Host microbe cross talk in the intestine in health and disease

PROJECT OVERVEW 

The gastrointestinal (GI) tract is home to trillions of commensal bacteria (microbiota) that play an integral role in the maintenance of intestinal homeostasis through continuous and complex bidirectional interactions with the host mucosal immune system. Disruption of this host-microbial interface is implicated in the pathogenesis of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders characterized by relapsing and remitting episodes of inflammation in the intestine. Indeed, the gut microbiota is altered in IBD patients, however it is not clear whether such shifts are causal of, or consequential to, disease development. Advancements in gnotobiotic technologies, in which mice harbor a defined microbiota, have facilitated interrogation of the causal role of gut commensals in disease processes. Importantly, studies utilizing germ-free mouse models of IBD have shown that the microbiota is required for optimal development of intestinal inflammation and pathology. Work in the Powrie lab has focused on a Helicobacter hepaticus + anti-interleukin-10 receptor (aIL10R) model, in which mice deficient in the anti-inflammatory cytokine IL-10 colonized with H. hepaticus develop inflammation in the colon (colitis). Interestingly, disease development in this model is microbiota-dependent, with model commensal bacteria displaying differential abilities to support pathogen-induced pathology. This project will build on this work, to understand the bacterial-bacterial and host-bacterial interactions that underpin differential disease outcomes in gnotobiotic mice following H. hepaticus + aIL10R treatment. This will be done through taking an interdisciplinary approach leveraging immunological, microbiological and bioinformatic techniques to assess differences in bacterial and host responses that precede or correlate with disease development. Subsequent steps will lencompass targeted mutagenesis of candidate microbial pathways, metabolite supplementation and/or blockade of host signaling to alter disease phenotype. Ultimately this work will inform the developing space of microbiome based IBD therapeutics.

KEYWORDS

Microbiome, inflammatory bowel disease, gnotobiotics, host-microbe interface

TRAINING OPPORTUNITIES

Training in conceptual and experimental aspects of immunology and microbiome. Cutting edge technologies including imaging, metabolomics, bioinformatics, genetically modified and gnotobiotic mice.

KEY PUBLICATIONS

https://www.kennedy.ox.ac.uk/research/research-groups/mucosal-immunology

1.        Uhlig HH, Powrie F: Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu Rev Immunol 2018, 36:755–781.

2.        Jeffery R, Ilott NE, Powrie F: Genetic and environmental factors shape the host response to Helicobacter hepaticus: insights into IBD pathogenesis. Curr Opin Microbiol 2022, 65:145–155.

3.        Jackson MA, Pearson C, Ilott NE, Huus KE, Hegazy AN, Webber J, Finlay BB, Macpherson AJ, Powrie F, Lam LH: Accurate identification and quantification of commensal microbiota bound by host immunoglobulins. Microbiome 2021, 9:33.

4.        Brugiroux S, Beutler M, Pfann C, Garzetti D, Ruscheweyh HJ, Ring D, Diehl M, Herp S, Lötscher Y, Hussain S, et al.: Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium. Nat Microbiol 2016, 2:1–12.

KEY THEMES

Immunity and microbiome