109 research outputs found
Can I borrow a microbiome? : Life-saving poop and the ethics of microbiome therapies
No full textWhat if we could transplant healthy bacteria into patients to fight diseases without using antibiotics? What might some of the implications be for society if we did this on a broad scale? This talk featured School of Population and Public Health Associate Professor Amee Manges, who speaks about fecal microbiota transplants (FMTs) and how this therapy can save lives, as well as University of Guelph Associate Professor Kieran O’Doherty who discussed the ethics of introducing such therapies across populations, including the possible consequences of changing many people’s normal microbiomes. The talk was MC’d by SPPH Assistant Professor Jennifer Gardy and was presented on September 22nd at UBC.Medicine, Faculty ofNon UBCPopulation and Public Health (SPPH), School ofUnreviewedFacult
Food animal reservoir for extraintestinal pathogenic «Escherichia coli» causing human infections
No full textStudies of extraintestinal infections caused by genetically related strains of Escherichia coli among unrelated people have demonstrated the epidemic potential of this group of bacteria. These related extraintestinal pathogenic E. coli (ExPEC) may have a common source. Our group recently described how retail meat, particularly chicken, may be a reservoir for ExPEC causing human urinary tract infections (UTIs). By moving upstream on the farm to fork continuum, this study tests whether the reservoir for ExPEC is in food animals themselves. A total of 824 geographically and temporally matched E. coli isolates from cecal contents of slaughtered food animals (n=349) and human UTI (n=475) sources were compared. Using 6 different typing methods, an evolutionary relationship was observed between E. coli isolates from the food animal reservoir and human UTI. Moreover, chicken was the predominant animal species from where the related isolates originated. Using an evolutionary model, chicken was determined to be the most likely source of the human UTI isolates. This study confirmed that an animal reservoir, principally in chicken, may exist for ExPEC causing community-acquired UTI.Les études portant sur les infections extra-intestinales causées par des souches d'Escherichia coli génétiquement apparentées, chez des personnes non reliées entre elles, ont démontré le potentiel épidémique de ce groupe de bactéries. Ces souches d'E. coli pathogènes extra-intestinales (ExPEC) apparentées auraient possiblement une source commune. Notre groupe a récemment décrit comment la viande de détail, plus particulièrement le poulet, pourrait être un réservoir d'ExPEC responsables d'infections urinaires (IUs) chez les humains. En se déplaçant plus en amont dans le continuum de la ferme à la fourchette, cette étude teste si le réservoir d'ExPEC se trouve dans les animaux de production eux-mêmes. Un total de 824 isolats d'E. coli de provenances géographique et temporelle communes, prélevés dans le contenu caecal d'animaux abattus (n=349) et de cas d'IU humaine (n=475) ont été comparés. Par l'utilisation de 6 différentes méthodes de typage, une relation évolutionnaire a été observée entre les isolats d'E. coli provenant du réservoir animal et d'IU humaine. De plus, le poulet était l'espèce animale prédominante parmi les isolats parentés. L'utilisation d'un modèle évolutionnaire a permis de déterminer que le poulet est la source la plus probable des isolats d'IU humaine. Cette étude a confirmé qu'un réservoir animal, principalement chez le poulet, pourrait exister pour les ExPEC qui causent des IUs acquises en communauté
Antibiotic usage and resistance gene carriage in children with severe acute malnutrition and human immunodeficiency syndrome co-morbidities living in low-resource settings
No full textAntibiotic resistance is the third largest contributor to mortality worldwide, and 30% of these deaths occur in newborns. The burden of resistant infections in children is disproportionately higher in low- and middle-income countries (LMICs) due to the overuse of antibiotics in food, food animals and health care settings. The prevalence of childhood co-morbidities like severe acute malnutrition (SAM) and human immunodeficiency virus (HIV) in LMICs increases the need for treatment and prophylactic antibiotic use. These conditions also increase the likelihood of secondary disease, thereby further increasing the need for antibiotics. Antibiotic resistance genes (ARGs) are the primary source of resistance in pathogens and are amplified with antibiotic exposure. There is an urgent need to understand the role of ARGs in diseases amongst infants and children, especially in LMICs, where their impact on mortality and morbidity is large. In this dissertation, chapter one reviews previous knowledge about the presence or carriage of ARGs and the impact ARGs have on morbidity and mortality in LMICs, especially morbidity and mortality due to SAM and HIV. Chapter 2 examines the natural acquisition of ARGs in healthy children living in rural areas of a LMIC using longitudinal data from the Sanitation Hygiene and Infant Nutrition Efficacy (SHINE) trial. Chapter 3 examines the changes in ARG carriage during