The microbiome is causally implicated in immune development. Early-life use of antibiotics impacts the gut microbiome and can increase the risk of childhood atopy (allergy) and asthma. However, it is currently unknown if the fungal microbiome (mycobiome) contributes to antibiotic-induced dysbiosis. For this project, we sampled microbiome data from a human clinical study to determine the impact of antibiotics on the intestinal mycobiome of infants. Additionally, we colonized mice with specific fungal species expanded following antibiotic treatment, to determine the impact of fungi on mice immune system development and susceptibility to allergic airway inflammation (asthma models). 

Respiratory syncytial virus (RSV) is a major cause of infant bronchiolitis and pneumonia worldwide and early-life RSV infection is associated with increased asthma risk. While the mechanisms involved in this connection are incompletely understood, the gut-lung axis is hypothesized to be involved given the roles of the gut microbiome in immune development, asthma risk, and lung immune responses to other respiratory viruses. While most microbiome studies are focused on gut bacteria, we and others have demonstrated that colonization with gut fungi potentiates mucosal and systemic immunity. Further, we recently showed that infant antibiotic use leads to an overgrowth of the fungi Malassezia restricta, and that colonization with this fungus increased susceptibility to allergic airway inflammation in mice. Thus, we hypothesized that colonization of M. restricta may also exacerbate inflammation after RSV infection and increase susceptibility to allergic airway inflammation post-infection.

The gut microbiome and the brain communicate bidirectionally via several host- and microbially-derived signaling mechanisms, forming a critical biological axis. This includes via the hypothalamic-pituitary-adrenal (HPA) axis, which is the principal regulator of stress responses in the body through the transient release of glucocorticoids (e.g., cortisol) to influence numerous physiological processes, such as inflammation. In experimental animal models, the microbiome has been causally implicated in HPA axis programming in early life; however, our understanding of how this translates in humans remains limited. Given the gut microbiome and the brain undergo periods of rapid development in parallel in early life, and the gut-brain axis is increasingly recognized as a key mechanism by which the microbiome influences host development and health outcomes, this suggests a direct relationship exists between gut microbial colonization patterns and the programming of stress physiology in early life. The relationship between the gut microbiome and stress response development is of particular interest in infants born prematurely, as they face intensified alterations to microbial colonization patterns due to their unique early-life circumstances (e.g., higher rates of C-section, antibiotic exposure, physiological immaturities at birth) and experience developmentally unexpected stress throughout their stay in the NICU. In this project, we aim to generate a better understanding of the relationship between the gut microbiome and stress physiology in preterm infants by leveraging the Alberta BLOOM Study - a longitudinal birth cohort of preterm infants - to examine the relationship between the gut microbiome and cortisol measurements in the first 8 weeks of life and how this relates to the degree of stress infants experience in the NICU.

Early-life colonization of the gut by bacteria (i.e. the gut microbiome) influences the development and function of many physiological systems including the hypothalamic-pituitary-adrenal (HPA) stress axis, which itself is critical for regulating homeostasis in the body and the prevalence of peripheral inflammatory diseases, like asthma and stress-related anxiety disorders. Brain microglial cells are suspected to mediate this connection between the gut microbiome and the brain, whereby their over-activation causes stress-related disorders and cognitive deficits, and their elimination blocks anxiety recurrence and prevents excessive immune reactivity in the brain. Moreover, mice that lack a microbiome have microglia that are phenotypically different and have defective immune responses. However, the role that the microbiome plays in the early-life development of microglia and the HPA axis has not been tested in the context of its impact on asthma susceptibility. Examining the connection between two critical physiological systems in the body will be important to understanding how immune deficits are related to stress.

The microbiome is causally implicated in immune development. Early-life use of antibiotics impacts the gut microbiome and can increase the risk of childhood atopy (allergy) and asthma. However, it is currently unknown if the fungal microbiome (mycobiome) contributes to antibiotic-induced dysbiosis. For this project, we sampled microbiome data from a human clinical study to determine the impact of antibiotics on the intestinal mycobiome of infants. Additionally, we colonized mice with specific fungal species expanded following antibiotic treatment, to determine the impact of fungi on mice immune system development and susceptibility to allergic airway inflammation (asthma models). 

It has been previously established that the gut microbiome plays a crucial role the development of several host systems including metabolism and immunity. While the role of the bacterial community has been extensively investigated, the fungal population (mycobiome) remains understudied in this context. Given the connection between inflammation and metabolic disease and the potent ability of fungal colonizers to modulate the immune system, it is plausible that the early-life gut mycobiome is involve in this complex relationship. This project uses a combination of clinical findings and gnotobiotic mouse models to identify fungal species in the early-life gut mycobiome correlated with metabolic markers and causally investigate their role in disease development in mice.

The Arrieta lab co-leads BLOOM, a prospective, longitudinal birth cohort study of premature infants born in Calgary called the Alberta BLOOM Study. This study follows premature infants from birth to three years of age, collecting comprehensive biological and clinical data that enables us to examine microbiome development during this period through a number of lenses. Given colonization patterns of the premature infant gut microbiome are known to differ from term-born infants, our goal is to better understand how these early alterations may impact infant development and long-term health outcomes, and to determine whether microbiome-based therapeutics may be employed to improve health outcomes in this population. More about BLOOM ? Visit our BLOOM website.

Gut microbial colonization begins during birth and is highly heterogeneous until the age of 2-3 years. Many aspects of human development that rely on microbe-host and microbe-microbe interactions are affected by several factors, including social geography. Studies have shown that the microbial species richness in rural infants is greater than in urban infants. Yet, little is known about the early-life gut microbial composition in rural areas from less industrialized world regions. Moreover, our overall knowledge of the non-bacterial community composition is limited although microbial eukaryotes are increasingly recognized to have critical roles in ecosystem ecology and host crosstalk. To address these gaps, we characterize the bacterial and eukaryotic microbiomes in fecal samples from a longitudinal human cohort of nine children established in Morelos, Mexico, sampled monthly from birth until 18 months of age (average 14 samples/child). Using shotgun metagenomic and 18S rRNA sequencing, we study the bacterial and eukaryotic microbiomes and their co-occurrence networks in these samples in response to the mode of birth (vaginal vs c-section).