Bailey Lab
The Bailey Lab investigates the integrative mechanisms by which the gut microbiome – a diverse community of microorganisms that coexist within our gastrointestinal tract – influences health. We primarily study the effects of various forms of stress on disease processes, immune responses and behavioral outcomes, with the central focus of understanding how the microbiome contributes to or mediates these phenomena.
In understanding these host-microbe relationships, we aim to identify microbial targets or develop microbial interventions that beneficially reshape the microbiome to improve targeted health or behavioral outcomes.
Our current key areas of study include:
- Effects of prenatal stress on offspring microbial colonization, immune development and disease
- Role of stress and the microbiome in intestinal inflammation and susceptibility to enteric disease
- Assessment of novel bacterial therapeutics to improve neurodevelopment in individuals with disorders affecting the gut and the brain, such as autism spectrum disorder and necrotizing enterocolitis
Current Projects
We have been working with collaborators, Gail Besner, MD, and Steven Goodman, PhD, (and members of their laboratories) at the Abigail Wexner Research Institute at Nationwide Children’s Hospital to develop novel, live bacterial therapeutics that can protect against inflammatory diseases and disorders. Our current therapeutic involves growing a beneficial bacterium [namely Limosilactobacillus reuteri (Lr)] on the surface of a dextranomer microsphere (DM) that has been saturated with maltose. The Lr utilizes the maltose to create a biofilm on the DM surface. The administered Lr biofilm has enhanced anti-inflammatory properties and is retained in the host for longer periods of time than traditionally administered Lr. Previous studies demonstrated that this enhanced Lr biofilm formulation significantly reduces the onset of necrotizing enterocolitis (NEC) in a rat model, with ongoing studies demonstrating that the Lr biofilm formulation reduces the onset of NEC in murine and porcine models. Necrotizing enterocolitis (NEC) is a serious gastrointestinal condition that occurs in ~10% of premature infants. Despite decades of research, there are currently not effective treatments for this disease and the mortality rate remains unacceptably high. Our novel Lr biofilm formulation has the potential to prevent this devastating disease and significantly reduce infant mortality, and we are now finding that this novel bacterial therapeutic is also neuroprotective. Infants that recover from NEC often have neurodevelopmental impairments due to neuroinflammation that develops secondary to the severe intestinal inflammation. We have found that our novel Lr biofilm formulation reduces the neurodevelopmental impairments in rodents that have survived NEC stress. Our ongoing studies are focused on assessing methods to enhance these Lr biofilm neuroprotective effects. The neuroprotective effects of our novel Lr biofilm formulation are also evident in murine models of autism spectrum disorder. A phase 1b clinical trial, conducted by Scioto Biosciences, utilizing our Lr biofilm formulation (designated SB-121 in clinical studies) demonstrated that this formulation is not only safe, but significantly improved autism spectrum disorder phenotypes in approximately half of the participant. Thus, we are conducting studies in murine models of autism spectrum disorder to determine approaches to enhance the efficacy of our Lr biofilm formulation so that it will be effective for all individuals with autism spectrum disorder.
Our Goal
The long-term goal of this project is to use validated animal models to develop live, bacterial therapeutics that can significantly improve gastrointestinal and brain health in specific patient populations. We are particularly focused on live, bacterial therapeutics that can be safely used in our most vulnerable patients (i.e., premature infants with necrotizing enterocolitis), as well as in individuals with gut inflammation and associated neurodevelopmental disorders (such as autism spectrum disorder).
Funding
This work has been funded through several National Institutes of Health grants, including R01HD116839, R01GM123482, R44GM122130 and R41GM122130. We have also received funding from Scioto Biosciences.
Prenatal stress (PNS) has been associated with neurobehavioral deficits and increased risk of acquiring early-life infections. Importantly, PNS alters the maternal microbiome which is passed from mother to offspring at birth and induces persisting shifts within the offspring microbiome. It is known that early-life intestinal microbial colonization is a critical mediator of immune development and that the gut microbiota influences both physiologic and mental health. Epidemiological studies report that children exposed to PNS in utero are more likely to exhibit mood and behavioral disorders and also possess increased risk of acquiring early-life infections including, but not limited to, respiratory infections. In this project, we induce PNS using an established model of chronic restraint stress during late gestation and aim to elucidate the role of the intestinal microbiome in mediating postnatal offspring health.