hospitalization with SAM and HIV, and during SAM recovery using longitudinal data from the Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) observational study. Chapter 4 investigates the impact of stopping or continuing prophylactic antibiotic use in HIV-positive children using data from the Antiretroviral Research for Watoto (ARROW) trial. I find that healthy children acquire a diverse array of ARGs upon birth, ARG carriage decreases significantly with age in healthy children, and most ARGs are closely associated with the abundance of Enterobacteriaceae that colonize the infant gut. Hospitalization for SAM leads to a less mature microbiota, associated with increases in Enterobacteriaceae-related ARG abundance. This effect was transient and decayed over time following hospital discharge. Continued prophylactic antibiotic treatment in HIV-positive children does not significantly alter ARG carriage but does selectively increase resistance specific to antibiotics used.Medicine, Faculty ofMedicine, Department ofGraduat
The role of the infant microbiota and childhood stunting in rural Zimbabwe
No full textChildhood stunting or linear growth failure is a major global health issue, affecting 22% of children under 5 years of age worldwide. Stunting impacts people across the life course. Stunting is associated with a greater number of infections, reduced childhood survival, impaired cognitive development, and reduced adulthood productivity, and contributes to an intergenerational cycle of poor growth and development. Decreased linear growth has been associated with community-level changes in the gut microbiome as well as specific changes in individual bacterial and decreased overall microbial diversity. However, the literature addressing the role of the gut microbiome on poor child linear growth is limited. We conducted an analysis of the infant fecal microbiota composition from 1-18 months of life from infants participating in the Sanitation, Hygiene, Infant Nutrition Efficacy (SHINE) Trial, a large cluster-randomized trial, designed to evaluate the impact of improved household water quality, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on linear growth and anaemia during the first 18 months of infant life in rural Zimbabwe. Using whole metagenomic sequencing, we were able to describe the infant fecal microbiota composition of SHINE Trial infants and examine relationships between the microbiota composition and HIV exposure status, SHINE trial interventions, and stunting status.
As expected, age was the major driver of microbiota composition and diversity. No major differences in the infant fecal microbiota by HIV exposure status, SHINE trial interventions, or stunting status were observed. These results highlight the complex nature of linear growth and demonstrate that infant fecal microbiota composition plays a smaller direct role on growth in SHINE infants. Our study also confirms that the SHINE WASH intervention did not influence infant growth through alterations to the fecal microbiota composition, confirming the primary SHINE results. However, the functional potential of the infant fecal microbiota of SHINE infants will be examined in future analyses; this may uncover relationships separate from microbiota composition and diversity alone.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat
Applications of metagenomic sequencing for virus detection and characterization of upper respiratory infections
No full textThe application of next-generation sequencing technologies to answer more routine
diagnostic and applied microbiological questions is becoming increasingly feasible. Current
reference-standard molecular diagnostic strategies are limited in that they require a priori
knowledge of a pathogen’s genome. Metagenomic next generation sequencing (mNGS) is a
pathogen-agnostic diagnostic approach that can be used for detection of viral pathogens and
characterization of viral infections. Chapter 1 of this thesis describes technological advancements
in mNGS technology for viral pathogen detection and diagnosis. This narrative review highlights
technical, logistical, and translational barriers to the widespread use of this technology in clinical
settings. In chapter 2, I describe the use of full-length 16S rRNA nanopore sequencing for
characterization of the upper respiratory tract microbiome in hospitalized and community-dwelling
individuals with and without active SARS-CoV-2 infection. We found significant
differences in beta-diversity, but not alpha-diversity in our study groups and identified several
differentially abundant taxa associated with SARS-CoV-2 infection status and disease severity.
Chapter 3 outlines the feasibility and performance of long-read mNGS as a diagnostic tool for
detection and characterization of SARS-CoV-2. We reported that mNGS is a highly specific
method for SARS-CoV-2 detection and is sensitive for specimens with higher viral loads. We
showed that this technology can also be used to characterize viral genomes. Finally, chapters 4
and 5 outline the development, optimization, and validation of a novel mNGS assay for detection
of viral pathogens. This assay was developed to address translational barriers to mNGS adoption.
