Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2015; 19: 3173-3180 Ethical aspects of Fecal Microbiota Transplantation (FMT)

V. DALOISO 1, R. MINACORI 1, P. REFOLO 1, D. SACCHINI 1, L. CRAXÌ 2, A. GASBARRINI 3, A.G. SPAGNOLO 1

1Institute of Bioethics, “A. Gemelli” School of Medicine, Catholic University of the Sacred Heart, Rome, Italy 2“G. D’Alessandro” Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo, Italy 3Internal Medicine and Gastroenterology, “A. Gemelli” School of Medicine, Catholic University of the Sacred Heart, Rome, Italy

Abstract. – The importance of human micro - change health condition. Anatomical or post- biota in preserving human organism healthy is surgery or irradiation conditions may influence, nowadays well acknowledged. The alteration of in a pathological way, microbiota too. Microbiota the microbiota can be the consequence of a per - can also easily be disrupted by use (especially a sistent use of antibiotics or immunosuppressive medications or abdominal irradiation or surgery, persistent use) of antibiotics, or for dietary in - 5 wrong diet, or can be caused by surgery or take, or malnutrition or advanced age . anatomical condition. These alterations can Microbiota is located in the nose, mouth, skin, cause many infections and diseases that today guts and genitals. Its composition varies accord - can be treated with Fecal Microbiota Transplan - ing to the different sites where it lies but is domi - tation (FMT), also called Bacteriotherapy, that is nated by bacteria (over 10 14 , about 1.5 kg, more the administration of a fecal solution from a donor into the intestinal tract of a recipient. than 1000 species, with a predominance of anaer - Although to date, FMT appears to be safe and obes), and other microbes, such as fungi, para - without serious adverse effects, there are some sites, viruses and archaea, many of which have ethical issues that are worthy to be investigated. not yet been cultured 6. The aim of this article is to highlight these is - There is also consensus on the maternal influ - sues in order to give some notes for a better im - ence on its composition according to which way plementation of this particular clinical practice. babies are born – babies born vaginally com - 7 Key Words: pared to babies delivered by caesarian section – Fecal microbiota transplantation, Innovative thera - playing an important role for the development of peutic procedure, Ethics, Donor. the immune system after birth. Studies have un - derlined that in the first case (babies born vagi - nally), the sterile intestinal tract of neonates is immediately colonized by maternal microbiota, while in the second one (by caesarian section) Introduction microbiota is mostly colonized by the environ - ment. The importance of human microbiota (former - Furthermore, microbioma, better defined as ly called gut or intestinal flora) in preserving hu - “the ecological community of commensal, sym - man organism healthy is nowadays well ac - biotic, and pathogenic microorganism that literal - knowledged . There is enough evidence that a bal - ly share our body space” 8 has been recognized to anced composition of intestinal microbiota repre - be different depending on each generation (ge - sents the basis of the wellbeing of human organ - netic profile). ism 1-3 . Scientific literature shows that our organ - In order to deepen these features, in 2007 the ism contains over 100 trillion of microbiota: American National Institute of Health (NIH) some of them are essential for the human organ - Roadmap for Biomedical research funded the ism, others are harmful 4. Moreover, microbiota Human Microbiome Project (HMP), to better un - can be subjected to many alterations that may derstand how these unique microbial ecosystems

