Donors' experiences and attitudes of fecal microbiota transplantation: An empirical bioethics study from China

Donor participation is a critical part of ensuring the development of human microbiome research and the clinical application of fecal microbiota transplantation (FMT). Most FMT donors are still not sufficiently aware of the risks associated with the act of donating gut microbiota, especially the risk of data privacy disclosure. Enhanced awareness of the moral responsibility of the researchers and ethical oversight by ethics committees are needed. Fecal microbiota transplantation (FMT) is a technique that transplants gut microbiota (fecal suspensions or purified fecal microbiota) from a healthy donor into a patient. It is currently the most effective treatment for recurrent Clostridium difficile infection (CDI) listed in the American Gastroenterological Association clinical guidelines as a treatment strategy for CDI with three or more recurrences [1]. Studies have shown that FMT has potential applications in treating gastrointestinal diseases and other systemic diseases, including inflammatory bowel disease, irritable bowel syndrome, obesity, diabetes mellitus, and neurodegenerative diseases [2-5]. Although the exact mechanism of action is still unclear, FMT is gaining popularity both in China and worldwide, and increasingly, more medical research institutions are conducting FMT-related research. FMT success is primarily based on a positive clinical response in the recipient. Undoubtedly, selecting and retaining healthy and regular microbiota donors are one of the key components in the success and development of FMT. However, the current situation indicates that recruiting and retaining donors are challenging. On the one hand, FMT research is still in its early stages, and unlike other tissue donations (e.g., blood donation), gut microbiota donation is not as well known to the public, let alone the related yuck factors and stigmatization. On the other hand, the rigorous screening process and substantial time commitment limit the number of donors, with only 3%–20% of potential donors passing all necessary screening [6, 7]. Moreover, existing empirical studies primarily focused on the experiences and attitudes of doctors and patients, while the views and conduct of donors have been largely overlooked in the literature. It is impossible to provide an accurate panorama of FMT without evaluating it from donors' perspectives, as donors are critical to the success of FMT. On this basis, this survey is focused on microbiota donors to investigate the distinctive experiences and views toward the act of FMT and related ethical issues to identify and discuss the fundamental factors affecting their behaviors and attitudes. It is hoped that through identifying the potential obstacles and analyzing the ethical issues, a feasible and acceptable moral guidance can be reached to inform new laws and policies for FMT regulation. To investigate donors' experiences and views toward the act of FMT and related ethical issues, a total of 113 electronic questionnaires were distributed, of which 13 were invalid (older than the specified age range) and 100 were valid. In this survey, 47 male donors and 53 female donors accounted for the total number of microbiota donors. The ages of the donors ranged from 17 to 48 years old, with an average age of 27.19 ± 5.41 years. In terms of the educational level, a large portion of donors were postgraduates (67%), followed by undergraduates (30%). Students were the majority of the donors (61%), and their majors were mainly medical (34%) and science-based (16%), followed by professionals (19%), company employees (11%), and established staff (9%), whose monthly income was mainly between 5000 and 15,000 RMB (Figure 1A and Supporting Information Table S1). As shown in Figure 1B (and Supporting Information Table S2), more than half (58%) of the donors are in medical-related professions and have already known about FMT. Other sources of knowledge about microbiota donation were indicated as “family,” “internet,” and “academic meeting.” When asked about their perception toward FMT, “Miraculous” and “natural” were the top two options from donors' responses, which shows most donors hold positive attitudes. Regarding the perceived nature of gut microbiota, 67% choose “biological product,” followed by “drug” (34%), “tissue” (33%), “organ” (7%), and “waste” (7%). As shown in Supporting Information Table S2, 60% of microbiota donors believed that there are differences between donating gut microbiota and donating blood, while 32% believed “there is no difference” and 8% choose “don't know.” Among the 60 people, the perceived specific differences include the following: donating gut microbiota does not require immunologic matching when used for clinical treatment (60%), the screening procedure for donating gut microbiota is different from donating blood (58.33%), donating gut microbiota does not affect the physical body (50%), there is financial compensation for donating gut microbiota (26.67%),1 donating gut microbiota is similar to donating human “waste/garbage” (20%), and there is a sense of shame in donating gut microbiota (15%). In Figure 1C (and Supporting Information Table S3), among the microbiota donors, 60% had experience(s) of donating gut microbiota, half (30%) of which have donated >5 times