We developed and clinically validated an assay that is sensitive, specific, rapid, cost-effective,
and inclusive. In addition to successfully detecting four known viral pathogens, the assay
detected a total of nine respiratory pathogens that were missed by conventional molecular
diagnostic testing when originally tested. In summary, the work presented in this thesis
highlights the feasibility of using next-generation sequencing workflows in routine clinical
service for diagnosis of viral pathogens and characterization of viral infections. This thesis
represents novel, applied work that contributes to the field of microbiology and can have
immediate impact on clinical microbiology and diagnostic services for human and animal health
and public health surveillance.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat
Food reservoir for «Escherichia coli» causing community- acquired urinary tract infections
No full textClosely related strains of Escherichia coli have been shown to cause extraintestinal infections in unrelated persons. This study tests whether a food reservoir may exist for these E. coli. Isolates from three sources collected over the same time period and geographic area were compared. The sources comprised E. coli isolates from women with urinary tract infection (UTI) (n = 353); retail meat (n = 417); and restaurant/ready-to-eat foods (n = 74). E. coli were evaluated for antimicrobial susceptibility and O:H serotype and compared by using six different genotyping methods. We identified 17 clonal groups that contained E. coli isolates (n = 72) from more than one source. E. coli from retail chicken (O25:H4-ST131 and O114:H4-ST117) and honeydew melon (O2:H7-ST95) were indistinguishable from or closely related to E. coli from human UTIs. This study provides strong support for the role of food reservoirs in the dissemination of E. coli causing community-acquired UTIs.Il a été démontré que des souches de Escherichia coli étroitement reliées causaient des infections extraintestinales chez des personnes non-reliées. Cette étude teste l'hypothèse selon laquelle il existerait un réservoir alimentaire pour ces souches d'E. coli. Des isolats provenant de trois sources différentes et récoltés durant les mêmes périodes et régions géographiques ont été comparés. Les sources incluaient des isolats d'E. coli provenant de femmes soufrant d'infection urinaire (IU) (n=353); de viande vendue au détail (n = 417); et d'aliments de restauration/prêts-à-manger (n =74). Les E. coli ont été évalués pour leur susceptibilité aux agents antimicrobiens et leur sérotype O:H, et ont été comparés par l'intermédiaire de six différentes méthodes de génotypage. Nous avons identifié 17 groupes clonaux contenant des isolats d'E. coli (n = 72) provenant de plus d'une source. Des E. coli provenant de viande de poulet (O25:H4-ST131 et O114:H4-ST117) et de melon au miel (O2:H7-ST95) étaient indistinguables ou étroitement reliés à des E. coli provenant d'IUs. Cette étude supporte fortement le rôle des réservoirs alimentaires dans la dissémination du E. coli causant des IUs acquises dans la communauté
Design and validation of a sinonasal endoscopic score (SiNES) for chronic rhinosinusitis outcome assessment
No full textChronic rhinosinusitis (CRS) is a debilitating disease that affects the sinonasal cavity and significantly reduces patients’ quality of life. Sinonasal endoscopy is the main strategy for evaluating and monitoring CRS patients. There are several endoscopic grading systems available, but they all have important shortcomings and limitations. There is an urgent need for a reliable score that can accurately reflect patient’s disease burden that is easy to use and applicable to all CRS subtypes.
In chapter 1 of this thesis, I review the main endoscopic scoring systems and describe their main advantages and disadvantages. Based on these findings, Chapter 2 describes the design and validation of the SiNonasal Endoscopic Score (SiNES), a new scoring system that incorporates the strengths of previous scores while addressing their limitations. This chapter further investigates the relationship between the newly developed SiNES and patient reported outcome measures (PROMs).
Chapter 3 explores the minimal clinical important difference (MCID) for the SiNES. This chapter incorporates the perspectives of both surgeons and patients and produces an MCID value that can be used for clinical trial development and patient monitoring.
Chapter 4 further validates the SiNES using data from the first 45 participants in the SinoNasal Microbiota Transfer (SNMT) trial, a landmark study that will determine whether SNMT can improve the health of recalcitrant CRS patients. The chapter includes data on how the SiNES correlates with objective olfactory outcomes, quality of life measures, and a diverse set of type 2 and non-type 2 cytokines.
