MULTI-OMICS INSIGHTS INTO MICROBIAL METABOLISM
Restricted (Penn State Only)
- Author:
- Rimal, Bipin
- Graduate Program:
- Bioinformatics and Genomics (PhD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 13, 2023
- Committee Members:
- Andrew Patterson, Chair & Dissertation Advisor
David Koslicki, Major Field Member
Emily Weinert, Outside Unit Member
George Perry, Program Head/Chair
Gary Perdew, Outside Field Member - Keywords:
- Microbiome
Metabolomics
Bile Acids
Bile Salt Hydrolase - Abstract:
- Microbiome studies continue to reveal the intricate relationship between gut bacteria and their host, with advancements in next-generation sequencing and metabolomics providing a deeper understanding of these interactions and uncovering novel roles. Shifting from traditional single omics approaches to multi-omics integration has led to new discoveries. In this study, a multi-omic approach was employed to uncover the novel role of bile salt hydrolase (BSH) as an amine N-acyl transferase. Bile acids, crucial mediators in host-microbiome communication, have been extensively studied, but their diversity is still being appreciated. This study found a correlation between the bsh gene and the ability of bacteria to produce bacterial bile acid amidates (BBAAs), a novel class of bile acids. Pharmacological inhibition of the BSH enzyme in Bifidobacterium longum reduced BBAAs production, while knockout of the bsh gene in Bacteroides fragilis eliminated BBAAs synthesis. Heterologous expression of the bsh gene in non-producing Escherichia coli facilitated BBAAs production, and purified BSH enzyme experiments with its substrate taurocholic acid (TCA) unequivocally demonstrated its essential role in BBAAs synthesis. In vivo observations in germ-free mice monocolonized with WT B. fragilis confirmed the presence of BBAAs, while their absence was observed in mice monocolonized with the bsh knockout strain. Furthermore, BBAAs were detected in growing infants, suggesting a correlation between their presence and the developing microbiome and colonization with bsh harboring bacteria. The early-life detection of these amidates raises questions about their impact on the host and their potential to shape the host metabolome. Initial studies indicated that these amidates activate host ligand-activated transcription factors, including the farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor, thereby potentially influencing host physiology. Additionally, through transcriptomics and untargeted metabolomics, a putative intermediate in the production of these amidates was proposed. Moreover, the integration of multi-omics approaches provides insights into the intricate interplay between xenobiotics (such as persistent organic pollutants) and pharmaceutical drugs with the gut microbiome. By combining metabolomics with next-generation sequencing data, bi-directional effects of these environmental pollutants and medications on the gut microbiome have been uncovered. Notably, the identification of microbial metabolites with consequential effects on the host has been a significant outcome of these investigations. The integration of multi-omics approaches enhances our understanding of the complexity of interactions between xenobiotics, the microbiome, and host physiology. These findings emphasize the importance of considering multi-omics integration to gain comprehensive insights into the impact of environmental factors, microbial metabolism, and host health.