Huntington disease (HD) is an inherited neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Metabolic dysfunction is a feature of HD that is recapitulated in HD mouse models. Our lab has shown that circadian feeding rhythms are disrupted in humanized HD mice and restored by suppression of brain HTT. Furthermore, when circadian feeding rhythm is artificially restored, in addition to normalization of metabolic function, liver and striatal HTT is temporarily reduced, demonstrating that HTT is involved in gut-brain feedback. The gut microbiome, which can regulate gut-brain feedback, has been implicated in the pathogenesis of other central nervous system disorders and we hypothesize it also plays a role in HD. The objective of this study is to investigate alterations in relative abundance of HD gut microbiota using existing plasma metabolomics data to identify candidate bacteria. If distinct microbiota profiles are demonstrated, this would provide the basis for future unbiased studies to investigate the complete HD microbiome.

No description available.

<p>   </p> <p>Ulcerative colitis is a chronic disease that affects more than 770,000 U.S individuals and the number will increase to 1 million by 2025, resulting in $7 billion cost to manage the disease. Ulcerative colitis is characterized by inflammation along the colon and is a risk factor for the deadly colitis-associated colon cancer (CAC). Emerging research shows that gut microbes, the microorganisms living in our intestine, regulate colon inflammation. Specifically, an imbalanced microbial community may promote the growth of pathogens that invade the host to cause or exacerbate colitis. Therefore, researchers have been searching for safe and cost-effective approaches to keep gut microbes balanced in a long run and thus to control colitis. To this end, my research investigates the microbial modulatory capacities of dietary phytochemicals including polyphenols and vitamin E forms, delineates the role of microbial interaction in their protective effects against colon inflammation and further utilizes such interactions to develop anti-colitis therapies. To address the research questions, I have performed three independent projects and discussed them separately in chapters 2-4. </p> <p>The first project (chapter 2) focused on the anti-CAC and anti-colitis effects of grape polyphenols supplemented through a whole grape powder. Polyphenols are natural chemicals found in plants and have been shown to alleviate colon inflammation in both clinical and animal studies, but the underlying mechanisms are not completely understood. In particular, the role of microbial modulation in polyphenol-mediated benefits is not fully established. Here we hypothesized that, polyphenols may attenuate colon inflammation via interacting with gut microbes. Through two animal studies, we found that 10% grape powder (10GP) diet, which contains 0.033% polyphenols, attenuated colitis-associated tumorigenesis, and prevented disease-induced microbial dysbiosis. Moreover, 10GP diet only mitigated colitis in conventional animals, but not antibiotic-treated, gut microbe-depleted animals. Collectively, these two studies demonstrated that the interaction with gut microbes played a causative role in the protective effects of 10GP against colon inflammation. </p> <p>Like polyphenols, vitamin E forms are also phytochemicals with phenolic structures and undergo liver metabolism followed by biliary excretion to the gut. In the second project, we investigated the anti-colitis effects of vitamin E-based synbiotics therapies. Previously, we found that d-tocotrienol 13-carboxychromanol (dTE-13’), a metabolite of the natural vitamin E form dTE, inhibited colitis-associated tumorigenesis in mice, modulated their gut microbiota and increased the relative abundance of a lactic acid bacterium, which is commonly used in food industry. Interestingly, a subspecies of this bacterium, named <em>Lactococcus. lactis</em> subsp. <em>cremoris</em> (<em>L. cremoris</em>), has been reported to attenuate ulcerative colitis in mice. Therefore, we reasoned that combining dTE-13’with <em>L. cremoris</em> may offer synergistic protection against ulcerative colitis by modulating gut microbes. Through two animal studies coupled with anaerobic cell culture, we found that combining <em>L. cremoris</em> with dTE-13’, not the parental dTE, showed superior anti-colitis effects, rendered gut microbes resistant to disease-associated dysbiosis and facilitated the microbial reduction of a double bond on dTE-13’ into dTE-13’ (2DB). Overall, these data suggested that dTE-13’ interacted with <em>L. cremoris</em> to benefit the host. </p> <p>To further corroborate the microbial metabolism of vitamin E forms under <em>in vivo</em> settings, we launched the third project (chapter 4) where we compared the metabolites formation of dTE and dTE-13’ between antibiotic-treated mice that had reduced gut bacterial load and conventional ones. We found that in dTE-gavaged animals, antibiotics treatment decreased the fecal amounts of dTE and its metabolites by 61% and 98%, respectively, while increased dTE level in the adipose tissue. Similarly, in animals gavaged with dTE-13’, antibiotics treatment led to a 98% reduction in its downstream metabolites. More importantly, antibiotics treatment reduced the ratio of the parental dTE and dTE-13’ to their metabolites in feces, especially the reduction from dTE-13’ (3DB) to dTE-13’ (2DB), suggesting the active role of gut microbes in the metabolism of dTE and dTE-13’. This observation is consistent with the results from the anaerobic study performed in the second project.</p> <p>In summary, we showed that grape polyphenols and vitamin E form-based synbiotics offered strong protection against colon inflammation and their interaction with gut microbes likely contributed to the observed benefits. In the study of grape polyphenols, we proved the causal role of gut microbes in polyphenol-mediated alleviation of colitis. In the subsequent study of vitamin E forms, we presented evidence that the superiority of the synbiotics might be rooted in the enhanced microbial metabolism of vitamin E forms. Together, these results supported the central role of gut microbes in the management of colitis and proposed two different classes of dietary phytochemicals that can manipulate gut microbes to benefit the host. Natural bioactive compounds like polyphenols and vitamin E forms are ideal candidates for long-term preventive measures as they have less side effects and are more cost-effective compared to drugs. Moreover, by understanding the targeting microbes of different phytochemical compounds, hopefully we will be able to customize phytochemical supplementation based on individual microbial profile and dietary habits. For instance, we may optimize the dosage and type used based on the microbes present in the gut, or add in probiotics to design more effective synbiotics just like the combination of dTE-13’ and <em>L.cremoris</em>.</p> <p>  </p>

