Professor Arjan Narbad and his research group at the Quadram Institute (QI) have collaborated with Dr Ngozi Elumogo,  Dr Crawford Jamieson and Dr Ian Beales, clinicians at the Norfolk and Norwich University Hospital (NNUH), to develop and implement a successful new treatment for debilitating bowel conditions caused by recurrent Clostridioides difficile (also known as Clostridium difficile) infections.

Dr Elumogo is a Senior Research Fellow in Translational Medicine at the Quadram Institute as well as being a Consultant Microbiologist and Chief of Laboratory Medicine Service for NNUH. Her role includes collaborative working between researchers and clinicians and ensures that the most applicable research is being carried out for clinical practice. She began looking into alternatives to repeat antibiotic treatments for chronic C. difficile patients in 2015. She travelled to Medical Centrehospital in Amsterdam to learn about their use of a technique called Intestinal Microbial Transplantation (IMT), also known as Microbial Replacement Therapy (MRT), Faecal Microbiota Transplantation (FMT) or bacteriotherapy. They shared their protocol with her and she was able to create a guideline for this promising intervention to be tested at NNUH. She then worked with Dr Crawford Jamieson to identify and gain consent from suitable patients in addition to screening donors using the NHS lab facilities at NNUH.

In August 2015, a pilot scheme began to treat patients using a protocol developed collaboratively between NNUH and the Quadram Institute. The procedure involved transferring the microbiota from healthy donors into 26 severely ill patients with recurrent C. difficile infections that had not responded to antibiotics. Quadram researchers were responsible for the slurry preparation in addition to carrying out analysis of the microbiome before and after transplantation. The procedure itself was carried out on the hospital ward or in the endoscopy unit.

The transplant involves faecal material (stool), collected from a healthy donor. The sample is screened and confirmed to be free from infections by the NNUH NHS microbiology lab. It is then mixed with saline, filtered and infused via a fine tube placed into the small bowel through the nose. It can also be directly introduced into the colon or large bowel via an endoscope.

The patients’ microbiome was monitored before and after IMT treatment, allowing the researchers to get a picture of how it differed from the donors before IMT, how it changed, and how long these changes persisted in the recipient over a period of months. By determining which bacteria were the most successful gut colonisers the team hoped to understand which bacteria were responsible for the benefits of IMT. In the future this would enable them to provide cultured bacterial strains that are just as successful as a full faecal matter transplant. The team have also been examining various delivery mechanisms and transplant preparation options, in order to maximise the ease of application and the success rate of future IMT interventions.

“This work has increased our understanding of how faecal transplantation improves the microbiome and has led us to investigate if this procedure may be applicable to other disease conditions such as Parkinson’s disease.” Dr Ngozi Elumogo, Senior Research Fellow, QI and Consultant Microbiologist NNUH.

A paper published in Infectious Diseases and Therapy in 2018 compared the IMT strategy from this group with another hospital. They saw that similarly high success rates were achieved regardless of whether fresh or frozen samples were used, or delivery was through the naso-jejunal tube or via colonoscopy[i]. This paper has had good academic outcomes and has been highly cited.

C. difficile is a bacterium that commonly lives in the gastrointestinal tract without causing disease; that is because normally it is kept in check by the many millions of other ‘healthy’ bacteria in the gut. However, when this normal balance is disturbed by illness or antibiotics it can proliferate and cause disease ranging from mild diarrhoea to severe life-threatening sepsis. During 2020-21 12,503 cases of C. difficle infection were reported in the UK, with 1,825 deaths occurring within a month of onset[ii]. Up to a third of C. difficile patients treated with antibiotics relapse. This is due to loss of the healthy bacteria that compete with C. difficile, which sets up a cycle of recurrent infections, leaving patients increasingly sick. IMT breaks this cycle and cures the patient by replacing the patient’s microbiome with a healthier one, delivering almost immediate health benefits.

“This new treatment genuinely provides new hope to patients with very disabling symptoms. Faecal transplant is a low-cost, low-risk, highly effective treatment.” Dr Ian Beales, Consultant gastroenterologist at NNUH.

The concept of competitive exclusion, where a host’s own bacteria successfully outcompete pathogenic bacteria for resources was pioneered at the Institute of Food Research (transformed into the Quadram Institute Bioscience in April 2017) in the 1980s, where a defined mix of bacteria given to chicks helped inhibit Salmonella growth, making chicken products safer. This expertise in gut bacteria, now expanded into humans, was crucial in the successful implementation of IMT within the hospital.

A very high success rate of greater than 90% was achieved in our patient cohort using IMT. Considering the restrictive nature of this illness, this represents a significant increase in health and wellbeing for individual patients (patients on the pilot study reported: improved quality of life and attending events they would not have been able to before treatment) compared with the 30% success achieved using conventional antibiotics. Treatment with IMT also represents an approximate treatment cost saving to the NHS of up to £8,402^[iii] per patient treatment cycle compared with traditional antibiotics, as shown below.

In addition, there is a reduction in the burden to the NHS of recurrent hospital visits. In 2019-20 gastrointestinal issues (NHS cost codes FD and FE) alone cost the NHS £2,321,597,908[iv]. Looking at C. difficile in Scotland, the extra impact on the health service amounted to 10,600 bed days a year and from October 2015 to October 2016 there were 1,150 cases of C. difficile infection in patients aged 15 and over. This cost the NHS in Scotland a total of £8,650,000; the additional costs of treating C. difficile infection, over and above the basic cost of a hospital bed and normal medical care, was £1,955,000[v]. Looking at individual patient cost burden, another author examined the cost of 3,304 C. difficile infections, treated with antibiotics, in Scotland and determined that reoccurring infections added a further £11,650 burden within six months[vi].