cumulatively; 40% of donors have been screened and qualified but have yet donated. we performed statistical analysis to investigate whether donors would like to continuously donate fecal microbes and manage their lifestyle if they have donated before. It was found that about 93% of the donors (60) that had donated before were willing to donate continuously, and about 77.5% of the donors (40) that had no donation experiences were also willing to donate continuously. Based on the distribution of the data, we used Fisher's Exact Test and calculated a p value of 0.032, which indicates that there is a difference in willingness to donate continuously between the sample with and without previous donation experiences, that is to say, people who had donation experiences were more willing to donate again. To become a qualified microbiota donor, strict control of one's diet, medications, and daily behaviors are required. As shown in Supporting Information Table S3, while 87% of donors was willing to discipline and manage their lifestyle to continue donating gut microbiota, 13% were not willing to do so. This result resonates with the findings shown in Figure 1B that most donors hold a positive perception toward FMT; it is reasonable that they are more likely to become donors, even regular donors. It is reflected that the awareness and perception of FMT are the main affecting factors affecting the donor's attitude toward donation. As shown in Figure 1C (and Supporting Information Table S3), when asked about the motivations for donating, the answers are largely mixed: the overwhelming majority of the respondents choose altruistic reasons, for example, “help patient” (80%) and “contribute to scientific research” (75%), whereas more than half also chose self-regarding reasons, for example, “for additional income” (64%) and “to receive my health information through the medical check-up” (62%). There are also other factors influencing the motivation for donating such as curiosity (28%) and preservation of their own microbiota (13%). When asked if the donors perceived any risks in donating gut microbiota, as shown in Figure 1D (and Supporting Information Table S4), only 53 donors answered affirmatively, and of the remaining 47 donors, 30 thought there were no risks associated with the act of donating gut microbiota and 17 were not sure if there were risks. At the same time, with respect to the risk in receiving FMT for patients, 79% of the donors believed there are “physiological risks,” while 52% for “psychological risks” and 43% for “social risks” (for the details of the risks, see Supporting Information Table S4). As shown in Figure 1E (and Supporting Information Table S5), when asked if the donors would agree to their donated gut microbiota being used in future open research studies, 61% of donors said yes and indicated re-consent is not required for subsequent studies would require their reconsent, 37% of donors said that they were not sure but felt that subsequent studies that differ significantly from the originally informed study would require their reconsent, and only 2% of donors said no. As Figure 1F reflected, donors who chose “additional income” as the motivations for donating were more likely to believe that they have ownership of the gut microbiota than those who did not (χ2 = 5.73, p < 0.05), as well as the rights to share the benefits of the study due to the special function or value of their gut microbiota (χ2 = 10.13, p < 0.05). The survey found that most donors (92%) recognize the physical (80%), psychological (52%), and social (43%) risks associated with FMT (Figure 1D and Supporting Information Table S4). However, when asked if the donors perceived any risks associated with the act of donating gut microbiota, only half of the donors (53%) answered affirmatively, and their concerns were mainly about the commercialization of gut microbiota (73.58%), unexpected findings during stool testing (67.92%), for example, detection of AIDS or bowel cancer, and privacy disclosure (62.26%), may be subject to ridicule and discrimination (30.19%) (Supporting Information Table S4). These results showed that most microbiota donors still have insufficient knowledge regarding the risks that come with the act of donating, despite the physical risks of donating fecal microbiota are negligible but the social risk, especially the risk of privacy disclosure should not be neglected. An important concern regarding privacy in the screening process of a microbiota donor is the level of access to personal information. During the initial phase of screening, individuals who wish to donate are required to truthfully complete an health questionnaire that includes questions about the presence of gastrointestinal disease, neurological disease, infectious disease, surgical or other medical histories, current physical condition and behaviors (e.g., bowel habits), dietary habits, medication history (e.g., antibiotics), family history, and so forth. After passing the initial screening, they also need to pass a screening interview and other health examinations (stool and blood testing) before they can officially join the donor line-up. In addition, donors who are able to donate long term are required to undergo periodic health examinations every 8–12 weeks and fill out a short questionnaire on the day of donation to check for any recent