Understanding Host Microbiome Interactions An Omics Approach

This book offers up-to-date information on different microbiomes, their community composition and interactive functions with the host, bringing together information from diverse research reports to provide an overview of the rapid developments in meta-omics technologies. It is a valuable resource for scientists, researchers, postgraduate and graduate students interested in understanding the impact and importance of next generation sequencing technologies on different hosts and their microbiomes.

Microbial interactions shape the world around us. One major determinant of the effect a microbe will have on its environment is the microbe's ability to colonize. For pathogens, colonization directly impacts the host's health and many hosts have mechanisms to limit or otherwise control microbial colonization. These limitations may also prove challenging for commensal or mutualistic microbes, which themselves may be critical many aspects of host health, including defending the host against pathogens. In this dissertation, I explore a spectrum of host-microbiome interactions, ranging from an individual mutualistic bacterial strains of the fungus-growing ant system to whole human gut microbial communities using several approaches to better understand defensive mutualisms. In Chapter 1, I discuss how understanding defensive symbiosis of social animal models, in particular insect systems, may help in understanding with human problems with controlling pathogens in large social populations. In Chapter 2, I present experimental colonization data and comparative genomics that suggests the lack of specificity from the symbiont in the fungus-growing ant and Pseudonocardia mutualism. To explore pathogen interactions with a more complex microbial community, in Chapter 3, I investigate how human gut microbial community responds to infection of the host in a gnotobiotic mouse model with metagenomics and metabolomics approaches. I contrast host without microbiota and hosts with microbiota but no infection to find that infection greatly perturbs the communities and I find particular metabolites in abundance on in the presence of both microbial community and pathogen. Expanding on human gut microbiome and germ-free mouse model approach, in Chapter 4, I use human stool samples as donors to inoculate germ-free in order to identify variability in the microbiome resistance to infection and apply metagenomic techniques to examine commonalities of resistant microbiomes. I find limited evidence of shared taxonomic groups in resistant microbes, but some indication of shared functional genes in the metagenomes associated with pathogen resistance. Together, these approaches provide insight into the complexity of host interplay with defensive microbes.

Only recently have we begun to appreciate the role of microbiome in health and disease. Environmental factors and change of life style including diet significantly shape human microbiome that in turn appears to modify gut barrier function affecting nutrient & electrolyte absorption and inflammation. Approaches that can reverse the gut dysbiosis represent as reasonable and novel strategies for restoring the balance between host and microbes. In the book, we offer summary and discussion on the advances in understanding of pathophysiological mechanisms of microbial host interactions in human diseases. We will not only discuss intestinal bacterial community, but also viruses, fungi and oral microbiome. Microbiome studies will facilitate diagnosis, functional studies, drug development and personalized medicine. Thus, this book will further highlight the microbiome in the context of health and disease, focusing on mechanistic concepts that underlie the complex relationships between host and microbes.

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.

This book is a concerted effort to put together the rapidly growing facets of biological data. It provides a platform for the readers to think about integrative approaches to solve complex biological problems. This fundamental book deals with the simplest concepts of omics to recent advancements in the field. The content is divided into seven chapters that provide insight into various omics approaches, omics technologies, and its applications. Each chapter delves into different molecular scales: genomics, transcriptomics, proteomics, and metabolomics. Further to provide a holistic view a chapter detailing microbiome has been included in the book. The sub-sections in the chapters is dedicated to introducing the various analytical tools such as next generation sequencing, chromatin immunoprecipitation, mass spectrometry, peptide mass fingerprinting, RNA Seq and NMR spectroscopy. It entails a chapter focused on the bioinformatics resources for analysis of the omics data. In summary, this comprehensive book emphasizes the recent advancements in the study of biomolecules spanning from DNA to metabolites.

The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics and Dysbiosis is a one-stop reference on the state-of-the-art research on gut microbial ecology in relation to human disease. This important resource starts with an overview of the normal microbiota of the gastrointestinal tract, including the esophagus, stomach, Ileum, and colon. The book then identifies what a healthy vs. unhealthy microbial community looks like, including methods of identification. Also included is insight into which features and contributions the microbiota make that are essential and useful to host physiology, as is information on how to promote appropriate mutualisms and prevent undesirable dysbioses. Through the power of synthesizing what is known by experienced researchers in the field, current gaps are closed, raising understanding of the role of the microbiome and allowing for further research. Explains how to modify the gut microbiota and how the current strategies used to do this produce their effects Explores the gut microbiota as a therapeutic target Provides the synthesis of existing data from both mainstream and non-mainstream sources through experienced researchers in the field Serves as a ‘one-stop’ shop for a topic that’s currently spread across a number of various journals

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This book examines applications of multi-omics approaches for understanding disease etiology, pathogenesis, host-pathogen interactions. It also analyzes the genetics, immunological and metabolic mechanisms underlying the infections. The book also explores genomics, transcriptomics, translational-omics, and metabolomics approaches to understand the pathogenesis and identify potential drug targets. It reviews the role of epigenetic reprogramming in shaping the host-pathogen interactions and presents bioinformatics application in the identification of drug targets. Further, it examines the potential applications of RNA sequencing and non-coding RNA profiling to identify the pathogenesis. Lastly, it offers the current challenges, technological advances, and prospects of using multi-omics technologies in infectious biology.

The spatial interaction between different biological agents and the host immune system plays a critical role in maintaining tissue homeostasis and influencing disease outcomes. These interactions can be characterized by their complexity and diversity, encompassing various scenarios: Harmonized Interaction, for example, the mutualistic relationship between the microbiota and the immune system is vital for maintaining tissue integrity and immune homeostasis. Hostile Interaction, for example when a viral infection occurs, it triggers a local immune response aimed at eliminating the pathogen. This immune response can result in systemic retaliation, leading to inflammation and other systemic effects. Dynamic Interaction, for example within the tumor microenvironment, there exists a dynamic interplay between tumor cells and immune cells. This complex interaction influences the efficacy of immunotherapy and can determine the outcome of the disease. However, studying these interactions requires methodologies that go beyond traditional single-domain approaches. To comprehensively understand these complex phenomena, we need methods that can capture and preserve spatio-temporal information, identify cross-domain feature responses in a high-plex format, and harmonize biological knowledge across different modalities and biological entities. This thesis work attempts to bridge this gap. Chapter 1 provides a background on tissue biology and the methodologies developed so far, and the unmet need in this field. Chapter 2 introduces MicroCart, an experimental assay for studying host-microbiome interactions, highlighting its design, validation process, and compatibility with different modalities. Chapter 3 presents Redsea, a computational method addressing lateral signal contamination in imaging, emphasizing its significance in improving imaging quality. Chapter 4 discusses Mario, a data integration algorithm enabling the matching and integration of data from different single-cell proteomic and multi-modal methods. Chapter 5 focuses on MaxFuse, a data integration algorithm designed for 'weakly-linked' modalities, facilitating the creation of a spatial-trimodality dataset, showcasing its benefits and applications.