Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biomedical Informatics

First Advisor

Chittibabu Guda

Abstract

Colorectal cancer (CRC) is the most common malignancy and the second most common cause of cancer-related deaths in the world. It is a multifactorial disease mediated by genetic, environmental, and lifestyle factors. Over time, the accumulation of genetic and epigenetic changes results in the activation of oncogenes and deactivation of tumor suppressor genes in the colon and rectal region which finally leads to tumor development. The gut microbiome is the main factor linking the effects of diet and environmental factors to host metabolism. Several studies showed the dysbiosis of gut microbiota in CRC patients with an increased proportion of pathogenic microbes and a reduction in the gut commensals. And it is also evident from the studies that pathogenic bacteria contribute to the CRC through DNA damage, pro-inflammatory signals, and altered signaling pathways. This strong link between the gut microbiome and CRC represents the gut microbiome as an ideal biomarker for CRC diagnosis and further harnesses it to develop new therapeutic interventions for CRC. Currently, the gut microbiome has gained immense importance in cancer research and human health.

In this dissertation, a meta-analysis of shotgun metagenomic CRC datasets belonging to different geographical regions was performed using three distinct methods and identified 21 global microbial biomarkers for CRC. Co-occurrence network analysis of gut microbes showed higher co-occurrence correlations among the pathogenic species in CRC networks; in contrast, the control networks showed higher co-occurrences among gut commensals.

Functional analysis of gut microbial communities showed variations in the enrichment of metabolic pathways and microbial contributors to the metabolic pathways between CRC and control gut communities. Analysis of butyrate synthesis pathways revealed the differences in the source of butanoate in control and CRC metagenomes.

Pangenome gene family analysis of CRC-associated pathogenic species showed the high variability of these microbial species across the geographic regions, mainly attributed to differences in the accessory genes involved in bacterial virulence and antibiotic resistance. We further leveraged the predicted metabolome of microbial communities and showed the differences in metabolite composition of CRC and control groups. Our analysis also revealed altered metabolite and microbial interactions in CRC, reflecting the role of gut microbiota in CRC.

Using metabolic modeling of CRC- and control-associated microbes on three different diet media identified the metabolic flux differences in isoprenoid and butyrate biosynthesis pathways in CRC and control communities. Overall, this study reported detailed taxonomic, functional, and metabolic differences between dysbiotic CRC and healthy control gut communities, which could serve as microbial and metabolite biomarkers for CRC. These findings could serve in understanding the dysbiosis in CRC and the development of non-invasive diagnostic and therapeutic strategies.

Download

Share

COinS