Institute of Cellular Medicine

Staff Profile

Dr Christopher Stewart

Faculty Fellow

Background

The number of babies surviving preterm birth is increasing, resulting in increasing numbers of neonates susceptible to preterm disease. The most common diseases affecting preterm infants are necrotising enterocolitis (NEC; leaky gut) and late onset sepsis (LOS; bacteria in blood). The main risk factors for these diseases are immaturity of the neonate and abnormal bacterial colonization. However, despite several decades of study, the mechanisms of these diseases remain poorly understood, with no single or combination of bacteria reproducibly shown to cause disease.

‘The Great North Neonatal Biobank’ (http://www.ncl.ac.uk/biobanks/collections/neonatal/) has a large collection of samples from preterm or newborn babies with complex health needs. Using this resource, we identified a unique bacterial community that only occurred in the gut of control infants. This community had a high overall diversity and was rich in bifidobacteria, which is considered a ‘healthy bacteria’.

While immensely informative for hypothesis generation, clinical samples are not well suited to determine mechanisms involved in disease pathobiology. Furthermore, animal models of prematurity prevent clear translatability into human populations. Advancing existing high-throughput discovery work, my research seeks to interrogate microbial-host cross-talk using a novel and powerful co-culture model that accurately mimics the conditions of the gastrointestinal tract. The model utilises patient tissue that would otherwise be discarded to derive intestinal ‘enteroids’. Human intestinal enteroids grow into ‘mini guts’ and the co-culture model permits the addition of anaerobic bacteria to the patient derived enteroids. This allows us to determine how bacteria (the microbiome) influence health and disease.

This ex vivo modeling promises to lead to major advances in our understanding of how microbes promote health, or cause disease, in the gut of preterm infants. The developed methodologies can also be applied to study microbial-host cross-talk in a wide range of gastrointestinal disease beyond preterm infants, including diseases affecting pediatric and adult populations.

Such knowledge from the basic science has great potential for the development of new treatments and clinical management of patients.

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Research

My research interests are focused on the ecology of microbial communities and host responses in human health and disease. My research typically focuses on early life (neonatal through to childhood) and is split into two major areas:

1) Multi-omic investigation of clinical samples: Applying high-throughput next generation sequencing and mass spectrometry based approaches to generate large datasets from clinical samples, including stool, nasopharyngeal aspirate, saliva, oral swabs, tissue resections, and blood. Such datasets typically include information relating to the presence of microbes and their genetic capacity, as well as microbial and host protein and metabolite levels. Bioinformatics and statistical analysis can then be applied to determine differences between diseased and control groups, plus what specific microbes/genes/proteins/metabolites are associated with each group. Although disease mechanism requires further work, this area of discovery research typically yields several testable hypotheses.

2) Novel models to elucidate microbial-host crosstalk and interrogate the mechanisms of gastrointestinal disease: The potential to interrogate microbial-host cross-talk promises to lead to major advances in our understanding of how microbes promote health or cause disease. Due to recent scientific advances we now have the ability to take patient tissue that would otherwise be discarded and derive intestinal ‘enteroids’ from the tissue. These human intestinal enteroids are able to grow into ‘mini guts’ in the laboratory and can differentiate into all the major cell types of the intestine. They also secrete mucin and respond to viral or bacterial infection. Because the tissue is derived from patients with disease, and retains the genetic, epigenetic, and exposure history, human intestinal enteroids have several major advances over animal models. With collaborators at Baylor College of Medicine (Houston, USA), we have pioneered a powerful co-culture system that mimics the conditions of the gastrointestinal tract and simultaneously allows bacteria and patient derived enteroids to interact directly. We can then test how the addition of specific bacteria influences the health or disease status of the cells, such as by measuring epithelial integrity, bacterial translocation, and markers of disease (e.g., inflammatory cytokines). This work allows microbial-host cross-talk to be investigated and can lead to mechanistic understanding of disease processes, which can be directly translated into clinical care of patients.

Publications