The human gut microbiome, a huge community of microorganisms residing within our digestive system that interact to aid digestion, protect against pathogens and create essential metabolites, has been suggested to play a role in health and disease. However, much of the literature (arising from animal or observational human studies) attempting to assess this relationship has so far been inconsistent and unable to prove cause-and-effect relationships. Whilst traditional epidemiological studies have gone some way in assessing the association between the gut microbiome and health, these study designs are small and limited in their ability to draw causal inference due to the existence of other factors associated with both the gut microbiome and health (“confounding”), the possibility of reverse causation (where an association is actually due to a disease causing variation in the gut microbiome rather than the reverse) and many forms of bias. Thus, these limitations can distort or skew our observed association and lead us to draw false conclusions. Additionally, randomized controlled trials (RCTs), the best and most effective way of assessing causality in epidemiological studies, are not feasible, expensive and likely unethical within a healthy human population. I propose to address this question – does the gut microbiome cause adverse health and disease?

With the UK Research and Innovation (UKRI) Future Leaders Fellowship (FLF), I will combine my expertise in the design, analysis and interpretation of causal inference methods (such as Mendelian randomization (MR)) and population health sciences with microbiome health to address the fundamental problem in the study of the gut microbiome in human health – causality. Analogous to nature’s RCT, MR is a method that uses randomly allocated genetic variation within a population (identified by genome-wide association studies (GWAS)) as a proxy for a “confounded” exposure (i.e., the gut microbiome) to improve causal inference in an association between that exposure and an outcome (e.g., colorectal cancer). In my current role, I lead several projects and am involved in international collaborations, upon which I will build in this fellowship. Specifically, within a working group of six individuals, I am involved in a GWAS of the gut microbiome in the Flemish Gut Flora Project (FGFP; N~3000) and a GWAS of dietary composition within the Social Sciences Genetics Association Consortium.

With the established collaborations, data resources and world-renowned expertise in epidemiology and causal inference methods available to me at the Medical Research Council Integrative Epidemiology Unit (MRC-IEU), the UKRI FLF will enable this interdisciplinary, collaborative, data-driven and large-scale research with the aim of challenging the impact of the gut microbiome on important health outcomes (specifically, colorectal cancer, type 2 diabetes and inflammatory bowel disease) alongside one of the key exposures dominating the literature as a regulator of the gut microbiome - dietary intake and composition. To achieve this aim, I have identified a novel set of deliverable objectives to complete within the first four years of the UKRI FLF scheme: (1) collate data and results from the GWAS of dietary composition, the gut microbiome and outcomes of interest; (OB2) use these results in MR analyses to understand the causal role played by diet on the gut microbiome and of the gut microbiome on health; (OB3) perform targeted follow-up analyses with comprehensive measures of the microbiome and the product of their biological processes within the gut. I will be the first to unify epidemiological and genetic data with causal inference methods and gut microbiome research, areas in which I have been building experience, but which have yet to be brought together. The gut microbiome has great potential to have clinical importance to improve health given well-directed therapeutic development.