Corresponding Author: Dario Sacchini, MD; e-mail: dsacchini@.unicatt.it 3173 V. Daloiso, R. Minacori, P. Refolo, D. Sacchini, L. Craxì, A. Gasbarrini, A.G. Spagnolo that live in and on our bodies contribute to hu - Fecal Microbiota transplantation man health and disease. HMP includes projects The characteristics above mentioned of micro - on ethical, legal and social implications (ELSI) biota have pointed out to the possibility of em - arisen from this field 9. As stated within the Pro - ploying microbiota for transplantation. To be ject description the goals were: (1) “To take ad - more specific, Fecal Microbiota Transplantation vantage of new high-throughput technologies to (FMT), also known as bacteriotherapy, represents characterize the human microbiome more fully a therapeutic alternative for patients suffering by studying samples from multiple body sites from some gastrointestinal conditions. At the be - from each of at least 250 “normal” volunteers; ginning FMT was used exclusively for patients (2) To determine whether there are associations affected from recurrent Clostridium difficile in - between changes in the microbiome and fection (RCDI) not responsive to standard thera - health/disease by studying several different med - pies and it proved to be effective in eradicating ical conditions; and (3) To provide both a stan - these bacteria 27,28 . More recently, other studies 29,1 dardized data resource and new technological ap - have underlined the broadened application of this proaches to enable such studies to be undertaken clinical treatment, which is proved to be effective broadly in the scientific community” 9. A key goal against other infections and diseases, such as in - of the HMP has been to characterize the human flammatory bowel disease (IBD), irritable bowel microbiome in healthy adults and develop a ref - syndrome, obesity and many others. erence set of microbial genome sequences (the Administration of a fecal microbiota solution “Healthy Cohort Study”) 10,11 . is performed via colonscopy, nasogastric tube As noted by Slashinski et al 12 in citing Juengst and retention enema 30 , or more recently, via oral and Huss 13 , “Human microbiome research is con - capsules 31 . It seems safe, up to now, or with few sidered part of a new phase of genomic research, transient adverse effects, such as fever or diar - aptly referred to as “ translational genomic re - rhea, but the efficacy and safety profile of this in - search ” aimed to benefit both individual and so - tervention have not yet been fully evaluated in cietal health”. controlled clinical trials. Further limitations to Gut microbiota can interact with the intestinal the delivery of FMT can be mentioned: the lack mucosa and influence intestinal permeability and of a consensus on the best protocol; the time is important for the absorption, distribution, me - stretch between stool’s donation and stool’s tabolism, and excretion of nutrients 14 and can screening; safety concerns about the possibility trigger (auto) immunity, playing indeed a para - to acquire diseases after stool infusion 32 . mount role in the systemic immunity not only of the local immune system 15,16 . The complex symbiotic relationship between Main Ethical Issues gut microbiota and their host causes physiologic functions to be disrupted when microbial compo - The ethical, Legal, and Social Issues (EL - sition is altered. In fact, a variety of disorders and SI) of Human Microbiome Research diseases, such as enteric infections 17 , functional Since the beginning of the HMP it is has been diseases of the gastrointestinal tract 18 , inflamma - recognized that human microbiome research, like tory bowel disease (IBD) 19 , colorectal cancer 20 , other areas of genomics, raises ELSI issues that liver diseases 21,22 , and also non -gastrointestinal deserve careful considerations 33 . In fact , based on diseases such as obesity and metabolic their experience of participation in the develop - syndrome 23,24 , allergic diseases 25 and autism 26 , are ment and initiation of the HMP , Mc Guire et al 34 associated with alterations of gut microbiota . identified five major research ethics issues associ - Therefore manipulating the microbiota could ated with conducting human microbiome research: (in some cases it is already possible) improve or informed consent and respect for autonomy; in - prevent some pathologic conditions. Several in - forming subjects of research-related results; data terventions targeting the intestinal microbiota sharing and protection of privacy; invasiveness of have been used to maintain and improve host sampling and minimizing risk; and diversity of health. These include antibiotics, probiotics, pre - subjects and justice. Subsequently, in an another biotics, but the restoration of healthy gut micro - work, to better understand the relevance of these biota by fecal microbiota transplantation (FMT) issues to individuals involved in human microbio - constitutes the most promising effective thera - me research, McGuire et al 35 interviewed scientists peutic option . and NIH employees involved in the HMP and in -

