1. Research Background:

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. We aim at unraveling the mechanisms underlying metabolic disease, through the study of the physiology of the entire holobiont (the host and its associated commensal microbes) and how it is influenced by environmental factors (e.g. diet, drugs). Such approach is essential to develop new predictive tools for drug action and discover novel and efficient pharmacological approaches to treat disease. Recent findings from our lab highlight the therapeutic power of genetically or pharmacologically manipulating intestinal microbiota to ensure host metabolic health, treat disease (e.g. type-2 diabetes and cancer) and improve healthy ageing. Ultimately, our goal is to identify precise and robust drugable mechanisms in both host cells and gut bacteria that will be harnessed for the treatment of metabolic disease and create avenues for translational applications for treating human disease.

2. Research questions addresses by the group:

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?

3. Possible projects:

The traditional approach in ageing research often focuses on the host organism alone—how the body ages, how genetic and environmental factors influence this process, and how it leads to diseases and disorders. However, we suggest to treat the host-microbiota as a unified biological entity. This view recognizes that ageing is not just a phenomenon happening at the level of the host, but is co-regulated and influenced by the microbiota. The microbiota, particularly the gut microbiome, plays a significant role in metabolism, immune function, and overall health, which directly impacts the ageing process. In younger individuals, the gut microbiota is relatively stable, but with age, microbial communities become more unique. This uniqueness has been observed in both human and mouse studies, where older individuals exhibit a microbiome that differs markedly from their younger counterparts. However, the question arises: What drives these microbiota changes? The primary drivers of these changes, independent of diet and drugs, remain poorly understood and points to a clear gap in the current research. The observation that an increasing "compositional uniqueness" in the microbiome might reflect healthy aging rather than disease suggests that as we age, the microbiome adapts in ways that could be beneficial, or at least neutral, for the host. It also highlights that the microbiome’s metabolic outputs—such as metabolites—are crucial for understanding these dynamics. While genomic approaches have been dominant in microbiome research, focusing only on genetic composition likely misses important aspects, such as the functional or metabolic redundancy of microbiota that may not be immediately apparent through genomics alone. Our goal is to illuminate how the complex relationship between the host and the metabolism of commensal bacteria significantly impacts the ageing process. Specifically, we delve into the hallmarks of ageing, including deregulated nutrient sensing, mitochondrial dysfunction, proteostasis and altered intercellular communication including inflammageing. To address this gap, our proposed study, employing a combination of wet and dry lab approaches, aims to directly investigate the temporal dynamics of functionally unique or redundant microbiomes in normal and accelerated aging, assessing their relevance to the hallmarks of ageing.

4. Applied Methods and model organisms:

Model Organisms: 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.

Applied Methods: 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.

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.

5. Desirable skills and qualifications:

Professional Qualifications:

• Completed Masters degree in life sciences, microbiology, computational or related fields. A background in physiology, metabolism or ageing is a plus.

Personal skills:

• Proficiency in written and spoken English is mandatory.
• Evidence of great communication and team work skills, curiosity-driven science and excellent problem-solving skills.

Technical Skills:

• Experience in animal tissue handling, organoid or cell culture is desirable.
• Experience in microbiology or systems/computational biology is desirable.
• Experience in C. elegans husbandryis desirable.
• Experience in microbiology or systems biology is desirable.
• Experience with mass spectrometry (e.g metabolomics) is desirable
• Proficiency in R studio (and/or other) programming language is desirable.

6. References:

Mineo A. et al., (2024) The Sex and Reproductive Plasticity of Intestinal Muscles. SSRN (preprint- In revision for Cell)

Martinez-Martinez et al., Cabreiro F. (2024) Chemotherapy Modulation by a Cancer- Associated Microbiota Metabolite. SSRN (preprint – In revision for Cell Metabolism)

Klunemann M et al. (2021) Bioaccumulation of therapeutic drugs by human gut bacteria. Nature.

Martinez-Miguel, VE et al, Cabreiro F (2021) Increased fidelity of protein synthesis extends lifespan. Cell Metabolism

Essmann C et al. Cabreiro F. (2020) Mechanical properties measured by Atomic Force Microscopy define new health biomarkers in ageing C. elegans. Nature Comms.

Bana B. and Cabreiro F. (2019). The Microbiome and Aging. Annu Rev Genet.

Pryor R et al. Cabreiro F. (2019) Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. Cell

Scott TA et al., Cabreiro F. (2017) Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans. Cell

Cabreiro F. et al. (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell

Cabreiro F. et al. (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature.