Determining how the microbiota and dietary selenium influence the function of long-lived intestinal macrophages to promote gut health

Changes to environmental factors such as microbial colonisation and dietary nutrition, brought about by modern lifestyles, are having significant impacts on human health. Some of these changes are having negative impacts on the quality of life we experience and limit our health and wellbeing. Our gut is an extremely important organ in our bodies that allows us to extract the nutrients and water from the food we eat. As well as food, it is in close contact with the large community of good bacteria that live inside us. It also provides a route of entry into our bodies for harmful bacteria. This variety of stimuli entering our bodies through our gut represents a challenge for our bodies, which need to maintain a constant environment necessary for the gut to do it's job. Disruption of this carefully balanced environment can lead to illnesses such as inflammation, food intolerance and cancer. I have recently described an immune cell in the gut that is present from birth and stays with us over the course of our lifetime. Initial results suggest that this population could help to maintain a healthy gut. My research aims are to discover how these gut immune cells maintain a healthy gut and whether we can boost their function using bacteria and food nutrients.

Maintenance of gut health is critical for longevity and wellbeing. Deterioration of gut health can lead to the development of infectious, inflammatory and functional gut diseases, as well as an increasingly recognised range of extra-intestinal diseases such as immune-mediated and metabolic disorders. Environmental factors such as microbial colonisation and dietary nutrition have been shown to affect the health status of this essential and life-supporting organ. I have recently described a novel long-lived population of intestinal macrophages that dominate the macrophage pool in the neonatal period, persist into adulthood and produce the selenium-containing anti-inflammatory enzyme, Gpx3.

Key to the translation of basic research for human impact is the identification of functionally conserved pathways in animal models and humans. Using single-cell RNA-sequencing I will identify markers of corresponding long-lived gut macrophage in humans and mice. Employing these markers, I will then assess the function of long-lived human intestinal macrophages in vitro to identify common mechanisms in mice and humans underpinning gut health. Using transcriptional and epigenetic profiling of long-lived macrophages from recolonised germ-free mice I will identify genes and transcription factors in long-lived gut macrophage that are controlled by the commensal microbiota. I will use a combination of selenium-altered diets and Gpx3 deficient mice to delineate the importance of dietary selenium and the production of Gpx3 by long-lived gut macrophages for the maintenance of gut health. Together, these experiments will identify mechanisms by which the commensal microbiome and dietary nutrition alter the development and function of long-lived intestinal macrophages to promote gut health. This opens up the opportunity for evidence-based microbial and dietary supplementation to promote outcomes that favour the maintenance of organ function and health

My impact goal is to identify and engage with academic, public and private stakeholders that will benefit from my research. Examples of stakeholders I would like to interact with are members of the general public, especially young people, governmental and non-governmental organisations and research and industry partnerships.

The main beneficiaries of my research will be academics studying macrophage biology, gastrointestinal health, dietary nutrition and the microbiome. My main contribution to these beneficiaries will be through he generation of new knowledge and resources. This knowledge and resources will be made available to the wider research community primarily through publications and use of data repositories.

The wider public will also benefit from increased mechanistic understanding of how changes to environmental factors such as microbial colonisation and dietary nutrition can impact their health. This new knowledge may lead to the development of new evidence-based health promoting products by private companies and development of evidence-based public health policies. My impact within these non-academic spheres will be achieved through a mixture of public engagement events and participation in events aimed at bringing academics, health policy makers and private industry together.