3174 Ethical aspects of Fecal Microbiota Transplantation (FMT) dividuals were recruited to participate in the In March 2014, FDA announced a draft guid - Healthy Cohort Study. These authors reported ance for industry entitled “Enforcement Policy findings related to three major ELSI issues: in - Regarding Investigational New Drug Require - formed consent, data sharing, and return of results. ments for Use of Fecal Microbiota for Transplan - These data demonstrate that investigators and re - tation to Treat Clostridium difficile Infection Not cruits were similarly sensitive to these three key Responsive to Standard Therapies” 37 . These ethical issues but the concerns they raised were guidelines aim to provide directions not only largely not HMP-specific: complexity and length about the clinical aspect of stool transplantation, of informed consent document (ICD), the request but, and even more, about the information to be to maximize the accessibility and utility of HMP given the patients undergoing such therapy. - data whit a sharing plan protecting individual pri - ticularly, the document underlines the importance vacy (some subjects in this study indicated they to obtain adequate informed consent from the pa - would like to be informed of new evidence of tient or his/her legally representative; it also en - identifiably so they can re-evaluate their willing - visages the stool to be obtained from a donor ness to consent to public data release). known to either the patient or the licensed health care provider treating the patient. Furthermore, it The Ethical Issues Related To FMT provides donor and stool to be qualified by It is important to emphasize that the FMT is an screening and testing performed under the direc - innovative therapeutic procedure certainly inter - tion of the licensed health care provider for the esting and promising, but still in the phase. purpose of providing the FMT product to treat Currently, in fact, at clinicaltrials.gov (access on his/her patient. March 13, 2015) 59 clinical trials have have reg - The main reason to choose a “known” donor istered to test FMT, including 21 for Clostridium (family member, partner), instead of a “univer - difficile infection and 26 for bowel diseases, es - sal” donor, is to reduce the so-called “yuke fac - pecially inflammatory. So, from the ethical point tor”, that is the repugnance of the patient toward of view it is necessary to consider several aspects receiving a fecal infusion and for the higher rate of this innovative therapeutic intervention that of resolution of the pathology to be treated 29,30 . could be used in many areas of the clinic. But this choice is preferred also for the likeli - Before going into details, it could be interest - hood of low risk of transmitting an occult ing to pay attention to the fact that, initially, the pathogen with the stool sample or other factors Federal Drug Administration (FDA) classified of susceptibility to disease 38 . In fact, some com - human feces used for medical purpose as drugs. plications of bacteriotherapy are due to the trans - In other words, the procedure of fecal transplan - mission of pathogens contained in stool, such as tation was considered as an experimental drug 36 , bacteria, viruses, fungi and parasites. For these therefore requiring drug-regulation policy. Only reasons, donor’s stools are screened for ova and in a second time the opinion on this topic has parasites (Giardia, Helicobacter and others), and changed and human feces have been classified as donor’s blood is screened for Hepatitis (A, B and a human tissue, allowing physicians to perform C) and for HIV. Donors are excluded as such also fecal microbiota transplantation more easily and if they have received antibiotics recently. Poten - to deliver this new treatment to more patients 32 . tial donors should be questioned about their trav - Ethical aspects concerning FMT can be - el history, sexual behaviour, previous operations, marized as follows: (1) Donors’ selection; (2) blood transfusions, and other factors that increase Safety concerns and ratio risk-benefit; (3) In - the risk of transmissible disease 39,40 . Donors are formed consent. also screened for a family history of autoimmune and metabolic diseases as well as malignancies Donors’ Selection (in first- and second- degree family members) . Fecal microbiota transplantation presents Once a donor is selected, blood and fecal sam - unique challenges in recruiting healthy donors. ples must screened for pathogens 41 . Donor selection for FMT is more simpler than for other organs, because the immunologic Safety Concerns and Ratio Risk Benefit matching between donor and recipient is not re - To date, FMT appears to be safe. Most patients quired but it is important to carefully screen and treated with FMT experience diarrhea on the day select donors to avoid causing a new disease in of infusion, and small percentage report belching the recipient. and/or abdominal cramping or constipation 42,43 .

