We ask questions about how communities of microorganisms that normally live within us (human microbiome) are involved in the development and maintenance of health. We use next generation sequencing and other technologies to learn about the function of the microbiome at multiple body sites.
Resistance gene carriage in children who are randomized to continue on cotrimoxazole prophylaxis or to stop cotrimoxazole prophylaxis (a sub-study of the ARROW Trial)
The WHO recommends cotrimoxazole prophylaxis, starting at 4-6 weeks of age of life, to reduce the incidence of opportunistic infections and mortality among HIV-exposed (but not infected) and HIV-infected infants and children. Long-term exposure to cotrimoxazole may increase the carriage of antibiotic resistance organisms by the gut microbiota, which may result in subsequent resistant infections. This study will test whether resistance gene carriage is increased in children who are randomized to continue on cotrimoxazole prophylaxis or to stop cotrimoxazole prophylaxis. It is a sub-study of the ARROW Trial.
The role of microbiota maturation in infant undernutrition (ongoing project)
Almost 45% of all deaths in children < 5 years of age are due to early childhood undernutrition. Undernutrition, caused by chronic protein and micronutrient deficiency, in conjunction with environmental enteric dysfunction (EED), leads to poor linear growth (stunting). The intestinal microbiota plays a key role in postnatal development of the gastrointestinal, metabolic, neurological and immune systems and may act as a frontline sensor of nutrient status. These observations suggest an interconnected relationship between microbiota maturation, EED, immune homeostasis and linear growth. Our hypothesis is that microbiota immaturity, together with environmental enteric dysfunction (EED), is a major unrecognized contributor to global childhood undernutrition. The aims of this study are to: (1) Test the effect of the SHINE Trial interventions on microbiota maturity in human infants, with or without EED, on growth faltering; (2) Define age and growth discriminatory microbiota taxa and functional metabolites within microbiota derived from each of the SHINE Trial intervention arms; and (3) Test if effects of microbiota maturity are modified by diet, pathogen exposure and other environmental factors.
The role of the child intestinal microbiome on severe acute malnutrition (SAM) and SAM recovery
Health Outcomes Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) is a prospective cohort study examining the microbiota and host-microbiota-derived metabolic pathways that contribute to severe acute malnutrition and recovery from malnutrition in Zimbabwean and Zambian children. We are performing the sequencing and bioinformatics associated with this ongoing project.
Antibiotic resistance in the developing microbiomes of children with severe acute malnutrition and human immunodeficiency virus infection
Severe acute malnutrition (SAM) and human immunodeficiency virus (HIV) infection carry a high risk for death in low-middle income countries; sub-Saharan Africa experiences 90% of these deaths. The co-occurrence of SAM and HIV increases the risk of mortality in children by nine-fold, primarily due to infectious diseases. Despite antibiotic treatment and prophylaxis being critical components of SAM and HIV management, respectively, by reducing morbidity and mortality, the selection and amplification of antibiotic resistance is a growing concern. To better understand antibiotic resistance profiles in SAM and HIV, we examined baseline antibiotic resistance gene carriage profiles and their associations with the developing microbiome, using whole stool metagenomics in three studies from sub-Saharan Africa.
Transfer of Sinonasal Microbiota via Nasal lavage from a Healthy Donor to Treat Refractory Chronic Rhinosinusitis: A Prospective Safety and Efficacy Study
Chronic rhinosinusitis (CRS) is a very common inflammatory condition of the paranasal sinuses that affects up to 12% of the North American population. Although the pathophysiology of CRS remains unknown, there is significant consensus that the presence of biofilm and bacterial infection plays an important role. The antibiotic options for CRS treatment are limited, and are often unsuccessful in eradicating the infection or unable to stop biofilm reoccurrence. We will investigate the efficacy of sinonasal microbiota transplant (SNMT) for treating recalcitrant CRS. SNMT is the replacement of a patient’s existing dysbiotic sinonasal microbiota with a microbiota from a healthy donor, characterized by high levels of beneficial bacteria that can outcompete the existing pathogens and restore the microbial balance in the sinuses. We propose to study the safety, efficacy, durability and mechanism of SNMT treatment by itself and post-antimicrobial photodynamic therapy, in recalcitrant CRS sinus cavities associated with biofilm. We will use metagenome sequencing to determine if the use of SNMT reduces the density of opportunistic pathogens and increases the density of healthy microbiota.
The gut microbiome and estrogen receptor-positive female breast cancer
Breast cancer is the most diagnosed cancer worldwide. Breast cancer survivors face serious long-term health consequences that negatively impact quality of life. Estrogen is a known cause of hormone receptor-positive breast cancer, the most prevalent form of breast cancer, and therefore primary risk factors include those that contribute to individual variation in estrogen exposure (e.g., diet, obesity, reproductive factors), although mechanisms are not well understood. The identification of the ‘estrobolome’ in the human gut—bacterial genes and functional pathways that metabolize estrogens and modulate estrogen homeostasis—has provided new insight into estrogen control in postmenopausal women. We are conducting a clinical study of 70 breast cancer cases and 70 controls to examine microbial pathways implicated in the estrobolome and breast cancer risk. We will use whole metagenome sequencing paired with targeted metabolomics to better detect differences in microbial genomes and to provide functional evidence for microbe-breast cancer associations by identifying estrogen-modifying metabolites in the fecal microbiome.
Next-generation sequencing based diagnostics for respiratory infectious diseases
Current gold-standard respiratory diagnostic assays are limited in that they are targeted; untargeted or unknown pathogens will be missed. Metagenomic next-generation sequencing can unable unbiased detection and characterization of pathogenic organisms in clinical samples. We are working with BugSeq Bioinformatics Inc. and the US Biomedical Advanced Research and Development Authority to develop an agnostic next-generation sequencing based diagnostic assay. Through this joint academic-industry collaboration, we are developing an end-to-end comprehensive and fully agnostic assay using the Oxford Nanopore sequencing platform to detect viral pathogens from respiratory samples.