Prof. Dr. Filipe Cabreiro

Dysregulation of host metabolism and immunity underlies a vast proportion of human diseases but also ageing. Recent evidence shows that disease arises from the complex interactions between the genetic make-up of the host and the environment. The microbiota, a key environmental factor, regulates most aspects of human physiology and consequently the propensity for ill-health but the dynamics and factors that govern the interactions between host and microbe in the context of disease are poorly understood.

Our research: Our research focuses on answering several key fundamental questions. For example, how do microbes communicate with host cells? What molecules or mechanisms are implicated? What organelles and cellular mechanisms sense microbial cues? How do cells mount adequate responses to such cues to maintain cellular homeostasis during ageing? How do microbes hijack host cellular metabolism for their own benefit.

Our successes: Our work in this area of research has been focusing on understanding in great detail the mechanistic role played by microbes and/or nutrition in ageing and healthspan. My team and I have recently investigated the effect of genetic, dietary and microbial impact on worm healthspan and lifespan. In particular, we found that worms that are grown with a vitamin B₁₂ high-producing bacterial strain compared to a low producing one such as E. coli, maintain healthspan of worms for longer during ageing (Essmann et al., 2020, Nature Comms). We have also developed a high-throughput screening approach to study the interaction between host genetics and environmental stresses or pathogenic infection (Benedetto et al., 2019, Aging Cell). These studies further support a key role for microbial commensalism and pathogenicity in regulating healthspan and lifespan in a host-genetic dependent manner. Importantly, we have developed novel 3 and 4-way high-throughput drug-microbe-host screens that allowed us to define the key signalling and metabolic pathways in bacteria that regulate the host response to therapeutic drugs. In a 3-way high-throughput drug screen of drug-microbe and C. elegans using the Keio collection of E. coli single gene deletion mutants (Scott et al., 2017, Cell) we tested more than 55,000 individual conditions, and identified vitamins B₆ and B₉ and ribonucleotide metabolism as key microbial contributors to 5-FU action, an anti-cancer drug. This work also implicates a role of microbes in controlling autophagy, one of the key mechanism regulating ageing (Lopez-Otin et al., 2013). Further, we have investigated the role of the dietary-restriction mimetic metformin, the most widely prescribed type 2 diabetes drug, in regulating ageing. We and others, have shown that metformin regulates host

physiology and ageing by altering the microbiota (Pryor et al., 2019, Cell; Cabreiro et al., 2013, Cell). Our work shows that the effects of metformin on host lipid metabolism and lifespan, depend on both E. coli and nutrition, providing a mechanistic explanation for human data. This was made possible using a combination of C. elegans, Drosophila and human microbiome computational modelling together with and an array of multi-omic, screening, biochemical and genetic approaches at the host and microbial level. Overall, our 4-way drug-microbe-nutrient-host high-throughput screening approach led to the identification of a nutrient signaling pathway in bacteriathat when activated by metformin regulates the positive effects of the drug on the host lipid metabolism. We have recently used the worm as a model to validate a novel mode of action employed by bacteria to reduce drug efficacy on host (Klunneman et al., 2021, Nature) Finally, using C. elegans and a synthetic biology approach, we characterized whole-cell bacterial biosensors in vivo in an ageing host. We show these bacterial sensors are capable of detecting and reporting on changes inside the intestine of C. elegans after introducing exogenous chemical inducers into the environment (Rutter et al., 2019). This workprovides evidence that C. elegans is colonized by microbes that are alive and functionally respond to cues within their intestinal environment throughout ageing.

Our work on the effects of drugs and longevity has also revealed that rapamycin extends longevity through a novel aging mechanism – improved protein fidelity, in an evolutionarily conserved manner (Martinez et al., 2021, Cell Metabolism).

Our goals: We aim at developing experimental and computational tools to study the causal relationship between host genetics, microbial genetics and nutrient interactions in the context of ageing. We aim at discovering pharmacological and/or pharmacomicrobiomic (drug-microbe) approaches to treat metabolic disease and improve ageing. Finally, we aim at testing evolutionary conservation of findings in mouse models and humans.

Our methods/techniques: We utilize a combination of tractable genetic models such as the nematode C. elegans, widely used for studying host-microbe interactions, human-cell derived gut organoids and cell cultures, and mouse models (including germ-free) to identify mechanisms driving ageing in an environment-dependent manner.

We combine high-throughput genomic/chemical screening approaches. These include the screening of thousands of bacterial strain collections and or drug and nutrient compounds. We utilise CRISPr/cas technology and synthetic biology approaches to modify bacteria. Finally, we perform multi-omics experiments (e.g. transcriptomics, proteomics, metabolomics) at the holobiont level. And utilize a systems biology computational approach for data integration. This holistic approach will provide phenotypic, genomic and biochemical molecular datasets that will enrich our understanding of the fundamental processes underlying host-microbial cross-talk at the systemic, cellular and molecular levels.