Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics

The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station’s history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (Bacillus anthracis), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of citie

Bacterial multi-omics profiling reveals novel routes to immune evasion and disease outcome: Towards targeted therapeutic strategies

Thesis advisor: Tim van OpijnenAlthough vaccines and antibiotics have been historically successful in combating bacterial infections, limited vaccine coverage and the rise of antibiotic resistance emphasize the need to develop alternative, broadly effective, and/or targeted treatment strategies to reduce the health burden of bacterial infections. Rather than relying on therapeutics solely targeting the bacterial pathogen, such as standard antibiotics, therapies that simultaneously focus on host responses are emerging. In this thesis, we propose 'host-informed therapies' (HITs) in two categories: those that aid patients with fully functional immune systems and those that aid patients with perturbed immune processes, as promising alternative or adjunctive treatment strategies for bacterial infections. The host-pathogen interaction during infection is a highly dynamic process between diverse bacterial pathogens and hosts with varying degrees of susceptibility. Systems biology approaches have provided an understanding of host-pathogen parameters globally through the detection of putative biomarkers for diagnosis and identification of critical interactions to discover novel drug targets. However, there remains a gap in understanding bacterial pathogenesis in the context of designing novel host-informed therapies. Here, we use Streptococcus pneumoniae, the gram-positive pathogen responsible for the majority of bacterial respiratory tract infections worldwide, as a case study to: (1) Generate a genome-wide map of bacterial immune (complement) evasion targets to design novel host-informed therapies, (2) generate a dual host/pathogen transcriptome map to identify signatures of infection outcome, and (3) validate signatures of bacterial antibiotic tolerance in a mouse lung infection model. Overall, this work exemplifies how systems biology methods can elucidate the intricacies of bacterial pathogenesis but, more importantly, aid in the target identification, validation, and design of antibacterial host-informed therapies.Thesis (PhD) — Boston College, 2023.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Biology

The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis

Type 1 Diabetes (T1D) is regarded as an autoimmune disease characterized by insulin deficiency resulting from destruction of pancreatic beta-cells. The incidence rates of T1D have increased worldwide. Over the past decades, progress has been made in understanding the complexity of the immune response and its role in T1D pathogenesis, however, the trigger of T1D autoimmunity remains unclear. The increasing incidence rates, immigrant studies, and twin studies suggest that environmental factors play an important role and the trigger cannot simply be explained by genetic predisposition. Several research initiatives have identified environmental factors that potentially contribute to the onset of T1D autoimmunity and the progression of disease in children/young adults. More recently, the interplay between gut microbiota and the immune system has been implicated as an important factor in T1D pathogenesis. Although results often vary between studies, broad compositional and diversity patterns have emerged from both longitudinal and cross-sectional human studies. T1D patients have a less diverse gut microbiota, an increased prevalence of Bacteriodetes taxa and an aberrant metabolomic profile compared to healthy controls. In this comprehensive review, we present the data obtained from both animal and human studies focusing on the large longitudinal human studies. These studies are particularly valuable in elucidating the environmental factors that lead to aberrant gut microbiota composition and potentially contribute to T1D. We also discuss how environmental factors, such as birth mode, diet, and antibiotic use modulate gut microbiota and how this potentially contributes to T1D. In the final section, we focus on existing recent literature on microbiota-produced metabolites, proteins, and gut virome function as potential protectants or triggers of T1D onset. Overall, current results indicate that higher levels of diversity along with the presence of beneficial microbes and the resulting microbial-produced metabolites can act as protectors against T1D onset. However, the specifics of the interplay between host and microbes are yet to be discovered.Funding Agencies|NIH NIDDKUnited States Department of Health &amp; Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases (NIDDK) [1K01DK117967-01]; G. Harold &amp; Leila Y. Mathers Foundation</p

Gut Microbiota Regulate Pancreatic Growth, Exocrine Function and Gut Hormones

Growing evidence indicates an important link between gut microbiota, obesity, and metabolic syndrome. Alterations in exocrine pancreatic function are also widely present in patients with diabetes and obesity. To examine this interaction, C57BL/6J mice were fed a chow diet, a high-fat diet (HFD), or an HFD plus oral vancomycin or metronidazole to modify the gut microbiome. HFD alone leads to a 40% increase in pancreas weight, decreased glucagon-like peptide 1 and peptide YY levels, and increased glucose-dependent insulinotropic peptide in the plasma. Quantitative proteomics identified 138 host proteins in fecal samples of these mice, of which 32 were significantly changed by the HFD. The most significant of these were the pancreatic enzymes. These changes in amylase and elastase were reversed by antibiotic treatment. These alterations could be reproduced by transferring gut microbiota from donor C57BL/6J mice to germ-free mice. By contrast, antibiotics had no effect on pancreatic size or exocrine function in C57BL/6J mice fed the chow diet. Further, 1 week vancomycin administration significantly increased amylase and elastase levels in obese men with prediabetes. Thus, the alterations in gut microbiota in obesity can alter pancreatic growth, exocrine function, and gut endocrine function and may contribute to the alterations observed in patients with obesity and diabetes