3175 V. Daloiso, R. Minacori, P. Refolo, D. Sacchini, L. Craxì, A. Gasbarrini, A.G. Spagnolo

Adverse events were reported for some patients was used in patients with IBD. High fever and a (3 of 317): upper gastrointestinal tract bleeding, temporary increase in C-reactive protein were the peritonitis, or enteritis 30,38 . In another case re - most reported adverse events related to the infu - port 44 , nasoduodenal FMT for Crohn’s disease re - sion of feces 47,48 . The uncertainty of available da - sulted in transient adverse effects, including fever ta on both efficacy and safety of FMT in IBD ob - and abdominal tenderness in 3 of 4 patients. ligates to proceed with caution. However, these effects disappeared for all pa - FMT has been proposed as a therapeutic op - tients over the following 2 days. tion for irritable bowel syndrome (IBS) and other Although the use of microbiota and specifical - functional diseases of the gastrointestinal tract. In ly fecal microbiota transplantation have already a case series of patients with IBS or IBD, FMT been reported as generally safe in many scientific cured the disease or alleviated symptoms in 52% researches, more studies need to be done. Long- of subjects. In patients with chronic constipation, term follow up programs are in fact not yet avail - FMT led to the improvement in bloating, abdom - able. To date, not so much can be said, for exam - inal pain, and bowel frequency 29 . ple, on a potential association between FMT and Later FMT was used to treat patients with infection, inflammation, or gastrointestinal ma - other conditions such as metabolic syndromes lignancies. So far, from the ethical standpoint, and obesity. The application of FMT to the while we are waiting for results of clinical trials management of metabolic diseases has recently to better evaluate safety, we should use protocol achieved preliminary but interesting results 49 . with severe criteria for the screen of pathogens. These findings indicate that the intestinal mi - As regards the potential benefits, to date, most crobiota could actually cause obesity and in - clinical experience has focused on the use of sulin resistance. FMT in patients with relapsing or occasionally FMT has shown efficacy in some neurological Clostridium difficile infection. Subsequently, diseases, but data are still few and fragmentary. FMT was used to treat patients with inflammato - An improvement of neurological symptoms was ry bowel disease (IBD) with o without Clostridi - resulted in 3 patients with multiple sclerosis who um difficile infection. For these diseases and con - underwent FMT for chronic constipation 50 , as ditions were obtained excellent results: FMT, in well as in a patient with Parkinson disease 51 who contrast with standard therapies, have eradicated received FMT for the same reason. In an uncon - the Clostridium difficile infection and replaced trolled study 52 of 60 patients with chronic fatigue missing component of the microbiota 41 . Two sys - syndrome and gastrointestinal dysfunction treat - tematic reviews concluded that FMT resolves re - ed with FMT, 50% had resolved depriva - current Clostridium difficile infection in approxi - tion, lethargy, or fatigue during a 15- to 20-year mately 90% of patients 42 . According to the cur - follow-up period. rent guidelines for diagnosis, treatment, and pre - Finally, in a patient with idiopathic thrombo - vention of C. difficile -associated disease, FMT cytopenic purpura who underwent FMT for ul - can be considered in clinical practice after the cerative colitis, a progressive but significant in - second recurrence of the infection 45 . crease in platelet levels has been observed 53 , tes - The use of FMT for inflammatory bowel dis - tifying the potential benefits of FMT in immune eases is represented only by small open-label tri - disorders . als, case series, or case reports, most of which In conclusion, FMT seems to be a safe e have been published only as abstracts at confer - promising treatment for recurrent Clostridium ences. Many of them have experienced FMT in difficile infection. Well-designed randomized patients with IBD and Clostridium difficile infec - controlled trials are needed to establish the effi - tion. Among different investigations, there is a cacy of FMT for other diseases. large methodological variability, with regard to stool and patient preparation, number of infu - Informed Consent sions, route of delivery, and outcome In a clinical trial the informed-consent process evaluation 46 . Clinical results, in terms of symp - represents a key element expressing a fundamen - tom reduction, clinical remission, and suspension tal ethical and medico-legal value: it is a volun - of IBD treatment, are promising but the evidence tary agreement to participate in clinical trials is weak. based on the understanding of the objectives, Also the safety data of FMT in Clostridium risks and possible benefits of the research. Due to difficile infection were not confirmed when FMT the nature of the research, the experimental field