Honeybees (Apis mellifera L.) are the major insect pollinators of many different crops. A drastic decline in the honey bee populations has been reported over the past decade. While many factors have contributed to this decline, pesticides, poor nutrition, and Varroa mites are the most common concerns noted by scientists and beekeepers. Aside from direct toxicity from pesticides, it has been observed that sublethal pesticide doses have effects on honey bee physiology and behavior such as oxidative stress, disruption of foraging and homing, and changes to honey bee neurophysiology. The primary objectives of this project were to examine honey bee gut microbiome, physiology, and pesticide exposure along an agricultural intensification gradient and to examine the interactive impacts of pesticide exposure and poor nutrition on honey bees in a controlled laboratory cage setting. Sixteen honey bee colonies were placed in four locations across Mississippi with varying degrees of natural forage availability.

Antimicrobial resistance poses a significant challenge to human health and is also a pressing One Health concern. The routine use of antibiotics as growth promoters in agricultural animals has contributed to the emergence of antibiotic resistance, which can subsequently affect human populations. Discontinuing this practice has led to a surge in infections and therapeutic antibiotic use in these animals. This increased susceptibility to infections may be linked, at least partially, to the loss of colonization resistance resulting from alterations in the microbiome. This study focuses on poultry, as the consumption of chicken meat can introduce antibiotic-resistant microbes into the human population. The overarching hypothesis for this research project is that a rationally designed consortium of microbes sourced from healthy chickens will increase colonization resistance and decrease susceptibility to infections as an alternative to growth-promoting antibiotics. The first goal was to analyze the broiler chicken’s gut microbiome and to establish a comprehensive culture collection of microorganisms from healthy chickens. Culture-enriched and culture-independent 16S sequencing was applied to assess the cultivability of the samples and to analyze their microbial profiles. Isolates were identified using MALDI-TOF and 16S rRNA gene sequencing. Frozen samples (from antibiotic-free farms) had a greater microbial diversity than fresh samples (from a university research facility). However, a greater proportion of the microbiome was recovered by culture from the fresh compared to the frozen samples. A strain collection of 1121 isolates representing 121 species was constructed. In Aim 2, I carried out a functional screen to identify isolates from the culture collection that inhibited the growth of the predominant poultry pathogens, E. coli and C. perfringens. Several isolates were identified that inhibited one or the other pathogens and a small number of isolates killed both pathogens. These microbes form the basis of therapeutic consortia to increase colonization resistance in chickens. / Thesis / Master of Science (MSc) / In the poultry industry, antibiotics have been used to promote chicken’s growth. This has contributed to the spread of antibiotic resistance to animal/human pathogens. When the use of growth-promoting antibiotics is stopped, the chickens become more susceptible to infections. These chickens have possibly lost protective bacteria that help fight pathogens. I thought that bacteria from healthy chicken’s intestine could help fight pathogens. To do this, I isolated a large collection of chicken gut’s good bacteria from healthy birds after individually separating them from the mixture using growing methods and sequencing. I separated bacteria from frozen and fresh mixtures, found that more bacteria grow from fresh mixtures. I then tested individual bacteria from this collection to see if they stop pathogenic bacteria like E. coli and C. perfringens from growing. I found that many bacteria could do this which may be used to develop a therapeutic community of good bugs to colonize chickens to make them more disease resistant.