Finally, Chapter 5 consolidates the findings of the entire thesis and gives some perspectives on future research directions.Medicine, Faculty ofMedicine, Department ofGraduat
Medication exposures, intestinal microbiota alterations and «Clostridium difficile» colonization and infection in hospitalized patients
No full textClostridium difficile infection (CDI) is the leading cause of infectious diarrhea in hospital settings. Broad-spectrum antimicrobials and other medications such as proton pump inhibitors can disrupt the integrity of the intestinal microbiota, thereby impairing colonization resistance and allowing C. difficile to infect the gut. In this thesis, I used a variety of metagenomic approaches to investigate the complex relationships between medication exposures, intestinal microbiota composition, intestinal epithelium integrity and subsequent development of C. difficile colonization or infection in two distinct patient populations. Fecal specimens collected prior to the onset of C. difficile colonization or infection were evaluated by 16S ribosomal RNA gene or whole metagenome shotgun sequencing to examine the structure and diversity of the intestinal microbiota and quantify host DNA excretion (as a marker of intestinal inflammation) during the at-risk period. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Incertae Sedis XI and use of laxatives was associated with reductions in the abundance of secondary bile-acid producers (Clostridium and Eubacterium genera). The diversity of the intestinal microbiota was significantly reduced prior to an episode of CDI, while human DNA excretion was increased. Cephalosporin and fluoroquinolone use, as well as a decrease in the abundance of Clostridiales Incertae Sedis XI were significantly and independently associated with risk of CDI. In contrast to CDI cases, asymptomatic patients exhibited elevated abundances of potentially protective bacterial taxa at the onset of C. difficile colonization, such as Clostridiales Incertae Sedis XI, Clostridium and Eubacterium. These results indicate that intestinal colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic colonization to CDI and these protective microorganisms could be used as targets to restore colonization resistance against C. difficile.L'infection à Clostridium difficile (ICD) est la principale cause de diarrhée infectieuse en milieu hospitalier. Les antimicrobiens à large spectre et autres médicaments tels que les inhibiteurs de la pompe à proton peuvent perturber l'intégrité du microbiote intestinal, compromettant ainsi la resistance à la colonization par des pathogènes et permettant à C. difficile d'infecter l'intestin. Dans cette thèse, j'ai utilisé une variété d'approches métagénomiques afin d'investiguer les liens complexes entre l'exposition aux medicaments, la composition du microbiote intestinal, l'intégrité de l'épithélium intestinal et le développement subsequent de colonization ou d'ICD dans deux populations de patients distinctes. Des échantillons fécaux collectés avant la survenue de colonization ou d'ICD ont été évalués par séquençage du gène d'ARN ribosomal 16S ou de fragments aléatoires du métagénome entier afin d'examiner la structure et la diversité du microbiote intestinal et de quantifier l'excrétion d'ADN hôte (en tant que marqueur d'inflammation intestinale) durant la période à risque. L'exposition aux céphalosporines et aux fluoroquinolones a diminué la fréquence des Clostridiales Incertae Sedis XI et l'utilisation de laxatifs était associée à une reduction dans l'abondance de producteurs d'acides biliaires secondaires (genres Clostridium et Eubacterium). La diversité du microbiote intestinal était significativement réduite avant un épisode d'ICD, alors que l'excrétion d'ADN human était accrue. L'utilisation de céphalosporines et de fluoroquinolones, de même qu'une diminution de l'abondance des Clostridiales Incertae Sedis XI sont significativement et indépendamment associés au risque d'ICD. Contrairement aux cas d'ICD, les patients asymptomatiques démontraient une abondance élevée de taxa bactériens potentiellement protecteurs lors de l'apparition de la colonization par C. difficile, tels que Clostridiales Incertae Sedis XI, Clostridium et Eubacterium. Ces résultats indiquent que la colonization de l'intestin par des taxa bactériens clés pourrait prévenir la proliferation du C. difficile ou la transition d'une colonization asymptomatique à une ICD et ces microorganismes protecteurs pourraient être utilisés comme cible afin de restaurer la resistance à la colonization par C. difficile
Impact of direct-acting antivirals on extrahepatic manifestations and ethnic disparities : insights from a large population-based cohort using linked health administrative data
No full textBackground: Direct-acting antivirals (DAAs) have demonstrated efficacy in reducing morbidity and mortality related to extrahepatic outcomes of chronic hepatitis C (HCV) infection. However, population-based evidence assessing the impact of DAA treatment on extrahepatic manifestations (EHMs) and their burden across ethnic groups remains limited.
