugars which are required for C. difficile colonization and pathogenesis. Based on preliminary studies the central hypothesis is that the production and consumption of specific metabolites (secondary bile acids and sugars) by the indigenous gut microbiota contribute to colonization resistance against C. difficile. The rationale that underlies the proposed research is that the targeting of metabolites required for C. difficile colonization has the potential to improve directed therapeutic approaches for this infection. Guided by strong preliminary data, this hypothesis will be tested by exploring the following key questions: 1) Can restoring microbial-mediated secondary bile acid metabolism in the large intestine restore colonization resistance against C. difficile? and 2) Can restoring bacteria that are able to compete for the same nutrients (sugars) as C. difficile requires for growth reestablish colonization resistance against C. difficile? To answer the first key question, we will select for and characterize bacteria that are capable of secondary bile acid metabolism. Genetic engineering of bacterial strains for efficient enzyme delivery to the gastrointestinal tract will be evaluated in vitro and in vivo, in a mouse model of CDI. Under the second key question, we will screen and characterize bacteria that are able to compete for the same nutrients as C. difficile. Bacteria will be evaluated by competition assays in vitro and in vivo, in a mouse model of CDI. Both approaches will explore how these bacterial strains alter C. difficile colonization resistance in the gastrointestinal tract as well as how they alter the surrounding environment including the microbiome, metabolome and host response. The proposed research program in this application is innovative because it represents a departure from the status quo, namely in the approach of using a targeted bacterial therapy to restore secondary bile acids and competition, ultimately restoring colonization resistance against C. difficile. The proposed research is significant, because it will lead to the identification of bacteria and new-targeted approaches to be used for therapeutic interventions to prevent or treat CDI, and potentially other metabolic diseases.
Dr. Casey Theriot and members of her lab will be responsible for running mouse models of Clostridium difficile infection (CDI) with potential therapeutics against C. difficile, provided by Locus Biosciences. She will be responsible for running the relapse model of CDI with potential therapeutics and assessing disease based on weight loss, bacterial load, toxin activity and histopathological changes to the mouse large intestine. She will also help to interpret the results of the mouse models. It is expected that she and her team will meet once a month with Dr. David Ousterout of Locus Biosciences for a conference call to discuss research progress, benchmarks, and strategy. She will continue to provide additional data that are relevant for these approaches as they become available. She will work with the team to draft publications and to present data from this proposal at local and national meetings.
The microbiota-derived bile acid pool in the gastrointestinal (GI) tract is linked to many human diseases including obesity, diabetes, cancer, and GI disorders including Clostridium difficile infection. These diseases are associated with significant morbidity, mortality, and increased healthcare costs. Despite the importance of bile acids to host metabolism and colonization resistance against enteric pathogens, our knowledge of how the gut microbiota modulates the bile acid pool remains rudimentary, presenting a significant roadblock to improving preventative and therapeutic approaches against the above-described GI and metabolic diseases. The objective of this application is to demonstrate that specific members of the gut microbiota are capable of deconjugation and dehydroxylation of primary bile acids into secondary bile acids, which are important for host health and colonization resistance against C. difficile. Based on our preliminary data we hypothesize that members of the gut microbiota capable of deconjugation (Lactobacillus spp.) and dehydroxylation (non-pathogenic Clostridium spp.) of primary bile acids into secondary bile acids contribute to colonization resistance against C. difficile. The rationale that underlies the proposed research is by altering the bile acid pool with candidate microbes there is potential to improve targeted therapeutic approaches for C. difficile infection and other human diseases. Guided by strong preliminary data, this hypothesis will be tested by exploring the following specific aims: 1) To determine whether Lactobacillus and non-pathogenic Clostridium species from the gut microbiota are capable of deconjugation and dehydroxylation of primary bile acids into secondary bile acids; and 2)Demonstrate that modulation of the bile acid composition correlates with decreased disease susceptibility of C. difficile in mice. The approach is innovative, because it represents a departure from the status quo, namely in the approach of using a targeted bacterial therapy to restore the population of secondary bile acids, ultimately restoring colonization resistance against C. difficile. The proposed research is significant, because it will lead to the identification of specific bacterial strains used for therapeutic interventions to rationally alter the bile acid pool in the gut, modulating CDI, and potentially other metabolic diseases.
Aim 1. Identify metabolites in the gastrointestinal tract that contribute to C. difficile colonization and pathogenesis. Cecal and fecal contents of mice treated with broad-spectrum antibiotics and challenged with C. difficile will be analyzed by unbiased liquid chromatography-mass spectrometry to determine the identity and levels of metabolites throughout infection. Using novel mass spectrometry techniques and state of the art instruments we will define the gut metabolome associated with different disease states of C. difficile infection (CDI). Aim 2. Determine the physiological concentrations of gut metabolites that modulate C. difficile pathogenesis. Gastrointestinal metabolites that correlate with the C. difficile lifecycle: germination, outgrowth, and toxin production, will be investigated by using both targeted metabolomics (GC- and LC/MS), ex vivo and in vitro studies.
- Research Area of Emphasis: Computational Biology and Bioinformatics
- CVM: Focus Area
- Research Area of Emphasis: Gastroenterology
- Research Area of Emphasis: Global Health
- Focus Area: Graduate Infectious Diseases
- Research Area of Emphasis: Infectious Diseases
- Population Health and Pathobiology: PHP Faculty
- CVM: Population Health and Pathobiology
- CVM: Research Area of Emphasis
- Study: Lactobacillus Manipulates Bile Acids to Create Favorable Gut Environment
- Study: Inflamed Environment is C. diff Paradise
- Drug Used to Treat Liver Disease Also Affects C. diff Life Cycle, Reduces Inflammation in Mice
- Study Shows CRISPR Effectiveness Against Colitis Pathogen
- Theriot, Lanzas named University Faculty Scholars
- CVM Researcher Awarded Grant for Innovative Disease Work
- Grants Awarded to GI Research Projects at the CVM
- Compounds Kill C. diff, Don’t Affect Other Gut Bacteria In Vitro
- A Moveable Feast: Antibiotics Give C. diff a Nutrient-Rich Environment, No Competition
- Fighting Antibiotic-Resistant Bacteria in Food Animals
- Theriot Earns NIH Grant to Fight Bacterial Infections
- Gut Check: Grants Awarded for Gastrointestinal Disorders Research
- CALS & CVM Partner on Animal Agriculture Research
- Antibiotics pave way for C. difficile infections by killing beneficial bile acid-altering bacteria
- College of Veterinary Medicine Welcomes Dr. Casey Theriot