Alzheimer’s Disease is a devastating disease and a major medical challenge of the 21st century without preventative treatment available and absence of a cure. Due to the profound clinical impact on patients with the disease, and emotional and financial impact on their loved ones, there has been extensive research into therapeutic agents. Unfortunately, many of the studies are abandoned or fail due to a lack of complete understanding of the complex pathophysiology of Alzheimer’s Disease, and ineffective drug targets. While the etiology of disease remains controversial, the accumulation of both amyloid beta protein and neurofibrillary tangles has been the most supported theory for the past thirty years. Also in recent years, the gut microbiome has gained much attention for its unexplored potential and role in health and disease, and the Mediterranean Diet has been deemed the “healthiest” diet for the sixth consecutive year by health experts. This study reviews the current understood pathophysiology of AD and standard diagnostic criteria. This thesis aims to provide an overview of the neuroprotective effects of the Mediterranean Diet, the alterations of the gut microbiome that are associated with the Mediterranean Diet, and the alterations of the gut microbiome associated with Alzheimer’s Disease. Based on the analysis of the large number of studies presented, this thesis concludes that the Mediterranean Diet optimally modifies the ratio of Firmicutes:Bacteroidetes in the gut of people with Alzheimer’s Disease and reduces pathological and symptomatic progression of disease.

The human gut microbiome is a complex microbial ecosystem residing in the lumen of our gastrointestinal tract. The type and amounts of microbes present in this ecosystem varies based on numerous factors, including host genetics, diet, and environmental factors. The human gut microbiome plays an important role in normal host physiological functions, including providing energy to colonocytes in the form of short-chain fatty acids. However, gut microbial metabolites have also been associated with numerous disease states. Current tools for analyzing the gut microbiome, such as high-throughput sequencing techniques, are limited in their predictive ability. Additionally, “-omic” approaches of studying the complex array of molecules, such as transcriptomics (RNA), proteomics (proteins), and metabolomics (previously identified physiologically active molecules), give important insight as to the levels of these molecules but do not provide adequate explanations for their production in a complex environment. With a better physiological understanding of why specific metabolites are produced by the gut microbiome, more directed therapies could be developed to target their production. Therefore, it is immensely important to study the specific bacteria that reside within the gut microbiome to gain a better understanding of how their metabolic actions might impact the host. Within this framework, this study aimed to better understand the production of secondary bile acid metabolites by bacterial in the gut microbiome. High levels of secondary bile acids are associated with numerous pathophysiological disorders including colon cancer, liver cancer, and cholesterol gallstone disease. In the current study, three bile acid metabolizing strains of bacteria that are known members of the gut microbiome were studied. A novel strain of Eggerthella lenta was identified and characterized, along with the type strain, for its ability to modulate bile acid and steroid metabolism based on the atmospheric gas composition. Additionally, it was shown that the oxidation of hydroxyl groups on primary bile acids by E. lenta C592 inhibited subsequent 7α-dehydroxylation by Clostridium scindens. The gene involved in the production of a Δ4,6-reductase enzyme, responsible for catalyzing two of the final reductive steps in the 7α-dehydroxylation pathway, was putatively identified and characterized in Clostridium scindens ATCC 35704. Lastly, the transcriptomic profile of Clostridium scindens VPI 12708 in the presence of numerous bile acids and steroid molecules was studied. These studies contribute significantly to the understanding of why specific bile acid metabolites are made by members of the gut microbiome and suggest ways of modulating their production.

