Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Frederic D. Bushman

Second Advisor

Gary D. Wu

Abstract

In the last decade, primarily through the use of sequencing, much has been learned about the trillions of microorganisms that reside in human hosts. These microorganisms play a wide range of roles including helping our immune systems develop, digesting our food, and protecting us from the invasion of pathogenic organisms. My thesis focuses on the characterization of fungal, viral, and bacterial communities in humans, investigating the use of defined microbial communities to cure diseases in animal models, and examining the effects of human microbiome modifications through fecal microbiota transfers. In the first part of this thesis, I use deep sequencing of ribosomal RNA gene tags to characterize the composition of the bacterial, fungal, and archaeal microbiota in pediatric patients with Inflammatory Bowel Disease and healthy controls. Archaeal reads were rare in the pediatric samples, whereas an abundant amount of fungal reads was recovered. Pediatric IBD was found to be associated with reduced diversity in both fungal and bacterial gut microbiota, and specific Candida taxa were increased in abundance in the IBD samples. I, then, describe my use of a variety of experimental and computational methods to study the viral communities of immune-compromised lung transplant recipients. Anelloviruses, circular, single-stranded DNA viruses, were found in all lung samples but were 56 times more abundant in samples from lung transplant recipients as compared to healthy controls or HIV+ subjects. In the third part of this thesis, I describe the use of defined microbial communities in mice, and its ability to reduce the production of ammonia long term and mitigate hepatic encephalopathy. This was shown to be true in both mice on a normal protein diet or a low protein diet. Last, I investigate the transfer of viral communities between humans through FMT and characterize features associated with efficient transmission. A case series where feces from a single donor were used to treat three children with ulcerative colitis was used for the analysis. Ultimately this work showed that multiple viral lineages do transfer between human individuals through fecal microbiota transplants, but in this case series none of the viruses were known to infect human cells. In this thesis, I elucidate numerous roles for the microbiome in pediatric patients with IBD and lung-transplant recipients, show exciting new finding about engineering the microbiota to help with hyperammonia, and finally investigate a possible limitation about using microbial communities as therapeutics. Together this body of work provides insights into the assemblage of tiny organisms that live within us, constantly contributing.

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