3176 Ethical aspects of Fecal Microbiota Transplantation (FMT) is characterized by much more “grey-zones ” than Microbiota Commercialization clinical praxis. The subject is asked to undergo As it has been said, microbiota represents a clinical trial and to expose himself to situations – key-element to maintain an organism healthy. At both therapeutic and non directly therapeutic for this aim, some authors 56 pointed out that the aug - him – where balancing possible risks and bene - mented use of dietary supplements has dramati - fits is not easy and where also the researchers do cally increased the market in this sector. The not have a full information. Furthermore, a commercialization of dietary supplements to greater care is asked whereas information about avoid microbiota imbalance poses several ques - possible future risks is not yet available. Fecal tions (both scientific and ethical). First of all, microbiota transplantation seems to well adhere these authors report that the use of probiotics en - to such uncertainties. As it has been said, al - tails some safety-related considerations insofar though bacteriotherapy has been showed to be studies have suggested an “unpredictable behav - generally safe, randomized studies evaluating iour of both naturally occurring and genetic al - clinical safety are still in their infancy; very little tered microorganisms, each of which have the can be said about the transmission of occult potential to produces substances or gene-behav - pathogen . iours that are harmful to the body” 56 . From the Moreover, a specific attention should be given ethical point of view, we have to make sure that to the information schedule: the particular, and as people are aware and informed about these risks. it has been called “non elegant” aspect of the Furthermore, although this could be thought as sample might facilitate anxiety. Patients should speculative, one should also contemplate the pos - be well informed of what they are receiving. sibility of gaining money through the sell of a From the donor’s point of view, it is important healthy microbiota, thanks to dietary supple - to provide information about the procedure that ments that avoid dysbiosis. he/she must undergo before becoming a donor According to others 57 , future research should al - (sample screening for parasites, bacteria and so so take into account the possibility, and above all on, and blood screening for HIV, and others). the effects, of introducing novel kind of bacteria in the environment and in the human ecosystem .

Further Relevant Ethical Issues Research Ethics Committees and FMT As a part of clinical research, the Research Microbiota Fingerprint Ethics Committees (RECs) are called to verify Some researchers suggest that microbiome is some key-elements of a clinical research proto - unique to the individual 54 . If so, “microbiome col 58 . While contributing to more knowledge about technology may allow access to information such human health of persons who are enrolled in clini - as past exposures, locations an individual has vis - cal trials, RECs are invested of the responsibility ited in the past” 4. Said that, there could be also of guaranteeing their safety and protection. They new intersections with the forensic use of DNA in provide an opinion regarding the rights of the sub - so far this last one, employed to match a suspect jects in terms of their physical, psychological and to a crime scene sample, together with microbio - moral integrity, the principle of fairness and equal me, would represent a further dowel enriching opportunities and the rights of the people who can the toolkit of forensic science. access to centres for assistance. Recently Tridico et al 55 found out that hairs, in RECs may have an important role within FMT’s the specific pubic hairs, may provide data to in formulating more specific operating procedures . “augment other forensic results and possibly pro - vide association between victims of sexual as - sault and offender when other associative evi - Table I. Fecal micriobiota transplantation’s ethical issues. dence is absent”. As it can be understood, foren - Main ethical issues sic investigation may benefice from the possibili - Donor’s recruitment ty that microbiota is unique to each individual. Safety However, results extrapolated from interviews Informed Consent made by Hawkins and O’Doherty indicate that, at the present, in contrast to DNA, it is not possi - Other ethical issues Microbiota fingerprint ble to evaluate the stability of microbial finger - Microbiota commercialization prints over the time 4.