events that may be counterproductive to the act of donating [8-10]. In summary, a complete donation process requires long-term and continuous collection of a series of personal information from the donor regarding their behaviors, travels, lifestyle, and so forth. Information privacy contains important ethical values, such as freedom, dignity, and justice, which concerns the most basic human dignity and personality development of an individual, as well as the privacy interest of the collectives, and therefore must be protected. Recent studies in human microbiome research have demonstrated that personal microbiomes contain enough distinguishing features to identify an individual over time. Once information privacy is breached, it may negatively affect employment, insurance, and other aspects of one's life, bringing about “microbial discrimination.” Microbiota donors are particularly at risk for potential privacy breaches. While other types of donations, such as blood donations, also require the provision of personal information, they do not donate as frequently as microbiota donors. The increased frequency of donation implies frequent questionnaire screenings and health check-ups, which generates a greater amount of information and is therefore more at risk of privacy breaches compared with other types of donations [11]. Researchers should protect donors' privacy, especially during data storage and transmission. A donor's genetic information in particular is the “essential information of an individual,” capable of revealing his/her physical conditions, cognitive ability, and even mental attributes; once disclosed, it cannot be retrieved, and this may pose various potential risks that could be permanently detrimental to the individual when a human microbiome profile is combined with human genetic and other types of information; this could generate unprecedented personal-revealing information of a new magnitude. The possibility of privacy breaches relating to microbiome data cannot be ignored and warrants serious consideration. This information must be effectively protected and not collected, stored, or used by others against the donor's will or without his/her knowledge. Some researchers in Western countries have already suggested that the Genetic Information Nondiscrimination Act and Health Insurance Portability and Accountability Act in the United States and Personal Information Protection and Electronic Documents Act in Canada should be amended and extended to apply to human microbial samples. Since the genetic data of the human microbiome may be considered almost as individualized as our own genome, it seems reasonable to regulate both technologies at the same level to safeguard the protection of privacy. The question of what model of informed consent should be adopted for microbial sample banking, such as gut microbiota, has remained controversial. The traditional model of informed consent requires that participants be informed of the information and key elements of a specific study at the time of sampling, such as the purpose, nature, risks, duration, the right to withdraw from the study, and so forth. However, for gut microbial samples collected by FMT, there remain uncertainties about the specific duration of storage and diseases for which they will be used in the study, that is, the sample collection phase (informed consent acquisition) is separated from the research phase [12]. The currently more accepted model of informed consent is broad consent, that is, authorized biological samples and data can be used for future studies in broadly designated areas, and the consent of the sample donor must be reobtained only if the type of the study changes in the future [13]. Our survey found that the broad consent model is deemed acceptable to the majority of microbiota donors. However, some oppositions argued that broad consent is ethically flawed, in the sense that subjects are deprived of the opportunity to disagree with future studies [14]. However, unlike traditional clinical trials, research using biobank samples is not a direct intervention on the subject's body and thus does not involve physiological risks; its only risk is the disclosure of personal information and privacy of the sample donor [15]. We suggest using “process consent” proposed by Rhodes et al. [16] as a solution to the problem of informed consent for stool banks. Process consent “provides contributors with a description of the process that governs the distribution of samples and associated information to future researchers.” It requires biobank operators to identify the procedures and criteria by which future research endeavors will be evaluated and determine which future research projects should be granted access to the biobank samples and data. “Process consent” requires the biobank managers to develop a set of evaluation criteria for the procedure in advance and to establish a supervisory committee, where only research projects that are approved by a specified criteria-based review process will be given access to samples. In this way, process consent avoids the hassle of recontacting donors and obtaining renewed consent while “adding a measure of assurance to blanket consent.” This mechanism creates a “firewall” between donors and researchers and determines the use of stool bank samples and data according to established open and