Causes and consequences of variation in the mammalian microbiota

Project Information

MUSMICRO

Grant agreement ID: 851550

DOI

10.3030/851550

EC signature date 11 December 2019

Start date 1 February 2020

End date 31 July 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 771 166,00

EU contribution

€ 1 771 166,00

Coordinated by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 3 - MUSMICRO (Causes and consequences of variation in the mammalian microbiota)

Reporting period: 2023-02-01 to 2024-07-31

Summary of the context and overall objectives of the project

The mammalian gut houses a dense and diverse microbial community called the gut microbiota, which varies widely among individuals. A large body of lab-based research suggests these microbes provide important functions for their animal hosts, yet we know little about what forces shape the gut microbiota or its impact on host biology and fitness in natural populations.

In this project, we are investigating the causes and consequences of gut microbiota variation in a natural population of the species with the best laboratory tools, and knowledge, for the mammalian microbiome: the house mouse. We are pairing detailed studies of wild mice in their natural environment with lab-based experiments to investigate the causal impacts of naturally occurring microbiota variation. This project tackles the following three major objectives:

(1) To uncover the processes generating microbiota variation in the wild, including genetic, environmental and social influences. We aim to unpick the extent of genetic influence on the microbiota and which types of genes are involved, using a genome-wide association study. We also aim to shed light on the forces driving temporal microbiota dynamics within individuals.

(2) To test whether natural variation in the gut microbiota causally influences key host phenotypic traits of interest. We focus on two traits that lab mouse studies have suggested are under microbiota influence, and which we expect to be relevant to host fitness (overwinter survival): body condition (fat deposition) and host tolerance of cold temperatures. Using state-of-the-art wild-to-lab gnotobiotic experiments, we will test whether natural differences in these traits, both among individuals and within individuals across seasons, are driven by the gut microbiota.

(3) By combining results from Objective 2 with data on predictors of overwinter survival in among wild mice, we will shed light on whether the microbiome, and traits under its influence, play an important role in determining host fitness.

Overall, the findings from this project will shed vital new light on the reach of the gut microbiome's influence outside the laboratory in real-world settings, and answer the key unanswered question: does variation in the gut microbiome actually matter in nature?

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

So far, we have conducted regular fieldwork over a 2-year period to gather a large longitudinal dataset from our wild mouse study population, involving over 1500 captures of over 600 wild mice. We have characterised the gut microbiome from some of these samples, as well as environmental factors and phenotypes of interest (body condition and cold tolerance). We have also begun characterising the genomes of these wild mice using state-of-the-art methods, and will finish collecting this genomic information, as well as microbiome data, over the next six months. Analysed for Objective 1 have begun, though much remains to be looked out once the final large dataset is in hand. Under Objective 1, we have revealed key factors predicting microbiota variation in wild mice (season, age, environmental factors), including how the microbiome changes as mice develop during early life. We have also found that wild mice display clear variation in their cold tolerance and body condition. We are in the process of setting up an experimental facility in which to perform gnotobiotic experiments in the second half of the project, that will test whether this phenotypic variation is mediated by the microbiota. We have monitored overwinter survival of mice using our RFID loggers for two winters. Given severe delays and disruption to the start of this project due to the covid-19 pandemic, major results on the core objectives are yet to emerge. However, fieldwork and sample collection are almost complete, genetic and microbiome analyses are well under way, such that we are now almost ready to undertake full-scale analysis of the questions in Objective 1, and to carry out the key experiments in Objective 2.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

With the pandemic delaying and disrupting island fieldwork and our ability to begin data collection, we turned out attention towards project-related questions that were achievable despite this. This resulted in some unplanned and unexpected progress/results. These include the optimisation by a PhD student of an (epigenetic) method to age wild mice from faecal samples, which she then successfully applied to study how host age shapes gut microbiome variation during early life (under Objective 1). She uncovered strong parallels in early life gut microbiota assembly patterns between wild and laboratory mice. Both her method and findings are currently being written up as papers. The epigenetic ageing method may be useful in other wild mammal studies where age is a key variable of interest that cannot be readily assessed from other characteristics. During lockdown, we also analysed pre-existing data from a similar wild mouse system, to investigate the importance of maternal transmission in shaping the gut microbiota. This demonstrated a waning impact of maternal transmission on microbiota composition as hosts age. This progresses understanding of how long mothers influence the gut microbiota in mammals once offspring are independent, relevant to Objective 1. We also trialled different field-friendly methods of storing faecal samples to test which provide the most faithful transfer in faecal microbiome transplant (FMT) experiments, using standard laboratory mice. Results from this will not only facilitate our own work, but also support future studies aiming to test the impact of wild-derived microbiomes in FMT experiments. Thanks to a new collaboration developed during lockdown, we have also applied a new method of characterising animal genomes that is more state-of-the-art than our originally planned approach. Results from its application to our wild mouse system will showcase the use of this powerful and cost-effective methodology to others across a broad range of fields.

wild house mouse