3177 V. Daloiso, R. Minacori, P. Refolo, D. Sacchini, L. Craxì, A. Gasbarrini, A.G. Spagnolo

Beyond the particular attention to the informa - 2) PURCHIARONI F, T ORTORA A, G ABRIELLI M, B ERTUCCI G, tional schedule, RECs should consider the fol - GIGANTE G, I ANIRO G, O JETTI V, S CARPELLINI E, G SBARRI - NI A. The role of intestinal microbiota and the im - lowing ethical suggestions when clinical trials mune system. Eur Rev Med Pharmacol Sci 2013; are settled up. Suggestions are branched out ac - 17: 323-333. cording to concerns for patients and for donors. 3) COMPARE D, N ARDONE G. The role of gut microbiota in the pathogenesis and management of allergic Concerns for Patients: diseases. Eur Rev Med Pharmacol Sci 2013; 17(2 1. Patients must be informed about the procedure suppl): 11-17. they are undergoing, and above all they must 4) GUINANE CM, C OTTER PD . Role of the gut microbio - be aware they are receiving stool donated from ta in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap an healthy individual. Adv Gastroenterol 2013; 6: 295-308. 2. Patients must be informed about the lack of long term safety data. 5) KOOTTE RS, V RIEZE A, H OLLEMAN F, D ALLINGA -T HIE GM, ZOETENDAL EG, DE V OS WM, G ROEN AK, H OEKSTRA JB, S TROES ES, N IEUWDORP M. The therapeutic po - Concerns for Donors: tential of manipulating gut microbiota in obesity 1. Donors should be aware that to be effectively and type 2 diabetes mellitus. Diabetes Obes donors, their stool and blood will be screened Metab 2012; 14: 112-120. for ova, parasite, HIV, HCV and others. 6) SOMMER F, B ACKHED F. The gut microbiota – Master 2. Donors must be informed that similarly to ge - of host development and physiology. Nat Rev Mi - crobiol 2013; 2: 227-238. netic research, microbiome screening can re - veal the susceptibility to disease. So far they 7) DOMINGUEZ -B ELLO M, C OSTELLO EK, C ONTRERAS M, MAGRIS M, H IDALGO G, F IERER N, K NIGHT R. Deliv - have the right to choose “to know” or “not to ery mode shapes the acquisition and structures know” about them. of the initial microbiota across of multiple body habitats in newborns. PNAS 2010; 11: 11971- 11975. Conclusions 8) LEDERBERG J, M CCRAY AT . “Ome Sweet” Omics--A genealogical treasury of words. Scientists 2001; 15: 8. Microbiota represents a new challenge both 9) THE NIH HMP W ORKING GROUP . The NIH Human Mi - for its scientific-clinical characteristics and ethi - crobiome Project. Genome Res 2009; 19: 2317- cal aspects. Although the very updated litera - 2323. 59 ture confirms the positive safety/efficacy profile 10) THE HUMAN MICROBIOME PROJECT CONSORTIUM . Struc - of the employ of health microbiota (so called ture, function and diversity of the healthy human Bacteriotherapy or FMT), from the ethical point microbioma. Nature 2012; 486: 207-214. of view it is to make sure that the information 11) PROCTOR LM . The Human Microbiome Project in process has considered all the elements needed to 2011 and beyond. Cell Host Microbe 2011; 10; make the agreement to participate in clinical tri - 287-291. als effectively informed. 12) SLASHINSKI MJ, W HITNEY SN, A CHENBAUM , K EITEL FMT represents in some ways a challenge for WA, M C CURDY SA, M C GUIRE AL . Investigator’s per - spectives on Translating Human Microbiome Re - RECs. RECs are helpful in formulating more search into Clinical Practice. Public Health Ge - sharable procedure for this innovative therapeutic nomics 2013; 16: 127-133. procedure. Furthermore, although the good ex - 13) JUENGST E, H USS J. From metagenomics to the pectation of FMT, RECs should demand long metagenome: conceptual changes and the term follow-up to evaluate safety. rhetoric of translational genomic research. Ge - nomics, Society and Policy 2009; 15: 1-19. –––––––––––––––– –-– –– 14) TREMAROLI V, B ACKED F. Functional interaction be - Conflict of Interest tween the gut microbiota and host metabolism. The Authors declare that there are no conflicts of interest. Nature 2012; 489: 242-249. 15) MILLS KHG . TLR-dependent T cell activation in au - References toimmunity. Nat Rev Immunol 2011; 11: 807-822. 16) SEKIROV I, R USSELL SL, A NTUNES LC, F INLAY BB . Gut mi - 1) MENG -Q UE X, H AI -L ONG C, W EI -Q IANG WQ, W ANG S, crobiota in health and disease. Physiol Rev 2010; XIAO -C ANG C, F ANG Y, B AMG -M AO W. Fecal microbio - 90: 859-904. ta transplantation broadening its applications be - 17) DUPONT AW, D UPONT HL . The intestinal microbiota yond intestinal disorders. World J Gastroenterol and chronic disorders of the gut. Nat Rev Gas - 2015; 21: 102-111. troenterol Hepatol 2011; 8: 523-531.

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