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CURATOR
A pinboard by
Rozlyn Boutin

MD/PhD Student, Year 3, University of British Columbia/Michael Smith Labs

PINBOARD SUMMARY

Characterization of the microbial predictors of pediatric asthma susceptibility

Research suggests that colonization of the intestinal tract by commensal and symbiotic microbes, known as the gut microbiota, plays an important role in guiding the normal development of an infants' immune system. As a result, disruption of this colonization process and an altered microbiota community (dysbiosis) may predispose infants to developing diseases involving dysregulation of the immune system, such as asthma and allergies, later in life. Preliminary data from our lab and a paper recently published by the Lynch group indicate that Canadian and American children at high risk of developing asthma differ in the bacterial and fungal organisms present in their early life gut microbiota communities. However, the mechanisms by which these microbes influence the host immune system remain elusive. In order to further characterize the early life gut microbial signatures associated with asthma susceptibility prediction, I will perform high throughput sequencing of the bacterial and fungal DNA content of stool samples taken from infants in the Canadian Healthy Infant Longitudinal Development (CHILD) Study cohort who remained healthy or later developed asthma. Using this information, I will perform a series of in vitro experiments in immune cell lines to determine how these microbes influence asthma-related immunopathology. These data will also be used to inform future studies investigating environmental factors driving the development of asthma-associated states of dysbiosis. This project has the potential to identify putative biomarkers of asthma-associated dysbiosis in early life and to inform the unprecedented development of probiotic or anti-microbial therapies capable of altering the natural history or perhaps even the development of this currently incurable burdensome disease.

6 ITEMS PINNED

Shifts in  Lachnospira and Clostridium sp.  in the 3-month stool microbiome are associated with preschool-age asthma.

Abstract: Asthma is a chronic disease of the airways affecting one in ten children in Westernized countries. Recently, our group showed that specific bacterial genera in early life are associated with atopy and wheezing in one-year-old children. However, little is known about the link between the early life gut microbiome and the diagnosis of asthma in preschool age children. To determine the role of the gut microbiota in preschool age asthma, children up to 4 years of age enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study were classified as asthmatic (n = 39) or matched healthy controls (n = 37). 16S rRNA sequencing and quantitative PCR (qPCR) were used to analyze the composition of the 3-month and 1-year gut microbiome of these children. At 3-months the abundance of the genus,  Lachnospira  (L), was decreased (p = 0.008), while the abundance of the species,  Clostridium neonatale  (C), was increased (p = 0.07) in asthmatics. Quartile analysis revealed a negative association between the ratio of these two bacteria (L/C) and asthma risk at 3-months (quartile 1: Odds ratio (OR) = 15, p = 0.02, CI = 1.8 - 124.7; quartile 2: OR = 1.0, ns; quartile 3: OR = 0.37, ns). We conclude that opposing shifts in the relative abundances of  Lachnospira  and  C. neonatale  in the first 3 months of life are associated with preschool age asthma, and that the L/C ratio may serve as a potential early life biomarker to predict asthma development.

Pub.: 17 Sep '16, Pinned: 28 Aug '17

Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation.

Abstract: Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma. We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1-11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1-3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4(+) cells producing interleukin (IL)-4 and reduced the relative abundance of CD4(+)CD25(+)FOXP3(+) cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4(+)CD25(+)FOXP3(+) cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4(+) T cell dysfunction associated with childhood atopy.

Pub.: 13 Sep '16, Pinned: 28 Aug '17

Microbiota-Mediated Immunomodulation and Asthma: Current and Future Perspectives

Abstract: Opinion statement Estimated to burden over 300 million people and their families around the world, asthma is now considered one of the most common forms of non-communicable disease worldwide (Masoli et al. Allergy Eur J Allergy Clin Immunol 59:469–78, 2004 1). The epidemic rise in prevalence this disease has seen over recent decades (Platts-Mills J Allergy Clin Immunol 136:3–13, 2015 2) suggests that environmental factors are the primary drivers of this phenomenon. In particular, the importance of early life microbial exposure and the composition of the early life gut and lung microbiota are emerging as key determinants of asthma outcomes later in life. Borne out of epidemiological data showing associations between the composition of the early life gut microbiota and later development of asthma, interest in harnessing the human microbiome as a therapeutic tool to prevent the development of asthma is rising. As research elucidating the mechanisms, specific microbial species, and microbial products mediating this link continues, it is becoming clear that, like the disease itself, the relationships between microbes and their hosts are highly complex and heterogeneous across populations. As a result, probiotic trials aimed at the primary prevention of asthma have been largely unsuccessful thus far. Future work aiming to apply our understanding of the role of the microbiota in health and disease to the prevention of atopic asthma will likely need to take a population-specific approach and has the potential to dramatically change the face of current asthma treatment practices.Opinion statementEstimated to burden over 300 million people and their families around the world, asthma is now considered one of the most common forms of non-communicable disease worldwide (Masoli et al. Allergy Eur J Allergy Clin Immunol 59:469–78, 2004 1). The epidemic rise in prevalence this disease has seen over recent decades (Platts-Mills J Allergy Clin Immunol 136:3–13, 2015 2) suggests that environmental factors are the primary drivers of this phenomenon. In particular, the importance of early life microbial exposure and the composition of the early life gut and lung microbiota are emerging as key determinants of asthma outcomes later in life. Borne out of epidemiological data showing associations between the composition of the early life gut microbiota and later development of asthma, interest in harnessing the human microbiome as a therapeutic tool to prevent the development of asthma is rising. As research elucidating the mechanisms, specific microbial species, and microbial products mediating this link continues, it is becoming clear that, like the disease itself, the relationships between microbes and their hosts are highly complex and heterogeneous across populations. As a result, probiotic trials aimed at the primary prevention of asthma have been largely unsuccessful thus far. Future work aiming to apply our understanding of the role of the microbiota in health and disease to the prevention of atopic asthma will likely need to take a population-specific approach and has the potential to dramatically change the face of current asthma treatment practices.12

Pub.: 11 Jul '16, Pinned: 28 Aug '17