transparent criteria. Confidentiality is thereby ensured to the necessary level by limiting access to the identifying information. Although FMT has gradually accumulated positive evidence in clinical practice and research, words such as “feces” and “fecal bacteria” can be unpleasant and even cause repugnance among people. Actually, the “yuck factor” is frequently mentioned in the FMT literature and proven evidence in surveys, mainly on patients [17],2 doctors [18], and the public. For example, according to a survey conducted in Guangzhou City, university students were reluctant to promote and receive FMT treatment because they were “disgusted by the topic of fecal matter” [19]. Our survey also showed that among all microbiota donors (Supporting Information Table S2), more than half were actually from medical professions themselves. A portion of the donors rated FMT as “hardcore” (12%), “disgusting” (7%), and “shameful” (7%); moreover, 34% of the donors considered the disgust and shame associated with feces as one of the reasons why the public is reluctant to become a microbiota donor; in addition, 43% of donors believed that patients treated with FMT might face discrimination or humiliation (e.g., “eating other people's feces”), which can lead to low self-esteem. Donors are also likely to be ridiculed, as donating feces is still relatively “taboo” and not as widely publicized contrary to blood donation, which instead is often seen as an honorable and altruistic act. Due to the fear of being ridiculed for donating feces, some donors were reluctant to share their donation experiences with others. Surveys showed that 18% of donors do not want anyone to know about it. From an aesthetic viewpoint, the use of gut microbiota in the treatment of diseases was long pioneered in ancient China, and the fecal suspension used to effectively treat diarrhea, vomiting, and constipation was called “Huanglong Tang” (yellow dragon soup) and recorded in the book of “Zhouhou Beiji Fang” (which roughly translates to “handbook of prescriptions for emergency”) [20]. Similarly, some experts in China have suggested referring to FMT as “gut microbiota transplantation” to avoid the unpleasantness brought by the word “feces,” which at the same time also summarizes the essence of the technique more appropriately. To avoid stigmatization affecting donors and recruitment efforts, stool banks should focus on promoting the scientific and social value behind donating. On the one hand, donating microbiota is an act of altruism and a contribution to scientific research; on the other hand, there is also the opportunity to discover one's own health risks (e.g., infections such as HIV) during the process of testing blood samples by researchers, and our survey shows that vast majority of the donors want to be informed of such information and receive relevant health management advice and that more than half of the donors are interested in the free-of-charge medical check-ups carried out during donor screening in hopes of finding out their current state of health. By promoting the positive values behind donating, we can increase the social recognition and acceptance of gut microbiota donation and promote the recruitment of donors. In addition, stool banks should conduct more health talks related to FMT and gut microbiota donation to increase public awareness of FMT and reduce false, negative perceptions and misconceptions of gut microbiota donation. Human microbiome research has complicated the issue of gut microbiota ownership, not only because feces is traditionally considered waste but also because of microorganisms that exist in symbiotic relationships with the human body. As Hawkins and O'Doherty [21] argued, “it is not clear whether these microorganisms should be considered part of or separate from the human body,” and arguments can be made both. On the one hand, it is clear that the microbial genome is not part of the human genome and therefore should not be regarded as part of the human “self”; on the other hand, the human genome and microbial genome have a symbiotic relationship where they evolve in synergy to maintain human health, and as human microbiome research advances, it is understood that microorganisms in feces carry a large amount of unique and individualized identifiable information, suggesting that each individual has their own microbiome composition [22]. Ultimately, it seems that the dichotomy of human versus nonhuman and self versus nonself inevitably breaks down in this context. Furthermore, the classification of fecal microbiota is unclear. Is it a drug or biological product? Or is it an organ/tissue? There are diverse and varied understandings and definitions of fecal microbiota, and this has a significant impact on how it is regulated and the social acceptability of FMT. The US Food and Drug Administration (FDA) regulates human fecal microbiota as a biological product and drug in the way for medications, which means that doctors are required to submit an Investigational New Drug (IND) application before performing FMT [23], with the only exception of treating rCDI, given that the informed consent from the patient is obtained. However, the FDA's regulation of FMT under the drug paradigm has ignited criticism and skepticism from doctors, scientists, lawyers, and patients, as “inappropriate” and “actually harmful” dissuade doctors from using the product and limit access to care, “overly restrictive” [24], and “fails to achieve its intended objectives” [25]. Since it is not possible at present to provide the exact “active ingredients,” “potency,” “stability,” and “dosing” or to control the manufacturing process of FMT materials as drugs, we “cannot realistically impose the same regulations as for conventional “drugs” [26]. In contrast, some gastroenterologists consider the human gut microbiota to be a “virtual organ” and should be regulated as “human tissue” [26, 27]. They recommend that FMT should employ the same safety precautions used for transplanting blood, bone, skin, and so forth, and rigorous screening of stool donors for common pathogens should be a condition of the FMT protocol to reduce risks. At present, the legal status of human microbiota in China has yet to be determined. Some scholars [28] pointed out that the nature of gut microbiota is similar to human organs, tissues, cells, and genes, thus should be considered as a special article under civil law, and its legal status is between property and personal attributes, which should be subject to special regulation under life and health jurisdictions. In the United States, The FDA classifies stool for use in FMT as a biological product and a drug under traditional statutory definitions. In practice, however, the FDA exercises enforcement discretion, allowing physicians to use FMT for the treatment of CDI that does not respond to standard (antibiotic) therapies without requiring them to submit an IND application [29]. The results of our survey (Figure 1B and Supporting Information Table S2) showed that the majority of donors (69%) considered gut microbiota as a biological product. Moreover, gut microbiota was also considered as a type of drug (34%), human tissue similar to blood (33%), and organ (7%); interestingly, only a small percentage of donors (7%) regarded gut microbiota as human waste. When asked about the relationship between gut microbiota and humans, most donors (67%) saw it as part of themselves; a minority of donors (8%) saw it as part of the environment and not part of themselves; however, some donors (24%) viewed gut microbiota as neither part of themselves nor belonging to the environment and referred to them as having a special relationship with humans in general (Supporting Information Table S2). This may be due to the development of human microbiome research and media reports that have attracted public attention in recent years. The commercial prospects of stool-derived products can be affected by the way in which stool is regulated (or not regulated) [30]. With increasing interest in human microbiome and microbiome-based therapies, the related ownership issues that arise alongside therefore need to be revisited. Although ownership issues related to gut microbiota have yet been encountered so far, they have been highlighted in other similar cases, as exemplified by the Hela Cells controversy [31]. The Hela cell lines originated from the cervical cancer cells of a black American woman, Henrietta Lacks, are of great scientific value because they do not die of senescence and can divide indefinitely. However, the cell line was obtained without informed consent and has given the researchers a substantial amount of wealth, fame, and status, while Lack's family continued to live in poverty with no access to health insurance. One of the disputes was whether Lack's family should share in the financial benefits brought in by the Hela cell line. Ownership of something implies the ability to receive financial gains through the sales of that something, intellectual property rights, patents, and so forth. The field of FMT research also faces ownership and benefit-sharing dilemmas. A number of studies suggest that the success of FMT depends heavily on the diverse composition of microorganisms in fecal samples, which certain donor's gut microbiota does possess and results in significantly better FMT outcomes than the stool of other donors [32], and such a donor is termed as a “super-donor” [33], coined to describe those microbiota donors of “special value” [34]. The first record of the super-donor effect was an RCT that was investigating the efficacy of FMT in patients with ulcerative colitis. The results suggested that FMT was superior to the placebo with a significantly higher rate of endoscopic and clinical remission (24% vs. 5%, respectively). Seven out of nine patients who achieved remission had received FMT from the same donor. Although the observation of the existence of the FMT super-donor is not yet robustly supported by empirical evidence, and clear criteria for a super-donor are still lacking, we believe that this is a good point to investigate the donor's attitudes toward donation-related benefit-sharing issues, so we still included this concept in our questionnaire. In our survey, 83% of people who have read this information believed that if they were “super-donor,” they were entitled to receive a distribution of research benefits or financial compensation for their special contribution (Figure 1F). With the development of human microbiome research, it is likely that events similar to the Hela Cell case described above may happen to “super-donors” in the coming future. Imagine if the donated gut microbiota of a “super-donor” is proven to be effective in curing certain diseases or of great research value, should the “super-donor” be entitled to receive some financial benefits for their special contribution? What measures should be established to ensure their rights and interest be protected? These issues could become very difficult, as we examined in the last section, because of the ambiguous relationship between the microbial genome and the human genome, it is not clear whether these microorganisms should be considered part of or separate from the human body. However, we must acknowledge that the existence and efficacy of “super-donor” are still contentious and we must be cautious about the abuse and hype of this idea. There is a lack of large randomized controlled clinical trials of FMT; many observations, including FMT super-donor, are not yet sufficiently supported by empirical evidence. It is increasingly becoming clear that “one stool does not fit all” in the context of treating chronic diseases. It is proposed a donor-recipient matching approach “may be best way forward”: a patient is screened to identify the functional perturbations specific to their microbiome, and he/she could be matched to a specific FMT donor known to be enriched in taxa associated with the metabolic pathway that needs to be restored [33]. Interestingly, compared with donors who did not choose “additional income” as their motivation for donating, those who chose “additional income” placed significantly more importance on gut microbiota ownership (χ2 = 5.73, p < 0.05) and benefit sharing (χ2 = 10.13, p < 0.05). This corroborates Rhodes et al.'s proposition that the idea of making money from donating biological samples led to a focus on ownership and the fact that, as a right, they should share in the profits generated from the sample research [16]. The perception of ownership will greatly affect the issue of distributive justice for the commercial benefits generated by gut microbiota [35]; therefore, the issue of the ownership of gut microbiota needs to be brought to the attention of research managers and policy-makers. The survey revealed that the reasons people chose to donate gut microbiota are diverse and complex (Figure 1C and Supporting Information Table S3), with the majority wanting to contribute to the treatment of patients (80%) or to scientific research (75%), while more than half of the donors (64%) donate for the purpose of financial compensation. From the findings, it is clear that microbiota donors, more often than not, see donating gut microbiota as an altruistic act, which is consistent with the motivation people have when it comes to donating blood and sperm [36, 37], and that more than half (57%) are willing to donate despite the lack of financial compensation. Certainly, however, the results did find that microbiota donors do value financial compensation more. Gut microbiota donors can receive financial compensation of approximately 200 RMB for one successful donation, and if they donate 3–5 times every week, they can steadily increase their income by 2400–4000 RMB/month, which is a significant amount of income for either students or those who are already working. Financial compensation may help in the recruitment and long-term donation of donors, but we must be careful about the manner and amount of compensation to avoid the risk of “undue inducements.” Studies have shown that paid blood donation is associated with an increased risk of transfusion-transmitted infections, as paid donors may deliberately conceal the fact that they have an infectious disease to be financially compensated [38-40]. A similar problem may occur with gut microbiota donations. Although many infectious pathogens can be filtered out through microbiological testing, sexual habits, family history, travel history, dietary habits, and personal medical history can still be falsified to some extent. As mentioned earlier, donors who are able to donate long term are required to undergo periodic health screenings every 8–12 weeks; and if donors feel the need to conceal these conditions to receive excessive financial gains, the risk of FMT-associated infections will be increased. In summary, donor participation is critical to ensuring the development of human microbiome research and clinical applications of FMT. This study investigated the perceptions and attitudes of gut microbiota donors toward the ethical and social challenges arising from the act of donation, and effective responses to these challenges are necessary for the advancement of successful regulatory policies. To our knowledge, this study is one of the earliest questionnaire surveys for the ethical aspects of microbiota donation in China. However, this study has some limitations. FMT research is still in its early stages and gut microbiota donation is not well known to the public, combined with the strict screening process and the age limit of donors, which leads to the difficulty of collecting questionnaire samples, and in reality, the majority of donors are students. Findings generated from this relatively small sample size may not be generalizable to the large-scale general public. However, since we focused on the ethical aspect of this practice, we believe that this sample size is adequate enough for us to identify donors' primary concerns on bioethical issues related to FMT. Another limitation was that we did not perform