A robust donor screening programme is an essential part of FMT services to ensure safety for FMT recipients. Donor recruitment is challenging; using standard criteria applied in many FMT services to ensure safety and efficacy, one recent study reported that only 1.7% of prospective candidates qualified as suitable donors.71 Moreover, the study reported that due to a lengthy screening process, as many as 39% of the candidates were lost to follow-up even before their suitability was established. The reluctance of the public to donate their stool is also well documented and seems to stem from the social perception of stool, the lack of awareness of the importance of donation, and the logistic difficulties in collection and transport of the stool.72 Evidently, there is a need for a pragmatic approach for the recruitment and screening of potential donors.

The primary aim of donor screening is mitigating risk of pathogen transmission via FMT. A secondary aim of donor screening is to exclude potential donors who may have an ‘aberrant/adverse’ gut microbiome. While the complexity and relative novelty of exploration of the gut microbiome mean that there is no clear agreed definition of what a ‘healthy’ or ‘unhealthy’ gut microbiome is,73 either compositionally or functionally, there is the theoretical potential for transmission of gut microbiome traits (and therefore potential for transmission of risk of diseases with a link to the gut microbiome) via FMT. There are also some studies that include microbiome sequencing and other approaches to try and find which bacteria transplanted from donor to recipient are associated with success.74 75 So far, it has been difficult to define a core set of bacteria or functions underlying a good donor or successful FMT. At the moment, there is little evidence which allows FMT services to define a healthy microbiome which is most optimal for donation. Previous BSG/HIS guidelines3 acknowledged that research into donor factors is lacking. Therefore, the guidelines recommended a general approach that all healthy adults under 60 years of age with body mass index (BMI) under 30 kg/m2 could be potential candidates for donor screening. The recommendations then focused on an initial screening using a health and travel questionnaire, followed up by a battery of laboratory testing of blood and stools to further ensure the safety of FMT material. The guidelines also recommended regular reassessment of donors to ensure continuing safety. Since the guidelines were published, more evidence has become available, especially around the experience of donor screening and the retention of possible donors. The emergence of the COVID-19 pandemic also raised questions whether prospective donors should be tested for other, non-gastrointestinal pathogens, to ensure the safety of recipients.

Effect on success rates: there was weak evidence which suggested that this does not influence the effectiveness of FMT.22 24 52

Effect on adverse events: there were no studies.

Effect on success rates: there was weak evidence which suggested that this does not influence the effectiveness of FMT.23 27

Effect on adverse events: there were no studies.

Effect on success rates: there was weak evidence which suggested that this does not influence the effectiveness of FMT.23

Effect on adverse events: there were no studies.

Effect on success rates: there was weak evidence which suggested that this does not influence the effectiveness of FMT.27

Effect on adverse events: there were no studies.

Effect on success rates: there was weak evidence which suggested that this does not influence the effectiveness of FMT.27

Effect on adverse events: there were no studies.

The Working Party reviewed the above evidence and concluded that it is likely that routinely measured donor factors do not influence the effectiveness of FMT for treatment of CDI. The Working Party agreed that the use of universal donors is the most practical and cost-effective way to obtain donor stools. The previous practice of using related donors, which in early days before stool banks existed were the most reliable source of donor stools, is now outdated and should be avoided. There is no established evidence that stools from a related donor influence the effectiveness of the FMT, but there may be logistical difficulties and potentially additional costs related to donor screening. There is also a concern that stool microbiota may be less diverse in these donors. As a related donor may cohabit with a recipient, the overlap of environmental factors with the patient (eg, diet) may affect their gut microbiome and the success of FMT.

