Environmental Factors Shaping the Microbiota and Clostridioides difficile Infection / Joshua Soto Ocana.

Format:

Book

Thesis/Dissertation

Author/Creator:

Soto Ocana, Joshua, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Microbiology.

Cellular biology.

Molecular biology.

Cell and Molecular Biology--Penn dissertations.

Penn dissertations--Cell and Molecular Biology.

Local Subjects:

Microbiology.

Cellular biology.

Molecular biology.

Cell and Molecular Biology--Penn dissertations.

Penn dissertations--Cell and Molecular Biology.

Physical Description:

1 online resource (137 pages)

Distribution:

Ann Arbor : ProQuest Dissertations & Theses, 2023

Contained In:

Dissertations Abstracts International 85-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Language Note:

English

Summary:

The gastrointestinal (GI) tract is a complex ecosystem that is inhabited by a diverse collection of microorganisms termed the gut microbiota. Proper establishment of a healthy microbial community is essential for host health, as it controls tissue development, educates the immune system, and protects against colonization by pathogenic microbes. Due to the complexity of the GI environment, multiple factors can influence proper establishment of the gut microbiota and outcomes of infection.One of the most important enteric pathogens is Clostridioides difficile. This nosocomial pathogen is a leading cause of hospital-acquired infections in the US. C. difficile colonizes the colon and causes extensive damage to the colonic mucosa due to the production of two potent exotoxins. Manifestation of C. difficile disease in patients is broad and little is known about the factors that shape the severity of C. difficile infection (CDI). Recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI, but little is known about the underlying mechanisms. Here, we show that NSAIDs exacerbate CDI by increasing epithelial cell damage during infection. This mechanism is independent of the canonical target of NSAIDs, cyclooxygenase (COX) enzymes. Rather, NSAIDs disrupt mitochondrial functions in epithelial cells during infection leading to increased colonic damage and mortality. Moreover, we show how alterations to the microbial community can impact NSAID-mediated pathogenesis during CDI.Establishment of the microbiota early in life is primarily driven by mode of delivery at birth, feeding and dietary practices, and stochastic events in life. However, little is known about the impact of host-produced metal-chelating proteins and dietary metals on microbial community assembly. Here, we show that the metal-chelating host protein, calprotectin, is highly abundant early in life and that the ability of bacteria to scavenge metals in this metal-restricted environment is associated with successful colonization. Moreover, we demonstrate that elevated levels of metals in formula-fed infants markedly affect the gut microbial community.Overall, our findings define distinct mechanisms of how environmental factors can alter enteric infections and the establishment of the microbiome early in life.

Notes:

Source: Dissertations Abstracts International, Volume: 85-08, Section: B.

Advisors: Zackular, Joseph P.; Committee members: Hamilton, Kathryn; Brodsky, Igor; Abt, Michael; Hunter, Christopher.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2023.

Local Notes:

School code: 0175

ISBN:

9798381510263

Access Restriction:

Restricted for use by site license.