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The surface of the human body and its mucous membranes are heavily colonized by microorganisms. Our understanding of the contributions that complex microbial communities make to health and disease is advancing rapidly. Most microbiome research to date has focused on the mouse as a model organism for delineating the mechanisms that shape the assembly and dynamic operations of microbial communities. However, the mouse is not a perfect surrogate for studying different aspects of the microbiome and how it responds to various environmental and host stimuli, and as a result, researchers have been conducting microbiome studies in other animals. To examine the different animal models researchers employ in microbiome studies and to better understand the strengths and weaknesses of each of these model organisms as they relate to human and nonhuman health and disease, the Roundtable on Science and Welfare in Laboratory Animal Use of the National Academies of Sciences, Engineering, and Medicine convened a workshop in December 2016. The workshop participants explored how to improve the depth and breadth of analysis of microbial communities using various model organisms, the challenges of standardization and biological variability that are inherent in gnotobiotic animal-based research, the predictability and translatability of preclinical studies to humans, and strategies for expanding the infrastructure and tools for conducting studies in these types of models. This publication summarizes the presentations and discussions from the workshop.
Human and Animal Microbiome Engineering provides both basic and detailed information about microbiome engineering for the health enhancement of humans and animal populations. Contents provide updated information about current research topics in this emerging field including microbiome gene therapy, engineered probiotics and smart living biotic machines for the release of therapeutics. The book is divided into 4 sections covering microbiome engineering application with a focus on future perspectives in human health and enhancement; microbiome engineering in human health and disease including real-world case studies; animal microbiome engineering essentials; and microbiome engineering for livestock improvement. This is the perfect reference for researchers and scientists to further explore the relationship between host and microbiome and discover novel ideas about the concepts of microbiome engineering in the health enhancement of humans and animal populations.
The human gastrointestinal tract is home to a dense and dynamic microbial community. Recent advancements in sequencing technology have revealed numerous relationships between the composition of these communities and human and health and disease. In some cases, researchers have shown causal relationships between the presence or absence of particular microorganisms and disease. These findings offer promise for using microorganisms or microbial communities to modulate health and disease, but to date, we lack tools and mechanistic insight needed for rational engineering of these communities. Understanding how microorganisms enter, colonize, grow, and disperse to new hosts present key considerations for rational engineering of the human gastrointestinal tract. In this thesis, I use experimental studies of the human and murine gastrointestinal tract to address these considerations. In the first study, I examined endospores and other resistant cell types in the gastrointestinal communities of unrelated humans to identify the ecological role of these states in the distribution of bacterial populations in healthy people. I used this information to infer shared roles for these organisms in successional states in the human gut, and identify host- and diet-derived metabolites as environmental signals mediating the growth and colonization of these organisms. In the second study, I examined the potential for using targeted manipulations of diet to favor selective growth and colonization by an introduced bacterium in the murine gastrointestinal tract. I showed that resource exclusivity of this bacterium permits its selective expansion in this environment, and negatively impacts the growth of other commensals. Central to the goal of rational engineering of the gut microbiota, these studies reveal ecological considerations that may promote or inhibit colonization by introduced commensals in this complex ecosystem. This work invites provides a conceptual framework for integrating systems microbial ecology with engineering design to manipulate the composition of the gastrointestinal microbiota.
The human gastrointestinal tract is home to a dense and dynamic microbial community. The composition and metabolic output of the human gut microbiota have been implicated in many diseases: from inflammatory bowel disease, colorectal cancer, and diarrheal diseases to metabolic syndromes like diabetes. Treatment of these diseases will likely require targeted therapeutic interventions aimed at modulating the abundance and metabolism of specific commensal microbial species or probiotics. A promising avenue for such interventions is through diet, where the dietary components act as substrates for the species producing beneficial metabolites one wishes to enrich. In this thesis, I focus on a dietary intervention study in healthy individuals. Since the human gut microbiota is known for its highly heterogeneous composition across different individuals, it comes as no surprise that a more personalized approach is preeminent. We first test effects of multiple micronutrients spiked into a fixed diet. Using a highly controlled diet within the cohort, we identify strong and predictable responses of specific microbes across participants consuming prebiotic spike-ins. However, select macronutrient spike-ins like unsaturated or saturated fat and protein, produce no predictable response. We next investigate prebiotic supplement in diet further as well as its downstream products, short chain fatty acids, in the digestive tract. We look to alleviate the stress of a highly controlled, low complexity diet on participants by testing the effect of different prebiotics simultaneously ex vivo. We show that individuals vary in their microbial metabolic phenotypes (as in they produce different quantities and proportions of short chain fatty acids from the same prebiotic inputs) mirroring differences in their microbiota composition. Finally, we run a pilot study to elucidate how closely our ex vivo experiment results may reflect the in vivo changes following a short-term dietary fiber supplementation. In addition to obtaining preliminary data on this direct comparison, we also explore different parameters for generating high-throughput data on personalized dietary interventions. Together, these projects provide the framework for building a predicative model for the effect that prebiotic dietary supplementation will have on gut microbiota's composition. Such a prediction model would be equally helpful in both enhancing individuals' gut health and improving gut dysbiosis in cases of disease.
The gut microbiota is a complex community of microbial species inhabiting the digestive tract. Each microbial species is further composed of microbes with slightly different genetic variants also known as strains. While most evolutionary studies of the gut microbiome occur at the community-level or focused on narrow clades of vertebrates, few studies have examined the evolution of wildlife and their gut microbiome at the strain-level across the animal kingdom. In this exploratory study, we examine a wildlife gut metagenomic dataset to investigate the evolutionary dynamics of bacterial species and their respective host. In particular, this is the first examination of whether there is significant congruence between the phylogeny of bacterial strains and that of their respective hosts, which we refer to as strain phylosymbiosis, across the animal kingdom. Our analysis of the most abundant bacteria in our dataset revealed Akkermansia muciniphila and Bacteroides vulgatus exhibited strong signals of strain phylosymbiosis.
Together, they form a suite of complementary approaches to genetically engineer undomesticated gut commensal bacteria and probe the functional genetic networks in the gut microbiome, which will enhance our understanding of microbiome ecology and host-microbiome interactions. In addition, the expanded range of genetic manipulations made possible by these tools may enable production of more diverse, perhaps personalized, probiotics containing engineered functions, such as sensing disease markers or drug delivery.
The microbes that inhabit the human body are integral to human health and disease: from inflammatory bowel disease to allergy, metabolic syndrome to autism. Due to its high connectivity with human physiology, manipulation of the microbiota has therapeutic potential in a vast array of diseases. However, techniques for targeted modification of microbial communities are currently lacking. In this thesis, I present several technologies that can be applied to engineer and better understand the microbiota. First, we present a subtractive strategy for microbiota manipulation using CRIPSR-Cas engineered bacteriophage that can selectively remove target strains from a community based on the presence of target DNA sequences. Next, we describe an additive strategy whereby commensal Bacteroides spp. are genetically modified to perform novel functions within the murine microbiota. We developed a suite of genetic parts to facilitate organism design and engineering. These tools were then expanded to engineer outer membrane vesicles derived from Bacteroides as immunomodulatory agents. Finally, we leveraged the natural sensing abilities of bacteria to create cellular biosensors for biomarkers of gastrointestinal disease. Heme biosensors were paired with readout electronics to generate an ingestible medical device for in situ detection of gastrointestinal bleeding. The technologies described herein contribute to the progression of microbiome engineering towards clinical applications and the advancement of our understanding of how our smallest friends impact our health.