Is the Medical World Ready for Faecal Transplantation as a Therapeutic Option?
Posted 7th July 2017 by Jane Williams
The gut microbiota has become a favourite “organ” of the biomedical community, with the number of publications on different aspects of its architecture and function rising exponentially in the last few years. In part fuelled by advances in DNA sequencing technology, multiple studies have been conducted in patients with gastrointestinal (GI) related diseases (IBD, Coeliac, etc.) (1, 2).
These studies have unequivocally shown that gut dysbiosis is associated with these diseases, and sparked further research on how dysbiosis can alter immune responses in a pathogenic manner, and on how to restore the normal microbiota in these patients. More recent reports have also associated changes in the gut microbiome with other autoimmune diseases, those in which the target organ is outside of the GI tract (e.g. type 1 diabetes, rheumatoid arthritis, multiple sclerosis, etc.) (3, 4, 5).
In a more surprising set of discoveries, alteration of the relative proportions of commensal bacteria in the gut of patients with neurological conditions (e.g. autism and Parkinson’s disease) has been reported (6, 7). This new set of discoveries brings the gut and its immunoregulatory functions to a prominent place in the search for new therapeutics.
Modest but functionally relevant dysbiosis is found in multiple sclerosis (MS) patients
Recent reports, including ours, have indicated that increased prevalence of certain organisms is associated with MS (8). Presumably these are bacteria with pro-inflammatory properties, which could stimulate or perpetuate immune responses in susceptible hosts. Similarly, other bacteria were found at a lower frequency in these patients; these are presumably needed to control or attenuate immune responses.
New results by our group confirm these findings, and prove that the altered microbial balance seen in MS patients is functional in-vitro. Furthermore, we showed that when microbiota from MS patients is transferred into germ-free mice, they develop more severe disease symptoms when immunised with myelin antigens (a condition known as EAE, a commonly used experimental model of MS). These groundbreaking results suggest normalisation of gut microbiota as a potential therapeutic option for MS, and probably other common diseases associated with gut dysbiosis.
Faecal transplant is effective to control Clostridium difficile infections
One of the most stunning examples of the potential therapeutic power of faecal transplants (FMT) is exemplified in the treatment of Clostridium difficile infections. While C. difficile is not rare in healthy people, it is resistant to broad spectrum antibiotics that can effectively eliminate most gut bacteria. In C. diff-positive individuals, these communities are believed to be necessary to keep this organism in check.
Antibiotics (particularly in immunocompromised, hospitalised patients) can disrupt this delicate balance and cause C. diff to overgrow other populations and cause pathology and in some cases, death. C. diff infections can be treated with the use of Vancomycin, an extremely potent antibiotic (also associated with significant side effects). However, the success rate of this treatment is around 30%. In contrast, FMT has been shown to be a more effective strategy, with up to 90% of treated patients showing successful recovery.
Is FMT a viable option in MS and other common diseases?
The success of FMT in treating C. diff is opening up discussions for its application to other, less life-threatening, but more common diseases. Our own work in MS is moving in this direction and we are currently preparing the first phase 1b trial at UCSF, with a possible launch in late 2017. This study will focus on basic aspects of the procedure, such as stability of the transplanted microbiota, immunological functions and safety monitoring.
Modern drug development approaches involve high-throughput screening methods, chemical optimisation of targets, toxicity and pharmacodynamics/pharmacokinetics studies. While FMT may be seen as an unsophisticated approach, the introduction of millions of live organisms into a human host has commonalities with organ transplantation and cellular therapies. Commensal bacteria are the source of thousands of metabolites, some of them with notable therapeutic properties (9, 10) and providing or supplementing with the right organisms could have a lasting and beneficial effect in the host.
Ultimately, the adoption of this simple treatment modality will depend on the availability of other therapeutic options (several exist for MS, but none for Alzheimer’s or autism), and on the perceived risk/benefit ratio to patients by their physicians.
Sergio Baranzini, a Professor at the University of California, San Francisco will be examining the role of the gut microbiome in MS at the upcoming Microbiome R&D and Business Collaboration Forum: USA.
- H. Chu, A. Khosravi, I. P. Kusumawardhani, A. H. Kwon, A. C. Vasconcelos, L. D. Cunha, A. E. Mayer, Y. Shen, W. L. Wu, A. Kambal, S. R. Targan, R. J. Xavier, P. B. Ernst, D. R. Green, D. P. McGovern, H. W. Virgin, S. K. Mazmanian, Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352, 1116-1120 (2016).
- M. Rostami Nejad, S. Ishaq, D. Al Dulaimi, M. R. Zali, K. Rostami, The role of infectious mediators and gut microbiome in the pathogenesis of celiac disease. Arch Iran Med 18, 244-249 (2015).
- J. L. Dunne, E. W. Triplett, D. Gevers, R. Xavier, R. Insel, J. Danska, M. A. Atkinson, The intestinal microbiome in type 1 diabetes. Clinical and experimental immunology 177, 30-37 (2014).
- G. B. Rogers, Germs and joints: the contribution of the human microbiome to rheumatoid arthritis. Nat Med 21, 839-841 (2015).
- S. Jangi, R. Gandhi, L. M. Cox, N. Li, F. von Glehn, R. Yan, B. Patel, M. A. Mazzola, S. Liu, B. L. Glanz, S. Cook, S. Tankou, F. Stuart, K. Melo, P. Nejad, K. Smith, B. D. Topcuolu, J. Holden, P. Kivisakk, T. Chitnis, P. L. De Jager, F. J. Quintana, G. K. Gerber, L. Bry, H. L. Weiner, Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 7, 12015 (2016).
- M. De Angelis, R. Francavilla, M. Piccolo, A. De Giacomo, M. Gobbetti, Autism spectrum disorders and intestinal microbiota. Gut Microbes 6, 207-213 (2015).
- T. R. Sampson, J. W. Debelius, T. Thron, S. Janssen, G. G. Shastri, Z. E. Ilhan, C. Challis, C. E. Schretter, S. Rocha, V. Gradinaru, M. F. Chesselet, A. Keshavarzian, K. M. Shannon, R. Krajmalnik-Brown, P. Wittung-Stafshede, R. Knight, S. K. Mazmanian, Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 167, 1469-1480 e1412 (2016).
- B. A. Cree, C. M. Spencer, M. Varrin-Doyer, S. E. Baranzini, S. S. Zamvil, Gut microbiome analysis in neuromyelitis optica reveals overabundance of Clostridium perfringens. Ann Neurol 80, 443-447 (2016).
- N. Arpaia, C. Campbell, X. Fan, S. Dikiy, J. van der Veeken, P. deRoos, H. Liu, J. R. Cross, K. Pfeffer, P. J. Coffer, A. Y. Rudensky, Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451-455 (2013).
- M. S. Donia, M. A. Fischbach, HUMAN MICROBIOTA. Small molecules from the human microbiota. Science 349, 1254766 (2015).
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