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.

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<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>

<p>Recent observations illustrate fruit fly larval attraction to the distinct odour emanating from food occupied by other larvae. Growing evidence of bacteria as influential microorganisms of hosts suggested the closer examination of host-microbial interactions. We investigated the origin of the volatiles that are attractive to flies. Focal larvae showed no difference in attraction to axenic used food with axenic larvae and axenic fresh food. Additionally, mated females showed no difference in attraction to axenic used food with axenic larvae and axenic fresh food. When we supplemented the axenic disks with <em>L. brevis</em>, larvae showed a significant preference for the axenic used food with axenic larvae and <em>L. brevis </em>over axenic fresh food. Also, the supplementation of <em>L. plantarum</em> to axenic disks also resulted in larvae showing a significant preference for the axenic used food with axenic larvae and <em>L. plantarum </em>over axenic fresh food. Focal larvae showed a significant preference for <em>L. brevis</em> on scratched MRS agar and axenic used food with axenic larvae, but did not show a significant preference for <em>L. brevis</em> on scratched axenic food. In a learning experiment, focal larvae showed no preference for novel odours previously paired with standard used food over novel odours previously paired with axenic used food. In order to test whether <em>L. brevis</em> improves food quality, the three fitness parameters observed, larval development rate, egg-to-adult survival, and adult body mass, revealed inexplicable findings. These results provide evidence for the role of bacterial volatiles in mediating the social attraction observed in fruit flies.</p> / Master of Science (MSc)

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Us as humans are colonised by many microbial communities (the human microbiome) that interact with and regulate the host's physiology, and have been linked with several diseases. The high number of interactions that intercurre between the microbiome and the host requires rigorous statistical approaches to link any condition of interest to microbiome data. Many publicly available microbiome datasets are available that allow to study such interactions. However, strong inconsistencies are found among the reported associations when looking at the same condition in different studies. On the road to consistent statistical microbiome analyses that rely on public data, lack of standardisation and availability are barriers to define reproducible and generalisable associations. The main aim of my PhD was the development of meta-analytical approaches to identify microbial signatures as general hallmarks of health versus disease, integrating diverse cohorts and conditions. During my PhD training, I first explored the associations between the oral microbiome and peri-implantitis, an oral disease of dental implants, in which I defined a microbial signature discriminating diseased from control samples. I further developed and applied discriminative models to multiple colorectal cancer (CRC) cohorts, showing that the microbial signature defined on CRC samples is shared across different populations. To be able to further generalised microbial signature with host's conditions through a meta-analysis approach, I collected and analysed 20,533 public metagenomes from 90 cohorts, that are available through the curatedMetagenomicData (cMD) version 3, an R package providing standardised taxonomic and functional profiles and manually curated metadata. The cMD3 resource was used to derive an easy-to-compute oral-to-gut introgression score that I found systematically associated in a large meta-analysis of twelve diseases and with ageing. Finally, I applied the meta-analysis approach to study diet interventions in mice, exploiting a novel approach able to profile the unexplored fraction of microbiomes, and showing associations driven by previously uncharacterised species. Overall, this thesis contributes to strengthening the links between human and animal microbiomes in normal and altered host conditions.