There were no studies which investigated whether the donor factors affected the incidence or severity of adverse events, but the members agreed that, apart from the composition of the microbiota, they are not likely to influence the effectiveness of FMT. As mentioned above, some studies demonstrate that the composition of microbiota of the donor stool may predict the success or failure of FMT,74 75 but none of these studies met the inclusion criteria for these guidelines. The Working Party stressed that wherever donor factors have been investigated, this was done in situations in which all donors were screened for possible transmissible diseases and where safety of FMT material was established. Therefore, they stated that screening of all donors must remain in place to ensure the safety of FMT recipients. All donors should also be rescreened regularly to ensure ongoing safety.

The Working Party agreed a robust donor screening procedure remains mandatory. As per the original version of these guidelines, the screening should continue to comprise a questionnaire, to identify risk factors for an aberrant microbiome and pathogen carriage, and laboratory-based testing for pathogen detection. This should be an ongoing process that is repeated at appropriate intervals.

The Working Party discussed the reported FMT complications since the last guidelines which might influence updates in the recommended donor screening protocols. From one perspective, there have been a number of reported cases of infection post-FMT apparently related to pathogen transmission which may have been mitigated by additional donor screening processes, including C. perfringens, 76 atypical enteropathogenic Escherichia coli 77 and Shiga toxin-producing E. coli. 78 It is also important to highlight the well-publicised case of FMT-related infection transmission in two immunosuppressed patients who developed bloodstream infection after transmission of E. coli carrying an extended-spectrum beta-lactamase via FMT, leading to one death.79 80 There had been considerable concern since the emergence of SARS-CoV-2 regarding its potential for transmission via FMT (particularly related to its potential route of entry via the luminal tract and well-described gastrointestinal symptoms related to infection), and rapid consensus updates to donor screening were introduced to mitigate risk.81 However, despite this theoretical risk, there are no reported cases of FMT-related SARS-CoV-2 transmission described, to the knowledge of the Working Party. Since the last guideline, there has been an increased period of time for reporting of registry data and of prospective case series. Overall, FMT for rCDI appears safe with several years of follow-up post-treatment; there have been very few cases of infection potentially attributable to FMT and very low rates of new diseases which might feasibly be attributable to FMT.23 36 54 58–62 64–66 There is a need to strike an appropriate balance between screening practices that are robust enough to mitigate the potential risks of providing FMT while allowing sufficient pragmatism. Overly stringent screening focused on theoretical risk of every possible pathogen risks making the process impossible to comply with.

Regarding the recommended Donor History Questionnaire, the Working Party provided some updates to this compared with the original version of this guideline (box 2). For instance, the assessment for risk factors for bloodborne viruses has been updated to be consistent with those from UK Blood and Transplant. The Working Party noted that FMT services in certain settings aimed to recruit donors from within blood donation services, given the degree of overlap in assessment between blood and stool donation, although no such approach was currently being undertaken within the UK. Additional assessments have now been recommended, for example, enquiring about recent cold sores, anal ulcers and/or persistent pruritus ani, to screen for organisms that colonise the oral, rectal or perineal mucosa, including herpes simplex virus, pinworm and mpox (previously monkeypox) virus. Of note, the Working Party discussed that while a health questionnaire assessment is mandatory, it is beyond the scope of the committee to mandate specific content or specific exclusion criteria, and box 2 represents recommendations based on suggested best practice rather than compulsory questions. Questionnaire content and clinical interpretation of responses should be discussed and agreed at a local level following a robust risk assessment.

Laboratory-based blood screening of potential donors remains mandatory (box 3). The Working Party discussed that while a number of the pathogens listed in box 2 are not recognised to transmit via the faecal-oral route (being predominantly bloodborne pathogens), and the theoretical risk of them being transmitted via FMT being therefore low, there was still justification to screen for them out of a principle of caution. The Working Party again discussed and upheld their recommendation regarding Epstein-Barr virus and cytomegalovirus (CMV) testing being only recommended where there is the potential that the FMT prepared from that donor will be administered to immunosuppressed patients at risk of severe infection. Of interest, recent evidence suggests that only a very small proportion (approximately 1%) of CMV IgG or IgM-positive donors have detectable stool CMV DNA on PCR, and no CMV IgM-positive donors or those with stool CMV DNA have infectious virus on cell culture.82 Nevertheless, this recommendation has also been upheld on the principle of an abundance of caution. While the Working Party recommended consideration of a set of general/metabolic blood tests for donors, they did not set specific limits/thresholds for values. The examples were discussed of a donor with, for instance, incidental marked anaemia or raised C reactive protein as being at high risk of having significant undiagnosed disease which may impact the gut microbiome, and therefore being unsuitable for material donation.

