Deciphering host–microbiome genetic interactions in Inflammatory Bowel Disease

PROJECT OVERVIEW

The human microbiome is a complex and dynamic ecosystem of microorganisms that reside on and within the human body. These microbial communities play essential roles in maintaining human health, including immune regulation, nutrient metabolism and protection against pathogens. Increasing evidence suggests that the composition and function of the microbiome are influenced by a range of environmental and host-related factors including human genetics.

Recent advances in genomic technologies and computational biology have enabled genome-to-genome analyses, which allow for a more precise characterization of host–microbiome interactions. These approaches offer the potential to disentangle the intricate relationship between human genetic variation and microbial composition, particularly in the context of complex immune-mediated diseases such as inflammatory bowel disease (IBD).

This project will leverage data from the recently launched IBD-Response study (https://www.ibd-response.co.uk/), a UK-wide, multi-centre observational cohort collecting longitudinal data on patients with IBD. This rich resource provides a unique opportunity for integrated analysis of human genomic data, gut microbiome profiles, environmental exposures and clinical outcomes, including treatment response and disease progression.

Two elements of IBD Response allow novel and powerful analyses of the host-microbiome interaction. Firstly, the project includes whole-genome and metagenome sequencing of host and gut bacterial DNA, respectively, allowing the potential to study host-microbiome interactions at detailed strain- and sequence-variant resolution, including through de novo sequence assembly of bacterial genomes or detailed analysis of variation in host human leukocyte antigen (HLA) genes. Secondly, the study includes extensive collection of environmental exposures, including detailed information on patient diet and medical history, allowing us to understand how the environment mediates and modifies the relationship between host and microbe genetics. The overarching aim of the project is to develop and apply novel statistical methods and bioinformatic pipelines to identify and characterise genetic factors that modulate host–microbiome interactions in IBD. Through these efforts, the project aims to uncover novel biological insights into how host genetics shape the gut microbiome and how these interactions contribute to IBD heterogeneity.

This project sits at the intersection of genomics, microbiology, biostatistics and clinical medicine, and will provide broad training in computational biology, high-dimensional data analysis and translational research. The findings have the potential to advance both our fundamental understanding of host–microbiome interactions and their clinical relevance in chronic inflammatory diseases. 

KEYWORDS

Microbiome, human genetics, interaction, IBD, statistical genetics

TRAINING OPPORTUNITIES

The successful candidate will benefit from supervision by experts in genomics and computational biology with a focus on translational medicine. You will be based in the purpose-built labs at The Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation.

This project is ideally suited for students with a background in statistical genetics or microbiome informatics who wish to expand their applied knowledge in the biological sciences, as well as for those with a background in biology or clinical science who are interested in integrating biology with data science.

Comprehensive training will be provided in data science techniques, including statistical data analysis and visualization with R, developing computational pipelines with Python/Nextflow, and utilizing high-performance computing clusters. The student will gain expertise in analysing advanced sequencing datasets, such as whole genome, RNA, and proteomic sequencing.

The Kennedy Institute offers a vibrant PhD program, featuring a weekly journal club, seminars, student symposia, and regular internal presentations and training sessions. A core curriculum of lectures will provide a solid foundation in diverse subjects, including data analysis, statistical methods, and immunology summer school. In addition to institutional support, the successful applicant will benefit from the University of Oxford's college system. Students will also have the opportunity to collaborate closely with both computational and experimental scientists. In addition, this project will allow the student to develop national collaborations with leading researchers and clinicians via the IBD Response Data Analysis Group, with members at Newcastle University, the Sanger Institute in Cambridge and Kings College London. 

KEY PUBLICATIONS

Wyatt NJ, Watson H, Anderson CA, et al. Defining predictors of responsiveness to advanced therapies in Crohn’s disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine BMJ Open 2024;14:e073639. doi: 10.1136/bmjopen-2023-073639

Luo, Y., Huang, CC., Howard, N.C. et al. Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis. Nat Commun 15, 10393 (2024). https://doi.org/10.1038/s41467-024-54741-w

Jostins, L., Ripke, S., Weersma, R. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012). https://doi.org/10.1038/nature11582 

THEMES

Genetic and genomics, microbiome & metabolomics, data science, translational and precision medicine

CONTACT INFORMATION OF ALL SUPERVISORS

yang.luo@kennedy.ox.ac.uk

luke.jostins@kennedy.ox.ac.uk

jethro.johnson@kennedy.ox.ac.uk

uzma.khan@kennedy.ox.ac.uk