Marchesi Laboratory – Microbiome Manipulation Group

What we do

Our group is interested in the role and manipulation of the microbiome of different ecosystems, including the gut and vagina, in health, and how changes in the composition and function of the microbiome characterise and contribute to a range of different disease states. To explore this, we analyse patient samples using a range of advanced systems biology ‘omics’ techniques, including next generation microbial sequencing, metabolomics (done in association with the National Phenome Centre), and proteomics. We then investigate mechanisms as to how these microbiome changes may cause or exacerbate different diseases, using classical microbiology techniques, molecular techniques, or through the use of model systems (including rodent models, or chemostat/ colonic model systems).

Our laboratory includes a close collaboration between scientists and clinicians. One particular significant interest of our group is looking at ways to manipulate the microbiome as a novel paradigm for the treatment of a range of conditions, including via modalities such as probiotics and intestinal (faecal) microbiota transplant (IMT/FMT). A significant area of interest in the group involves using IMT as a discovery tool to better understand host-microbiome interactions, with the aim of understanding mechanisms underlying the efficacy of IMT and exploiting these to produce novel, targeted, microbiome-derived therapeutics.

Why it is important

It is only over the past decade that we have recognised the potential contribution of the microbiome to a range of disease states and therapeutic responses, e.g. stem cell transplants for blood cancers. While we have been able to define distinctive ‘microbiome signatures’ that accompany different diseases, there remains only a relatively small number of scenarios where we have been able to understand specific mechanisms by which the microbiome contributes to the onset and progression of disease, and much more research is required in this field. Furthermore, the concept that manipulating the microbiome may be a therapeutic approach to disease is a surprising new concept that may potentially lead to new therapies and also improve the patient’s therapeutic journey.

How it can benefit patients

A large stream of our work relates to the administration of IMT to patients with a range of different conditions, e.g. infections with antibiotic resistance bacteria to liver disease and cancer treatments. This is obviously directly of benefit to the patients themselves; for instance, a single IMT in a patient with recurrent Clostridioides difficile infection can immediately break the cycle of months of unpleasant symptoms, recurrent antibiotic use and hospitalisation related to colonic inflammation, while an IMT in a patient with blood cancer prior to a stem cell transplant appears to protect them against bloodstream infections and other adverse outcomes after the transplant. However, there are also indirect benefits, as our ability to understand by what mechanisms IMT impacts upon interactions between the microbiome and host will allow us to discover novel, targeted, microbiome-derived therapies.

A further stream of work in the laboratory relates to exploring how the microbiome influences responses to therapies, including: medications that treat inflammatory bowel disease; the degree to which immune checkpoint inhibitor medications successfully treat cancer; or the level of immune response after SARS-CoV-2 vaccinations. In the future, this knowledge might be exploitable for ‘personalised medicine’ approaches, by allowing us to try and better match patients starting treatment to a therapy that we can be confident will work well for them.

Summary of current research

1. Characterisation of host-phenome-immune interactions in health and disease through integrative analysis of microbiome, metabonome and other omic datasets.
   
   
2. Exploring the potential role and mechanisms of efficacy of IMT in a range of clinical settings, including:
   - Infective diseases: C. difficile infection, intestinal colonisation with antibiotic-resistant bacteria.
   - Metabolic and liver disorders: including obesity, NAFLD, PSC, and cirrhosis.
   - Haematological disorders: including blood cancer patients receiving stem cell transplants.
   - Rheumatological disorders: including psoriatic arthritis
   
   
3. Understanding how the gut microbiota influences drug responses in a variety of oncological settings and how it can be harnessed to treat drug induced events, e.g. immune checkpoint inhibitor colitis
   
   
4. Novel approaches to samples and modelling the gut microbiota, for example swallowable capsules that can sample at any site in the GI tract (Nimble Science), using 3D printed swabs for faecal sampling (Opt Industries).