The Working Party discussed the need to update stool pathogen screening compared with the last version of the guideline (box 4). In one respect, they acknowledged the need to recommend additional screening, with faecal SARS-CoV-2 being of relevance given its potential for faecal-oral transmission, as discussed above. The Working Party recognised that a global consensus document designed for European practice developed at the height of the COVID-19 pandemic had recommended SARS-CoV-2 screening of each donated stool sample.81 The Working Party concluded that while an argument could be made for continuing with this approach based on risk assessment at present, the currently evolving risk landscape related to SARS-CoV-2 (related to a number of factors, including national COVID-19 vaccination roll-out) may mean that a modified protocol for SARS-CoV-2 screening may become appropriate over the lifetime of this guideline. Similarly, the Working Party noted a report of atypical enteropathogenic E. coli transmission related to FMT, and as such felt that more considered screening for this in donors was justified.77 The Working Party also discussed that new evidence had emerged since the last version of the guidelines that suggested against certain gastrointestinal pathobionts being transmitted via FMT. In particular, a Danish FMT service recently described 13 out of 40 donors as being Helicobacter pylori stool antigen positive, but that 26 FMTs administered from five positive donors had not resulted in any recipients becoming H. pylori stool antigen positive at a median of 59 days.83 While these data do not support the need for H. pylori stool antigen being part of screening, the Working Party also discussed the different risk burden that theoretical H. pylori transmission might have in the UK versus in the Far East, given its association with gastric cancer. It was noted that there are recent data demonstrating transmission of Blastocystis via FMT, but that this did not influence success of FMT as treatment for rCDI, and it was not associated with any gastrointestinal symptomatology over months of follow-up, suggesting no need to intensify donor screening for this organism.84

The Working Party noted recent literature exploring the impact of FMT upon the gut microbiota dynamics of potentially procarcinogenic bacteria. This topic first came to light from a study of 11 paediatric patients with rCDI (of whom 6 had underlying IBD), in whom 4 patients were found to have sustained acquisition of procarcinogenic bacteria post-FMT, after transmission from colonised donors. It was also noted that two patients experienced clearance of such bacteria after FMT from a negative donor.85 Using full genome sequencing, one of these patients acquiring procarcinogenic bacteria was shown to have durable donor-to-recipient transmission of E. coli with the colibactin gene (clbB), which has been associated with colonic tumours.86 A further retrospective study87 analysed stool metagenomes of matched pre-FMT versus post-FMT samples from 49 patients with rCDI, together with their matched donors. This showed higher prevalence and abundance of potentially procarcinogenic polyketide synthase-positive (pks+) E. coli in the gut microbiome of patients with rCDI compared with their healthy donors, and that the pks status of the post-FMT gut microbiome related to the pks status of the donor being used (with pks being negative in five out of eight of their donors at all time points sampled and detected in overall low levels otherwise). More specifically, persistence (8 out of 9 patients) or clearance (13 out of 18 patients) of pks+ E. coli in pks+ patients correlated with pks in the donor (p=0.004). While these data are of interest, the Working Party concluded that the small number of publications on this topic, unclear understanding of the true potential causative procarcinogenic nature of the bacteria being studied, and overall reassuring safety profile of FMT meant that there was no current clinical indication for routine metagenome screening for such bacteria or their genes as part of donor screening. Additionally, since the durability of engraftment of donor strains after a single FMT is variable but may be only several months in the case of a reasonable proportion of taxa,73 the real procarcinogenic risk could be even lower than previously suggested, should bacteria with these gene cassettes be those with limited colonisation duration. Further studies within this field should be undertaken and results monitored. The Working Party noted that FMT for rCDI is often being used in an older and frail population for whom the risk-to-benefit ratio of FMT is being considered over a fairly short period, that is, patients with limited alternate therapeutic options, with the aim of minimising further hospital admissions. This ratio would be different in the context of younger patients, particularly where FMT was used on a more exploratory basis, and this may influence the importance of considering the potential future role for screening for such bacteria.

