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 unravelling 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 druggable 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 to regulate the hallmarks of ageing? 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:

1. Cancer prevention by the ageing microbiome

Over the past 60 years, global life expectancy has increased by more than 20 years, yet age-related diseases like cancer remain a leading cause of mortality. Colorectal cancer (CRC) is strongly associated with ageing, with mitochondrial dysfunction, microbiome dysbiosis, and chronic inflammation playing key roles in tumour initiation and progression. The adenomatous polyposis coli (APC) gene, frequently mutated in CRC, interacts with age-related mitochondrial defects (e.g., impaired OXPHOS) and gut microbiota changes to drive carcinogenesis. Microbial metabolites, such as secondary bile acids, influence tumour development, while pathogenic bacteria (e.g., pks+ E. coli, promote inflammation and DNA damage. Based on extensive preliminary data in mouse models, we hypothesise that age-related mitochondrial dysfunction and microbiota-derived metabolites promote tumorigenesis. This proposal aims at 1) Identifying key microbiota functions and metabolites linked to ageing and their causal role in CRC; 2) Develop pharmaco-microbiomic strategies to prevent cancer initiation. We will perform mechanistic studies to explore how microbiota-derived metabolites interact with mitochondrial dysfunction to promote tumorigenesis in APC-mutant models. By performing multi-omics profiling (metagenomics, metabolomics), we will identify microbial and metabolic signatures associated with CRC in ageing. Additionally, conventionally raised, germ-free as well as gnotobiotic preclinical models of cancer and age-related mitochondrial dysfunction will be used to test the impact of pro-tumorigenic bacteria (e.g. comparison of pro- tumorigenesis metabolite producing bacteria vs non-producing). Finally, high- throughput drug screening approaches will be employed to identify FDA-approved drugs modulating the microbiota to suppress the production of metabolites that would otherwise promote cancer initiation, as a novel preventative strategy.

2. Role of the Gut Microbiota in Polycystic Kidney Disease with Age

Primary cilia are microtubule-based organelles critical for cellular signalling, and their dysfunction leads to ciliopathies, including polycystic kidney disease (PKD). PKD is characterized by renal cyst growth, driven by metabolic reprogramming, mitochondrial dysfunction, and altered cellular signalling. Emerging evidence suggests that the gut microbiome influences PKD progression through microbial metabolites such as short-chain fatty acids (SCFAs) and uremic toxins, modulating inflammation and fibrosis. However, whether gut dysbiosis is a cause or consequence of PKD remains unclear. This project investigates the gut-kidney axis in PKD using germ-free and conventionally raised JCK mice, a model of genetic PKD, to dissect how microbial metabolites impact disease progression. We will identify key microbial-derived metabolites that influence renal function and test their therapeutic potential using gnotobiotic colonization strategies. By integrating multi-omics approaches—metagenomics, metabolomics, and proteomics—we aim to uncover novel microbiome-mediated mechanisms in PKD and identify biomarkers for therapeutic targeting. Our findings could lead to microbiome-based interventions to slow PKD progression.

3. Unlocking the Pharmacology of Long Healthy Life with Microbes

Microbes are capable of producing molecules of great biomedical potential. For example, one of the most promising anti-ageing drugs - rapamycin - was discovered over 40 years ago from a soil sample of the Chilean island of Rapa Nui. Rapamycin is produced by the bacterium Streptomyces hygroscopicus and was originally discovered due to its antifungal properties. Further characterization showed the versatility of its bioactivity, which includes antifungal, immunosuppressive, anticancer and anti-ageing properties. Recently, a novel rapamycin analogue was shown to be highly selective for mTORC1 in vivo, unlike the parent drug, suggesting that unexpected drug modifications by microbes may lead to more powerful anti-ageing drugs. Discoveries of this nature drive the search for additional microbial molecules and properties and underlie the utilization of functional metagenomic libraries from complex bacterial samples. However, discovery of such molecules through current approaches has been limited to identifying molecules with anti-bacterial or anti-fungal activity. Here, we propose to develop a novel high-throughput host biosensor toolkit that will allow us to identify bacteria-derived molecules, or drug molecules modified by microbes with enhanced bioactivity to modulate host physiology, in particular, focused on longevity and healthspan regulating pathways. Taking advantage of the multidisciplinary skills and approaches we have developed in recent years; we now plan to:

• Aim 1) Develop a high-content screening C. elegans biosensor toolkit based on high-throughput RNA sequencing;
• Aim 2) Identify and generate bacterially modified FDA drug-derived metabolites or microbial adjuvants regulating FDA drug action in longevity and healthspan pathways;
• Aim 3) Validate novel pro-longevity molecules in middle-aged wild-type mice for improved healthspan and longevity effects using epigenetic clocks.

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, Biology, microbiology, biochemistry, computational or related fields. A background in physiology, metabolism or aging is a plus.

Personal skills:
Proficiency in written and spoken English is mandatory.
Evidence of great communication and teamwork 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 or mouse handling is 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. Cell Systems

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. AnnuRev 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.