By incorporating the PNS experimental design into gene knockout and germ-free animal models, our OSU collaborator, Dr. Tamar Gur, has shown that PNS-induced shifts in the maternal microbiota are essential in driving neuroinflammation and behavioral abnormalities in PNS-exposed offspring. However, mechanisms through which gut microbiome disturbances contribute to increased risk of early-life respiratory infection in PNS offspring have not been investigated. Our current findings demonstrate that PNS leads to a heightened state of immune activation in the lung and intestine of exposed offspring which correlate with changes in the intestinal microbiome and are exaggerated following mock respiratory infection with polyI:C. Most recently, we have combined microbiome analyses with transcriptomics, metabolomics, and flow cytometry to assess the immune response at a more granular level. Moving forward, we will investigate the implications of these immunologic differences in the context of infectious respiratory disease while continuing to probe for microbially-driven mechanisms.
This work will provide new insights into how PNS exposure affects the relationships between the intestinal microbiome, immunity and disease and has the potential to facilitate the development of microbial- or immune-targeted to mitigate or prevent childhood health adversities associated with PNS.
Our Goal
The goal of this work is to investigate the extent to which abnormalities in the microbiota of prenatally stressed offspring contribute to shaping early-life immunity and health. We also aim to understand how microbial, metabolic and immune differences observed in exposed offspring contribute to changes in disease risk within this population, particularly respiratory infection.
Funding
This work has been funded through several National Institutes of Health grants, including R21MH117552, R01MH129589, and R01MH134121.
The physiological stress response leads to changes in gut microbial composition that increase susceptibility and severity of enteric infection and gastrointestinal pathologies. However, the pathways involved in this stress-induced microbial dysbiosis have yet to be fully elucidated. In this study, we are utilizing two well-established stress paradigms: social defeat stressor (SDR) and restraint stress (RST) to induce a physiological stress response. In collaboration with Dr. Jacob Allen at the University of Illinois, our data show that RST exposure induces colonic microbial dysbiosis characterized by a loss of commensal microbial populations and a downregulation of important ROS/RNS producers and pro-inflammatory cytokines in colonic epithelial cells (CECs). This downregulation leads to increased susceptibility to enteric pathogens, and RST-exposed mice have a hyper-inflammatory response upon challenge with the bacterial enteric pathogen, Citrobacter rodentium. Studies are now testing the extent to which glucocorticoids produced during the physiological stress response downregulate essential antimicrobial players, leading to dysbiosis that drives increased susceptibility to colitis and worsened immunopathology.
Our work will uncover new interactions between the physiological stress response, the gut microbiome and colonic epithelium, and contribute to our understanding of the molecular mechanisms by which stress drives more severe immunopathology during colitis. Elucidating these mechanisms may reveal novel therapeutic approaches to treat gastrointestinal diseases.
Our Goal
The overarching goal of this project is to determine whether intestinal epithelial reactive oxygen species (ROS) activity contributes to stress-induced microbial dysbiosis and colitis outcomes. Additionally, we aim to elucidate how stress hormones produced during the physiological stress response alter the intestinal epithelium and gut microbiota.
Funding
This work has been funded through National Institutes of Health grant R01DK131133.
Inside the Bailey Lab
Our Research
The microbiome is an incredibly influential collection of microorganisms residing on and within the body, with the largest collection of microbes residing in the intestine. There is continuous feedback between host and microbiome wherein factors such as diet, age and stress can all influence microbiome composition. This, in turn, contributes to changes in microbially-derived metabolites and signals that act locally or serve as messengers along systemic bidirectional networks with influences on host metabolism, mood, immune function and disease. The gut microbiome in particular is recognized for its far-reaching effects on health, and disruption of this microbiome has been associated with various intestinal, metabolic, respiratory and mood disorders. Excitingly, novel strategies that rebalance the microbiome or introduce beneficial microbes have been found to alleviate disease symptoms and lend to improved health outcomes in many scenarios. In total, the microbiome represents a powerful tool and target for improving overall health.
We use a variety of next-generation high throughput sequencing technologies, such as metagenomic and bacterial 16S rRNA sequencing, RNA-sequencing and metabolomics analyses, to help us characterize the composition and function of the intestinal microbiome and changes in host responses. We also rely on a variety of conventional research tools including quantitative PCR, ELISAs, microbiology culture assays, histology, immunofluorescence, immunohistochemistry and cell culture assays.
Featured Publications
- Modulation of anxiety-like behavior in galactooligosaccharide-fed mice: A potential role for bacterial tryptophan metabolites and reduced microglial reactivity
- Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation
- Oral and middle ear delivery of otitis media standard of care antibiotics, but not biofilm-targeted antibodies, alter chinchilla nasopharyngeal and fecal microbiomes
- Stressed to the Core: Inflammation and Intestinal Permeability Link Stress-Related Gut Microbiota Shifts to Mental Health Outcomes
- T Cell-Induced Colitis Is Exacerbated by Prolonged Stress: A Comparison in Male and Female Mice
Collaborate With Us!
If you’re interested in collaboration, please email us at Michael.Bailey2@NationwideChildrens.org.