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Fecal transplant – do living microbes matter?

22.11.2016

Pilot study by the Cluster of Excellence "Inflammation at Interfaces" questions previous assumptions about the mechanism of action of fecal transplants against Clostridium difficile

Infections by the bacterium Clostridium difficile  are one of the plagues of modern medicine. Infection rates are increasing rapidly in hospitals and nursing homes. The main symptom of the infection, which is often tackled with the use of antibiotics, is diarrhoea, which can take on life-threatening proportions. Fecal transplantation – transferring stool from a healthy donor into the intestine of the patient – has proven to be an effective alternative. However, how stool transplants exactly work remains unclear. To date, it was generally accepted that living intestinal microbiota from the donor colonised the recipient.

This assumption has been challenged by the results of a recent publication by the Cluster of Excellence "Inflammation at Interfaces". In a pilot study, five seriously ill patients with Clostridium difficile infection received a stool transplant from healthy donors, from which all living microorganisms (e.g. bacteria or fungi) had been previously removed by sterile filtration. All five patients were free of symptoms within a few days, and remained so for an observation period of at least six and up to 33 months. Study leader Prof. Stephan Ott from the Department of Internal Medicine I at the University Medical Center Schleswig-Holstein (UKSH) in Kiel drew the following conclusions: “The effectiveness of stool transplants is apparently not based on living bacteria. In fact, it appears that the effects are produced by bacterial components, metabolic products or viruses.” The study has already been published online in the renowned scientific journal “Gastroenterology”.

The term microbiota transplantation is often used to refer to the transfer of stool from healthy donors to the intestine of a patient. This sounds a bit nicer than faecal transplant or stool transfer, but it doesn't completely eliminate the disgust factor associated with this treatment, which has been heralded as a magic weapon against various diseases for some time. For each treatment, approximately 50 grammes of stool from healthy donors is diluted with a physiological saline solution in a laboratory, coarsely filtered, and administered as a fluid – either directly into the small intestine via a tube, or into the large intestine via a colonoscopy or enema. Oral medication in the form of a capsule is also being developed.

To date, there has only been one generally accepted area of application, for which the benefits of stool transfers have been proven by controlled clinical studies: recurrent or persistent infection with Clostridium (C.) difficile. The bacterium, which primarily is a problem in hospital patients, causes severe diarrhoea, which can result in death and always considerably weakens the patients. In particular, there is also the danger that the infection may spread to other healthy people. Studies have shown that transferring fresh stool can permanently heal up to 90 percent of patients with recurrent C. difficile infections. The procedure is only performed in special gastroenterological centres which are experienced in this treatment.

Every donation of living microorganisms also involves potential risks, however. As such, it cannot be completely excluded that, for example, unknown pathogens may be transferred by specific microbiota in the donated stool, or even tendencies towards obesity or diabetes. There have been indications for this at least in laboratory mice, but up to now, no clinical problems have been reported in humans. For patients with a weakened immune system due to illness or immunosuppressive treatment, stool transfer should only be used with the greatest caution. It is therefore desirable to further reduce the risks of unwanted side-effects.

For this reason, a sterile filtrate was administered to the five immunosuppressed patients with C. difficile infections in the newly-published pilot study. “Using a special filtration technology, all intact microorganisms such as bacteria, fungi and protozoa were removed from the stool samples,” explained Cluster member Dr. Georg Wätzig from the Kiel biotechnology company CONARIS, which developed the filtration technology.

The surprising result: all five patients, two men and three women, who were previously treated with various antibiotics without success, were already able to be released from hospital on the day after transferring the sterile stool filtrate. “Within a few hours, the previously severe symptoms disappeared, and they did not return,” reported lead author Prof. Stephan Ott, senior physician at the Department of Internal Medicine I at UKSH Kiel and scientist in the Cluster of Excellence "Inflammation at Interfaces". The composition of the intestinal flora in the patients also changed dramatically, even though no bacteria were transferred. This was shown by analyses performed by the working group led by Prof. Philip Rosenstiel at the Institute of Clinical Molecular Biology at Kiel University. The filtrate only contained bacterial debris, metabolic products and viruses. The latter, in particular bacteriophages, which can kill bacteria, could also be relevant to the success of the treatment.

Despite the small number of cases of only five patients, the head of the clinic and last author Professor Stefan Schreiber, believes the study to be ground-breaking. “The intestinal mucosa probably reacts to DNA or RNA fragments, and this activates the intestinal immune system,” surmised the spokesperson for the Cluster of Excellence "Inflammation at Interfaces". However, whether in fact sterile filtered stool works just as well as stool transplantation with living bacteria, still needs to be proven in a blind controlled study. Said Stephan Ott: “If the data is confirmed in a larger number of patients, then it completely calls into question the prevailing idea of living microorganisms as the therapeutic principle of stool transplantation.”

Original publication:
Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Grasis JA, Cassidy L, Tholey A, Fickenscher H, Seegert D, Rosenstiel P, Schreiber S: Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients With Clostridium difficile Infection, Gastroenterology (2016), published online November 17, 2016
doi:10.1053/j.gastro.2016.11.010.

Stephan Ott, Cluster of Excellence "Inflammation at Interfaces", Consultant at the Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel. Photo: Herrmann/UKSH

Contact:
Prof. Dr. Stephan J. Ott
Department of Internal Medicine I
The Institute of Clinical Molecular Biology
Tel.: +49 (0)431 500-22227


Prof. Dr. Stefan Schreiber
Department of Internal Medicine I
The Institute of Clinical Molecular Biology
Tel.: +49 (0)431 500 22200



Cluster of Excellence "Inflammation at Interfaces"
Scientific Office, Head: Dr. habil. Susanne Holstein
Press and Communications, Sonja Petermann, Text: Kerstin Nees
Postal address: Christian-Albrechts-Platz 4, 24118 Kiel, Germany
Tel.: +49 (0)431 880-4850, Fax: +49 (0)431 880-4894
E-mail:
Website: www.inflammation-at-interfaces.de


The Cluster of Excellence "Inflammation at Interfaces" has been funded since 2007 by the Excellence Initiative of the German Government and the federal states with a total budget of 68 million Euros. It is currently in its second phase of funding. Around 300 cluster members are spread across the four locations: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH)), Lübeck (University of Lübeck, UKSH), Plön (Max Planck Institute for Evolutionary Biology) and Borstel (Research Center Borstel (FZB) – Center for Medicine and Biosciences) and are researching an innovative, systematic approach to the phenomenon of inflammation, which can affect all barrier organs such as the intestines, lungs and skin.

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