subgroup analysis among different majors targeting the key questionnaire issues; it was mainly because most of the participants were from science and medicine backgrounds. Data collected from participants of other professions are not sufficient for statistical analysis. This survey found that risks and privacy, informed consent, stigmatization, ownership, and benefit sharing are the most challenging ethical and social issues when it comes to donating gut microbiota. This study suggests that (1) most donors are still not sufficiently aware of the risks associated with the act of donating gut microbiota, especially the risk of privacy disclosure, so effective confidentiality measures, enhanced awareness of the moral responsibility of the researchers, and ethical supervision by ethics committees are needed to ensure the security of personal private information generated by the donation process; (2) to safeguard against the undue privacy violation related to the human microbiome, we agree with experts in the West to extend the existing legal frameworks designed to protect human samples and data to apply to human microbiome samples. Therefore, we propose that the Regulation of the People's Republic of China on the Administration of Human Genetic Resources promulgated by the State Council, which aims to enhance the protection of human genetic resources and tighten regulation and supervision, should be amended and extended to also include human microbiome research and applications. (3) Process consent is recommended as a solution to the problem of informed consent for stool banks, as it provides efficient and rational control over the use of resources in biobanks. (4) Efforts on increasing public awareness of FMT and donation are necessary not only to improve donor recruitment but also to reduce false and negative perceptions of gut microbiota donation to avoid stigmatization and discrimination against donors. From August to September 2021, we conducted a questionnaire survey through “Wen Juan Xing” online platform (wjx.cn) to collect information from the microbiota donors of Zhongshan Hospital affiliated with Xiamen University and Xiamen Treatgut Biotechnology Co., Ltd. Some questionnaires were also distributed through the platform of the R institute (mr-gut.cn). The questionnaire was designed by ourselves and the contents included three sections with 34 questions: basic information (six questions); knowledge and attitude toward donating gut microbiota (16 questions); and perceptions on ethical and social issues associated with donating gut microbiota (12 questions). Question formats included single choice, multiple choice, and written short answers. Please refer to the attachment for details of the questionnaire. To distinguish from other biological sample donors, the term “microbiota donor” is used throughout the questionnaire (for aesthetic reasons in China, we did not use the word “fecal donor” or “stool donor”) to refer to donors who have donated fecal samples or who have passed the rigorous screening process but have yet donated. This study protocol was approved by the Medical Ethics Committee of the School of Medicine, Xiamen University. The data obtained are presented in the form of frequency counts and percentages by category. A χ2 test was performed using R Studio statistical software to compare the perceptions of ownership and benefit sharing between two groups of microbiota donors (group 1, microbiota donors who chose “additional income” as their motivation for donating; group 2, microbiota donors who did not choose “additional income” as their motivation for donating). A 95% confidence interval, that is, p < 0.05, was used to determine the statistically significant difference. Yonghui Ma and Dawei Ke designed and conceived the idea of the paper. Yonghui Ma and Dawei Ke drafted the manuscript. Quan Zhang provided a statistical analysis of this study. Danyi Li provided important intellectual contributions throughout the revision of the paper. All authors read and approved the final manuscript. The authors acknowledge the support of grant 19ZDA039 from the National Social Science Foundation of China. They appreciate Zhangran Chen (Institute for Microbial Ecology Medical College of Xiamen University), Hongzhi Xu (Department of Gastroenterology, Zhongshan Hospital, Xiamen University), Canhui Lan (R Institute Co. Ltd.), and Chuanxing Xiao (Xiamen Treatgut Biotechnology Co., Ltd.) for their efforts in providing donors and proposing revisions to the paper. The authors declare that no conflict of interest. The ethics application (No. MEDXMU2021076) was approved by the Research Ethics Committee of the School of Medicine, Xiamen University. This study protocol was approved by the Medical Ethics Committee of the School of Medicine, Xiamen University. The data sets generated and/or analyzed during the current study are not publicly available to protect the participant's identity. However, the data are available from the corresponding author on reasonable request. Supplementary materials (figures, tables, scripts, graphical abstract, slides, videos, Chinese translated version, and updated materials) may be found in the online DOI or iMeta Science http://www.imeta.science/. The data that support the findings of this study are available on request from the corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.