The wild mammalian microbiome

The vertebrate gut teems with a vast, diverse community of bacteria that outnumber the cells of their host by at least an order of magnitude, the so-called gut microbiota. Recent advances in molecular biology have revolutionised research into these bacterial communities, and demonstrated their pervasive effects on host biology, health and disease. At the same time, their tremendous variability has come to light - they vary enormously across species, among individuals, and within individuals over time. Such variation demands an explanation, yet our current understanding of the ecological and evolutionary processes responsible remains limited. A key obstacle in this respect is that so far, microbiota research has focused heavily on just two model organisms - humans and laboratory mice, leaving a gap in knowledge about what shapes gut microbial communities in natural vertebrate populations. I outline a research programme that addresses this need, by developing wild small mammals as a novel system for microbiota research, and using them to address several key questions about which we currently know rather little: (1) Why do individuals within a single population show distinct gut microbial profiles, and what processes drive changes in these communities over time within individuals? (2) How exactly are gut microbes and other gut-dwelling organisms transmitted among hosts within a population - do their social interactions or shared use of space play a significant role in this process? (3) What ecological and evolutionary processes underlie variation across species in their gut microbiota?

To address the first two questions, I will use a common British rodent - the wood mouse - as a model study system. Wood mice are ideal for this purpose: in the wild, a large number of individuals can be uniquely marked and monitored throughout their lives in a relatively small area, with repeated sampling of their gut microbiota and fine-scale characterisation of their local habitat. Also, manipulative experiments both in the wild and in captivity are possible with this species. To address the first question, I will use a combination of detailed field observations and controlled experiments to build a comprehensive picture of the processes shaping within-population variation in gut microbial communities. Observational data on key hypothesized factors including genetic relatedness, diet, habitat, gut parasites, age and reproductive status will allow me to estimate their relative contribution to microbiota variation within and among individuals. I will also use a large-scale drug treatment experiment in wild mice to directly test how the presence of another key group of gut inhabitants - parasitic helminths, affects the microbiota. Finally, I will perform a "diet shift" experiment in captive wood mice, to test how changes in natural food groups shape the gut microbiota. To address the second question, I will use a novel 'social network' based approach in the same wild wood mouse population used above, to examine how animal social contacts and space use drive the transmission of gut microbes and gut parasites. Finally, to answer the third question, I will perform a multi-species study using wild small mammals (mice, voles and shrews) that co-occur across several different habitat types in Europe. This study will test for the first time whether a host's evolutionary heritage or their current environmental conditions (habitat and diet), dominate in shaping their microbiota.

This research will provide fundamental insight into the ecological and evolutionary processes affecting the mammalian gut microbiota, and thereby advance our knowledge about how and why these communities, which are so critical to host health, vary in nature. It will also fill an important gap in knowledge about how gut-dwelling organisms are transmitted among animals, with relevance to the control of infectious disease.

I identify four major groups that will benefit from this work.

(1) The academic community
As detailed in 'Academic Beneficiaries' this research will be of key interest to academic researchers from a range of disciplines, including microbial ecologists, infectious disease biologists and mammal ecologists. I will ensure my research achieves impact in these academic fields by publishing primary research in high impact journals (open access whenever possible), writing opinion pieces and commentaries, presenting my work at relevant conferences, and organising a workshop. The latter will facilitate the exchange of ideas and approaches between microbiota researchers working on both model and non-model organisms and forge new research directions capitalising on the strengths of different systems.

(2) Postgraduate and undergraduate students
I anticipate a significant student interest in my research. The wood mouse project I would use in objectives 1 and 2 has already proved popular among Imperial MSc and MRes students for research projects. Aurelio Malo has supervised 15 Master's projects on this system since setting it up, and I anticipate similar popularity going forward. I will engage postgraduate and undergraduate students to carry out their own research projects. Through their involvement, these students will benefit from training in microbial and disease ecology, field techniques and statistical analyses, as well as transferable skills in project and data management.

(3) The general public
Gut microbes and parasites/pathogens pervade everyone's lives, with vast numbers colonizing all animals including humans. With continual revelations about the complexity of these communities and their diverse effects on host biology, our symbiotic communities certainly capture the public's interest. Other aspects of this work are also likely to stimulate public interest, including insight into the social lives of familiar wild species, and how social interactions affect pathogen spread (currently a hot topic, for example with recent media spotlight on bovine TB). Through actively pursuing media coverage of published work, having an accessible website and blog, as well as outreach activities at public science events, I will maximise the impact my research has on public understanding and enjoyment of science.

(4) Disease control community
This work is relevant to and has potential to inform public health programmes. Millions of pounds are spent each year on deworming as part of disease control programmes in humans and livestock. The Neglected Tropical Disease (NTD) community has set ambitious goals (e.g. the London Declaration on NTDs) to control or eliminate helminths from human populations, largely through mass treatment programmes. Current strategies essentially ignore within-host community ecology: there is little consideration of how deworming may alter these communities, and the potential implications for successful disease control. Part of this proposal addresses exactly this question using wild mice as a model system, and the results will provide a test case on this key issue. I will ensure my research broadens awareness in this area by (i) communicating results at conferences attended by end-users in disease control, (ii) organising a symposium focusing on these issues at one such conference, and (iii) writing commentaries that highlight key questions and findings in this area, with collaborators in the human NTD world established through my current position.