Photo: Imperial College London website.
Imperial is partnering with biotechnology company EnteroBiotix on research into the potential of therapies based on the gut bacterial community.
The company produces capsules that contain diverse ecosystems of microbiota obtained from healthy and rigorously screened donors, which provide a compositionally consistent, safer and non-invasive alternative to current methods for transferring microbiota from donors to patients.
Scientists and clinicians from Imperial and other collaborating centres will use the company’s products to test the ability of intestinal microbiota transplant (IMT) to improve patient outcomes in conditions such as blood cancers and antibiotic-resistant infections, and to accelerate systematic research in the new science of the microbiome.
Upsurge of interest
The last decade has seen an upsurge of interest in the gut microbiome – the community of trillions of bacteria, fungi, and other microorganisms that live in the digestive tract – and its importance for human health. “Instead of viewing bugs as bad, we’re embracing them as being part of a symbiosis – a fundamental part of making us healthy and happy,” says Dr James McIlroy, EnteroBiotix founder and CEO.
Among the public, this surge is reflected in the popularity of probiotics, together with fermented foods such a kefir and kombucha, which contain large bacterial populations and are believed to be beneficial for gut and overall health. In medicine, this interest has been matched by growing evidence for the effectiveness of IMT, in which processed faecal matter – which is 85% bacteria – is transferred from healthy screened donors to patients with gastrointestinal problems and other conditions.
IMT and infection
One condition for which IMT has proven safe and effective is recurrent C. difficile infection (rCDI), a bacterial infection of the gastrointestinal tract that can sometimes lead to multi-organ failure and death. Even though antibiotics are an effective therapy for CDI, there is a risk of the antibiotics not working, or of patients having further recurrence of the condition once the antibiotics are finished, according to Dr Benjamin Mullish, a clinician and lecturer in Imperial’s Department of Metabolism, Digestion and Reproduction.
“Patients get into a cycle of treatment using antibiotics, then getting another infection and treating it again,” Dr Mullish explains. “What we’ve realised is that antibiotics may kill C. difficile, but also have the ‘collateral damage’ of wiping out the beneficial organisms in the gut that stop this pathogen from growing and causing infection. If you want to get rid of CDI, it appears to be a more effective strategy to restore the composition and function of your gut microbiome back to how it was before you became ill.”
EnteroBiotix is a UK company pioneering a new class of orally administered medicines that enable IMT to take place without an invasive procedure. Its capsules use donations from screened donors that are dried using a proprietary process, and tested using advanced pathogen-screening technology.
“One lesson from patient engagement in our studies was that a lot of the patients were hesitant about having IMT because of conventionally needing invasive ways of administering this, including tubes into their stomach or endoscopies,” says Dr Mullish. “They’re often pretty sick patients who are already going through lots of procedures, so we want to do everything we can to avoid any more if we can. Enterobiotix is a leading UK company pioneering the capsule-based approach for IMT so we’re very happy to be working with them.”
One of the first collaborations between Imperial and EnteroBiotix is on a project trialling the potential for IMT administered to patients with blood cancer prior to bone marrow transplant as a means of trying to alter their gut microbiome and try and improve outcomes.
Professor Julian Marchesi in the Department of Metabolism, Digestion and Reproduction, leading the research, explains: “Patients with blood cancers are a group whose gut microbiome is particularly under attack. They often receive strong chemotherapy, which has side effects of mouth ulcers and gut inflammation. Their nutrition might be poor, they receive frequent antibiotics because of their high rate of infections, and many of them end up colonised with antibiotic-resistant bacteria.
"That latter point in particular can especially be a problem when patients need a very demanding treatment, like bone marrow transplantation – haematologists are sometimes anxious about offering this or other treatments because patients are at such high risk of getting an infection which is untreatable.”
The phase IIa trial, funded by the Medical Research Council’s Developmental Pathway Funding Scheme and supported in-kind by EnteroBiotix, will build on evidence from earlier studies at Imperial and elsewhere, which demonstrated that IMT was safe, reduced complications that may occur after bone marrow transplant, and improved survival.
“’Pre-habilitation’ prior to a significant medical intervention isn’t new – one example is getting leaner and fitter, which is often recommended before major surgery,” says Professor Marchesi. “But it’s a new idea in the context of patients having bone marrow transplants, and definitely very novel to be targeting the gut microbiome as a means to pre-habilitate patients. At the moment, we just have correlations, but with this new trial we can start exploring cause and effect.”
This study – the Microbiota Transplant Prior to Allogeneic Stem Cell Transplantation (MAST) study – is being run by a multidisciplinary team that includes haematologists (Dr Jiri Pavlu and Dr Andrew Innes), microbiology and infectious disease experts (Dr Frances Davies and Dr Rohma Ghani), along with digestive diseases and microbiome experts (Dr Benjamin Mullish and Professor Julian Marchesi).
The study will be run across six of the UK’s leading blood cancer centres and includes, along with Imperial, UCLH, The Royal Marsden, King’s College London, Leeds Teaching Hospitals, and University Hospitals Birmingham.
Advancing microbiome research
The partnership between Imperial and EnteroBiotix, in addition to helping explore the safety, tolerability and efficacy of IMT based drugs for a range of conditions, is expected to help place microbiome research onto a more systematic footing. This trial will exploit another important advantage of the capsules, namely that their components are manufactured in a very standardised way, which is both better for patient safety, and allows researchers to start exploring the specific mechanisms as to how IMT may beneficially impact upon patients’ immune system and other aspects of their health.
Dr James Kinross, a clinical senior lecturer and consultant surgeon in the Department of Surgery & Cancer, says: “At the moment, IMT is a new science and is still a very blunt tool. It's a wholesale change of the ecology of the gut. But donors and patients with very variable gut ecologies and we don't know precisely which bugs need to go into which patients and for what reason – and then when those new bugs are transferred to a patient, how we sustain them to allow them to grow.”
“The products EnteroBiotix is developing are a very interesting experimental tool. By studying whether it works, we can learn about the microbiome and the very specific mechanisms that make microbiome treatments work. We could produce drugs for or leverage for biomarkers. Then we can refine it so we can deliver at scale for organisations like the NHS. That’s the company’s mission and it aligns with ours.”
Dr McIlroy of EnteroBiotix says: “When we founded EnteroBiotix there were 13 clinical trials listed on clinicaltrials.gov investigating IMT, now there are hundreds. Most of the studies published so far show the same thing – that transferring microorganisms from healthy to sick people can contribute to improving health outcomes. EnteroBiotix is developing a safer and more scalable approach to IMT that is compositionally consistent and is supported by a strong intellectual property position. Partnering with Imperial allows us to explore different research opportunities and takes us closer to fulfilling our vision to develop products that benefit patients.”
“The early data already generated so far by Imperial is very exciting,” he adds. “It is helping to build a strong case for microbiome enhancement. The Imperial team is a discovery engine and EnteroBiotix can help translate that into a commercial product that benefits patients around the world.”
This article was first published on 10 November by Imperial College London.