The Working Party also noted that a number of studies had proposed using stool metagenomics as a tool to assess stool donors, and proposed a variety of ecological or taxonomy-based metrics to select out and stratify potentially ‘ideal’ donors.88 Discussions within the Working Party concluded that while this was of research interest, there was no justification for use of any assessment of this nature as part of the donor screening/selection process at present. It was also observed that a small number of studies had suggested a potential role for additional modalities of laboratory assessment as part of donor screening; for instance, one study observed a trend towards increased gastrointestinal symptoms post-FMT for rCDI after receipt of FMT from a donor with positive small intestinal bacterial overgrowth, as assessed by positive lactulose breath test.89 Again, the Working Party felt that while this was of interest and supported future research, there was no current justification for this to be incorporated into the donor screening process.

As per their discussions regarding the health questionnaire, the Working Party felt that it was beyond the scope to mandate or exclude specific laboratory tests. Thus, the lists given in boxes 3 and 4 reflect suggested best practice but not compulsory testing. Laboratory-based testing and clinical interpretation of results should be performed and agreed at a local level following a robust risk assessment. Consistent with this, the Working Party noted the differences in laboratory donor screening approaches that are reported in different regions globally. These are consistent with the different prevalence and risk profile of different pathogens within each region.90 As highlighted by the case of COVID-19, the list of pathogens for which testing is undertaken needs to be constantly reviewed, revised and updated, based on local epidemiology and the latest evidence base. One area that may require particular focus in this regard is the potential for emergence of new viral pathogens or rise in population prevalence of known viral pathogens with established faecal-oral transmission, for example, poliovirus; the pertinence of this is highlighted by its detection within sewage water in London in 2022.91 92

The Working Party no longer supports the use of fresh FMT, because this approach does not allow for direct testing of the donor stool used to manufacture FMT prior to administration and does not allow for a period of quarantine in the case where additional donor testing may be required. Stool may be processed into FMT immediately from donors who have passed baseline screening, but the Working Party agreed that it should initially be quarantined. The Working Party also agreed that post-baseline screening is required prior to release of FMT from quarantine to further mitigate the risk of pathogen transmission. This post-baseline donor screening needs to take a safe but pragmatic approach, and should cover two aspects:

Bookend testing (box 5) on donated stool to pick up acquisition of asymptomatic, transmissible enteric pathogens during the donation period. Again, the exact framework should be defined by local policies and donation schedules, following a robust risk assessment. However, the Working Party recognised that there is a need to define the longest period the donor can donate without testing to ensure that safety of the recipient is not compromised. The Working Party agreed that this period should be no longer than 4 months. Bookend testing could include testing of pooled aliquots of donor stool used for manufacturing FMT. FMT could only be considered for release from quarantine once results have been demonstrated to be clear.

Bookend assessment and/or testing of donor to identify risk factors for pathogen acquisition since baseline screening. The exact framework should be defined by local policies and donation schedules, following a robust risk assessment. This could involve a donor questionnaire at each donation. FMT could only be considered for release from quarantine if no specific risks were identified. FMT manufactured from donors identified as having acquired risk factors during the donation period (such as unprotected sex with a new partner) would need to undergo continued quarantine, and only be considered from release once the appropriate repeat blood testing had been performed and results were demonstrated to be clear, ensuring that there had been a sufficient time period to allow for seroconversion.