Primates who disperse from their natal group may shape their adult stable gut microbiome through physical contact and shared environments with their new group members. However, it is possible that individuals retain the dominant microbiome composition that they developed as an infant in their natal group even after joining their new group, due to a combination of genetic inheritance and exposure to their natal group environment. Microbial exposure during early life, before an immune system has been developed, can exert strong selection on a developing individual, in effect creating a selection bottleneck. Therefore, the environmental signals transmitted from mother to infant are critical in developing an infant’s immunocompetence. Determining what adaptations take place in an individual’s gut microbiota during their life could help determine the maternal importance of gut microbe transmissions which may be essential to the evolutionary success of a species. We studied Eulemur rubriventer (red-bellied lemurs) who live in family groups. We tested whether individuals now living in different social groups as adults overlap in microbe composition, and if areas of overlap are distinct compared with unrelated individuals. We also tested whether the gut microbiomes of co-residents (dispersed adult group-mates) would be more similar than that of individuals living in different groups. Using census and genetic data, we determined the social group membership and relatedness of 15 individuals in Ranomafana National Park, Madagascar. Quantitative real-time PCR and Microbial 16S ribosomal RNA gene sequencing indicated that E. rubriventer kinship accounted for just 2.4% of variability in gut microbiome diversity. Our findings indicate that host adult social group explained 25% of the variation in composition of E. rubriventer microbiomes. Additional research incorporating an increased sample size to include additional kin dyads is necessary to fully understand the influence of genetic kinship and early life colonization on the GI microbiome. If initial microbial colonizing species are retained in adults, this demonstrates that early life colonization can persist through adulthood and perhaps preserve important microbial species across larger evolutionary time scales.

Analisamos a ação da liraglutida na flora intestinal e perda de peso de dois modelos de obesidade: por dieta hiperlipidica (HFD) e obesidade genética (ob/ob). Os modelos foram tratados com o fármaco durante duas semanas. Perfis metabólicos foram feitos por meio de testes glicêmicos e insulínicos, histologia do fígado, região cecal e coxins gordurosos, ingestão alimentar, peso corporal e metagenômica do conteúdo cecal. O tratamento induziu perda de peso com melhora dos níveis glicêmicos e redução da inflamação na região cecal e do fígado e foi capaz de reduzir o acúmulo de gordura hepática promovendo a redução da EHNA. A metagenômica mostrou mudança taxonômica geral, bem como a abundância relativa de bactérias envolvidas com peso e controle glicêmico:redução de Proteobacterias e aumento de Akkermansia muciniphila. Apresentamos evidências do fármaco revertendo DGHNA/EHNA e a perda de peso associados às mudanças da microbiota. Sugerimos uma lista de alvos bacterianos que podem interferir no metabolismo energético para o controle clinico de doenças metabólicas. / The study analyzed the effects of liraglutide on gut microbiota and weight-loss in two obesity model: induced by high fat diet (HFD) and genetic obese mice (ob/ob). Models were treated with liraglutide for two weeks. Metabolic profiles were measured by glycemic and insulin test, histological liver, cecal region and fat pad morphologies, food intake, body weight and metagenomic of cecal contents. The treatment induced weight-loss, improvement of glycemic parameters and reduction of inflammatory cells in the cecum and the liver and reduced fat accumulation in liver reverting NASH. The metagenomic showed a general changed in taxonomic structure as well the relative abundance of weight-relevant:reduction of Proteobacteria and increases of Akkermansia muciniphila. We showed evidences that liraglutide leads to improvement of NASH and weight loss associated with changes in microbiota. Moreover, by the profile of the gut microbiota, we present a bacterial target list that may affect energetic metabolism inducing a metabolic clinical controlled profile.

abstract: Machine learning (ML) has played an important role in several modern technological innovations and has become an important tool for researchers in various fields of interest. Besides engineering, ML techniques have started to spread across various departments of study, like health-care, medicine, diagnostics, social science, finance, economics etc. These techniques require data to train the algorithms and model a complex system and make predictions based on that model. Due to development of sophisticated sensors it has become easier to collect large volumes of data which is used to make necessary hypotheses using ML. The promising results obtained using ML have opened up new opportunities of research across various departments and this dissertation is a manifestation of it. Here, some unique studies have been presented, from which valuable inference have been drawn for a real-world complex system. Each study has its own unique sets of motivation and relevance to the real world. An ensemble of signal processing (SP) and ML techniques have been explored in each study. This dissertation provides the detailed systematic approach and discusses the results achieved in each study. Valuable inferences drawn from each study play a vital role in areas of science and technology, and it is worth further investigation. This dissertation also provides a set of useful SP and ML tools for researchers in various fields of interest. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2018