Antibiotics do not cure recurrent C. difficile infections – but this procedure can! It also prevents the risk of transmitting C. difficile to other patients / outbreaks, particularly in hospitals and care homes, by eliminating the source. Published research^[vii] regarding the cost effectiveness of IMT use in treatment of C. difficile has additionally illustrated that establishment of IMT treatment centres is considered economically viable.

The protocol has been further refined and shared with other researchers and clinicians through publication and knowledge exchange activities. The manuscript ‘Microbial taxonomic and metabolic alterations during faecal microbial transplantation to treat Clostridium difficile[viii]_’ has also been highly cited and created discussion and debate online.

Patient example:  Mrs Valerie Rowe, from Mulbarton, became ill in August 2015 and lost three stone in weight in a matter of months. She was diagnosed with C. difficile, which she had contracted in the community, and spent 13 weeks in hospital at NNUH as her health deteriorated. Part of her treatment involved a IMT procedure to treat the C. difficile infection. She stated “The treatment took just 20 mins and I hardly felt a thing. Before the procedure I was slightly anxious but there was really nothing to worry about. Now my health is 100% better and I haven’t had any reoccurrence of the C. difficile diarrhoea in the six years since the procedure!”

Dr Ngozi Elumogo and Professor Arjan Narbad

The National Institute for Health and Care Excellence (NICE) approves the use of IMT for treating recurrent C. difficile infections. The findings of the QIB/NNUH pilot study provide documented evidence in support of this policy.  The pilot scheme can now be expanded for patients across the region and in due course further afield. This is a strong example of how a therapy developed in collaboration with the Quadram Institute can bring about a step change in innovation that benefits society and the economy, reducing healthcare costs for the UK and beyond. In addition to expanding the geographical use of this intervention, the next step in the research is to examine the potential of IMT as a therapy for other conditions linked to the gut, such as ulcerative colitis and diabetes. For example, Dr Stefano Romano, a researcher at the Quadram Institute is currently looking at IMT as a possible intervention for Parkinson’s disease.

The collaboration between researchers at the Quadram Institute and hospital consultants at the NNUH has been a critical part of developing a successful intervention for recurrent C. difficile infections, but it is also helping us understand why this treatment works and what areas of medical intervention it may also be applicable to.

“In over 30 years of being at the institute, this has been one of the most rewarding pieces of research work, where you can actually see the benefit to patients immediately.” Prof. Arjan Narbad, Group Leader at QI.

The research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections at University of Liverpool in partnership with Public Health England (PHE) (now the UK Health Security Agency) and in collaboration with the University of East Anglia, University of Oxford and Quadram Institute Bioscience. We are grateful to the staff of the Norfolk and Norwich University Hospital for their help during the study, particularly Dr Philippa King who extracted the patients’ clinical details from case notes, and the donors and patients for their participation. The author(s) gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project BBS/E/F/000PR10356.

For more information you can read this interview with Arjan Narbad on the background to his involvement in this research and the future direction of the science in this area as well as this summary and this article.

References

[i] Goldenberg SD, Batra R, Beales I, Digby-Bell JL, Irving PM, Kellingray L, Narbad A, Franslem-Elumogo N. (2018) Comparison of different strategies for providing Fecal Microbiota Transplantation to treat patients with recurrent Clostridium difficile Infection in two English hospitals: A Review. Infect. Dis. Ther. 7(1):71-86. DOI: 10.1007/s40121-018-0189-y Epub 2018 Feb 15. PMID: 29450831; PMCID: PMC5840108.

[ii] 30-day all-cause fatality subsequent to MRSA, MSSA and Gram-negative bacteraemia and C. difficile infections, 2020/21. UK Health Security Agency. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1039272/hcai-all-cause-fatality-report-2021.pdf

[iii] Abdali ZI, Roberts TE, Barton P, Hawkey PM. Economic evaluation of Faecal microbiota transplantation compared to antibiotics for the treatment of recurrent Clostridioides difficile infection. EClinicalMedicine. 2020 Jun. http://doi.org/10.1016/j.eclinm.2020.100420.

[iv] National Schedule of NHS Costs – Year 2019-20 – NHS trusts and NHS foundation trusts https://www.england.nhs.uk/national-cost-collection/

[v] The cost of Clostridium difficile infections. Healthcare in Europe. https://healthcare-in-europe.com/en/news/the-cost-of-clostridium-difficile-infections.html

[vi] Robertson C, Pan J, Kavanagh K, Ford I, McCowan C, Bennie M, Marwick C, Leanord A. (2020) Cost burden of Clostridiodes difficile infection to the health service: A retrospective cohort study in Scotland. Journal of hospital infection. https://doi.org/10.1016/j.jhin.2020.07.019

[vii] Shaffer S, Witt J, Targownik L, Rubin D, Singh H, Bernstein C. ., (2020) Cost effective analysis of a faecal microbial transplant centre for treating recurrent C. difficile infection. Journal of Infection. https://doi.org/10.1016/j.jinf.2020.09.025.

[viii] Kellingray L, Le Gall G, Defernez M, Beales I, Franslem-Elumogo, Narbad A.., (2018) Microbial taxonomic and metabolic alterations during faecal microbial transplantation to treat Clostridium difficile. Journal of Infection. https://doi.org/10.1016/j.jinf.2018.04.012