Abstract

Microbes have co-evolved with us throughout history, building an ecosystem where trillions of bacteria, viruses, archaea and fungi coexist with their host. Collectively termed the gut microbiome, this community has been shown to be vital for human health and development. The gut microbiome starts assembling soon after birth and while undergoing a somewhat predictable ecological succession, it is also affected by host factors including age, genetics, and disease, as well as external factors such as birth mode, diet, and antibiotic exposure. Around three years of age, the gut microbiome stabilizes to an adult-like configuration, at which point there is less interindividual variation in composition. Throughout adulthood a “healthy” gut microbiome is thought to remain relatively stable, although host and environmental factors continue to influence this dynamic ecosystem, making each individual’s microbial ecological trajectory essentially unique. A period of higher instability similar to that of the neonatal microbiome seems to come later in life, however, as environmental and bodily changes associated with aging such as immune senescence, frailty and neurodegeneration influence the gut microbiome. In this Thesis, I investigated the effects of some of these external factors on the gut microbiome during both early and late stages of human life. In Chapter 2, I present results from a study investigating the effects of early life hospitalization and antibiotic exposure on the gut microbiome development of infants born prematurely (< 37 weeks of gestation). Most preterm infants are hospitalized and administered antibiotics soon after birth as they are extremely vulnerable to infection and other comorbidities. We compared the gut microbiome composition and development of antibiotic-exposed preterm infants with those of antibiotic-naïve preterm infants, all hospitalized in NICUs across the Midwest. From a subset of these infants, we additionally cultured and sequenced bacterial isolates from five genera that dominate the NICU-hospitalized preterm infant gut microbiome and that are known to be multi-antibiotic resistant. We found that early life antibiotics reduces microbial diversity and delays the gut microbiome developmental trajectory during the first two months of life. We also examined the load of antibiotic resistance genes (ARGs) encoded by bacterial members of the gut microbiomes in these infants given the widespread use of antibiotics in NICUs. Surprisingly, we found that ARG burden was largely similar across all infants, suggesting that the broader NICU environment may serve as a reservoir of ARG-carrying bacteria which seed the infants’ guts. Further, we found that multiple non-antimicrobial exposures associated with NICU hospitalization also influence the preterm gut microbiome composition. Finally, these findings are corroborated by our selective culture for NICU dominant taxa, which shows no effect of antibiotic exposure on plasmid and prophage distributions. However, we observed high similarity of plasmids in the microbiomes of different infants within and between NICUs and across different genera of plasmid hosts. In Chapter 3, I report findings from a study investigating the effects of preclinical Alzheimer’s Disease (AD) on the gut microbiome of older adults. A growing body of evidence from human studies has demonstrated that AD is accompanied by changes in gut microbiome composition. Evidence from animal models further suggests that the gut microbiome and its metabolites may contribute to the pathology of AD, although it is unclear whether this causal pathway operates in humans. We compared the gut microbiome composition, ecological dynamics and temporal stability as well as intestinal inflammation between cognitively unimpaired “healthy” participants with no biomarker evidence of AD and cognitively unimpaired “preclinical” participants with biomarker evidence of AD. Using cross-sectional data, we found that there is a significant alteration in the overall gut microbiome composition of preclinical AD participants. These individuals also had more interconnected gut microbiomes based on species-species co-occurrence networks and lower levels of intestinal inflammation based on quantification of inflammatory markers from stool. We further identified the enrichment of a group of PET-amyloid-associated species in the preclinical AD participant stools. Using longitudinal data, we found that the higher interspecies connectivity observed in the preclinical AD gut persisted after over a year’s time and was accompanied by increased stability of gut microbiome composition. Finally, measures of gut inflammation combined with the abundance of the PET-amyloid-associated microbial guilds improved the performance of machine learning models for preclinical AD status.

Committee Chair

Gautam Dantas

Committee Members

Andrew Kau; Barbara Warner; Beau Ances; Megan Baldridge; Phillip Tarr

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Human & Statistical Genetics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-12-2026

Language

English (en)

Download

Available for download on Friday, August 11, 2028

Included in

Microbiology Commons

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