Objective: We evaluated the impact of DAA treatment on incident EHMs and EHM-related mortality risks, while also assessing ethnic disparities in EHMs among people diagnosed with HCV in British Columbia (BC).
Methods: We used data from the BC Hepatitis Testers Cohort, including ~1.3 million people tested for or diagnosed with HCV between 1990 and 2015. To assess the impact of DAA treatment on EHMs, we created a 1:1 matched study population of individuals who were treated with DAAs and those who were never treated. We applied inverse probability of treatment weights and competing risk modelling to assess DAA treatment effects on incident EHMs and EHM-related mortality. Ethnic disparities in incident EHMs were examined across East Asians, South Asians, and Other ethnicities, further stratified by HCV treatment status (never treated, before treatment, after treatment, and spontaneously cleared).
Results: Successful DAA treatment was associated with reduced risks of renal, cerebrovascular, cardiovascular and neurocognitive conditions (36-48%), but not type 2 diabetes. It also decreased EHM-related mortality risks by 78-84% for all EHMs. In BC, South and East Asians had higher EHM incidence rates compared to other ethnicities, especially among untreated individuals. Following treatment completion, these rates decreased in both Asian groups. Adjusted analyses showed that South Asians had the highest risk of renal diseases and type 2 diabetes, while East Asians had lower risks of cardiovascular diseases and neurocognitive disorders. HCV treatment mitigated ethnic disparities in EHMs, except for diabetes.
Conclusions: DAA treatment can significantly reduce the risks of EHMs and EHM-related mortality, while mitigating most ethnic disparities in EHM incidence among Asian populations. These findings emphasize the importance of expanding strategies to diagnose and treat individuals living with HCV as early as possible to improve health outcomes and address ethnic disparities related to EHMs.Medicine, Faculty ofPopulation and Public Health (SPPH), School ofGraduat
Nosocomial rotavirus gastroenteritis in a Canadian tertiary-care hospital
No full textRotavirus (RV) is the leading cause of dehydrating gastroenteritis in young children. RV infections occur both in the community and in pediatric hospital-settings. Nosocomial RV gastroenteritis (nRVGE) incidence was assessed in a systematic review. Between 1 in 7 and 30 young children admitted to general pediatric wards will acquire nRVGE. Surveillance studies providing incidence estimates that include all inpatient hospital-wards are scarce.Our surveillance study assessed nRVGE incidence at a Canadian Pediatric Hospital. The incidence rate was 0.5/1000 inpatient-days (95%CI: 0.43-0.57) with no significant decline over the 10-year study period. Chronic medical conditions were present in 126 patients (59%). The efficacy of targeted RV vaccination of a high-risk population on reducing nRVGE was assessed using mathematical modeling. Among the high-risk group 49% (95%CI: 40-63%) of nRVGE could be prevented, corresponding to 22% (95%CI: 18-28%) of total cases. Our findings can support policy decision-making on RV vaccination strategies in Canadian children.Le rotavirus (RV) est la première cause de gastroentérite menant à une déshydratation chez le nourrisson. Ces infections surviennent tant en communauté qu'à l'hôpital. L'incidence des gastroentérites à RV nosocomiales (GERVn) a été résumée dans une revue systématique de la littérature : entre 1/7 et 1/30 enfants admis en pédiatrie acquerront une GERVn. Les études prospectives de surveillance permettant une estimation de l'incidence des GERVn sont rares. Notre étude prospective permet cette estimation dans un hôpital canadien pédiatrique de soins tertiaires avec un taux d'incidence de 0,5/1000 jours-présence (IC95% : 0,43 – 0,57), sans déclin significatif au cours des 10 années qu'ont duré l'étude. Des conditions chroniques étaient présentes chez 126 patients (59%) avec GERVn. L'efficacité d'une vaccination ciblée contre le RV chez une population à haut risque de GERVn a été évaluée à l'aide d'une modélisation mathématique. Parmi ces patients à haut risque, 49% (IC95% : 40-63%) des GERVn pourraient être prévenues, correspondant à 22% (IC95% 18-28%) des cas totaux.Nos résultats supporteront les décideurs quant aux stratégies de vaccination contre le RV à adopter pour les enfants canadiens
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