Frequently Asked Questions

Jessica R. Allegretti, MD, MPH and Zain Kassam, MD, MPH

Given that the field of fecal microbiota transplantation (FMT) and microbiome therapeutics is relatively new, there are many questions that arise from both patients and providers for its use in Clostridioides difficile infection (CDI) and beyond. This chapter provides a practical reference to frequently asked questions (FAQs) that patients ask FMT clinicians and frequent inquiries from clinicians when first starting to treat patients with FMT.

Patient FAQs: Common Questions From Patients Referred to You for Fecal Microbiota Transplantation

This sounds experimental. Why should I have this procedure done?

With each episode of CDI, the risk of a recurrence becomes exponentially more likely. Once a patient has 3 or more confirmed episodes of CDI, it is unlikely that additional courses of C. difficile antibiotics (eg, vancomycin, fidaxomicin) alone will lead to a sustained clinical cure. Additional antibiotics alone are likely to result in ongoing disruption of the patient’s intestinal microbiome.

FMT is still considered investigational therapy by the US Food and Drug Administration (FDA); however, its use is recommended in both US and European clinical practice guidelines for the prevention of recurrent CDI (rCDI) following standard-of-care (SOC) C. difficile antibiotics.

Overall, FMT appears well-tolerated, and current data suggest the short-term safety profile is favorable as long as there is robust donor screening. Long-term data are still emerging; however, the current data suggest FMT does not have a concerning long-term safety profile (see Chapter 7: “Discussion: How Do You Discuss the Risks and Benefits of Fecal Microbiota Transplantation?”).
The majority of patients with rCDI will be cured after a single FMT following SOC C. difficile antibiotics.

If I have a fecal microbiota transplantation, does this mean I will never get Clostridioides difficile infection again?

Unfortunately, you cannot guarantee your patient will never get CDI again. FMT is used to reduce the risk of subsequent CDI episodes and break the cycle of recurrence they are currently in.
There is always the possibility of CDI in the future, especially in the setting of systemic antibiotic use. CDI patients who undergo an FMT and have no recurrence at 8 weeks post-intervention have an approximately 10% chance of having another CDI episode, and this risk is mainly derived from future courses of antibiotics. Patients who have systemic antibiotic exposure after FMT but prior to week 8 have an approximately 3-fold risk of CDI recurrence compared with those who do not receive antibiotics.

Do I have to provide my own donor?

We recommend you follow institutional best practices regarding procuring material from a patient-selected or universal donor. Most commonly, health care facilities use the universal donor approach, leveraging banked material either from an external stool bank or from a hospital-based stool bank. Patient-selected donors who complete the same screening procedures can be used, although there can be operational challenges. In some rare clinical situations, patient-selected donors may be the recommended donor strategy (see Chapter 6: “Donor: How Do You Select and Screen Candidate Donors for Fecal Microbiota Transplantation?”).

How long do I have to retain the material after the fecal microbiota transplantation?

Retention of material after lower gastrointestinal (GI) administration (eg, colonoscopy, flexible sigmoidoscopy, enema) can often be difficult, especially in older patients with poor baseline sphincter control. There are limited data to suggest that longer retention leads to better outcomes.
We recommend the patients retain the material while they are in the procedure recovery unit. However, if this is not possible, it is important to counsel patients that it is not an issue if they are unable to retain and it is not likely to impact the results. Given that the material is often infused into the right colon or cecum, the first material the patients will pass is likely their own residual stool and bowel preparation because no suctioning is done on the withdrawal of the endoscope.
It is reasonable to have patients use the restroom before they leave the endoscopy unit, especially for those with long commutes.
It is recommended to offer patients an absorbent pad/undergarment to ensure no leakage on the way home.
The administration of loperamide prior to the FMT can be considered to assist with retention; however, there are no data to suggest this will improve outcomes, and most experts do not use loperamide.

When will I know if the fecal microbiota transplantation worked?

Most patients will describe feeling better within 24 hours of the FMT procedure.
It is common for patients not to have any bowel movements for the first few days post-FMT. This may lead to concern in some patients, so we recommend counseling about this post-FMT constipation phenomenon.
Clinical cure is generally defined as an absence of CDI through week 8. Approximately 86% of patients who experience a CDI recurrence will do so by week 4, and the mean time to CDI recurrence is approximately 14 days after FMT. Accordingly, you can often provide reassurance to your patients that there is a high likelihood of clinical cure if they have not experienced a CDI recurrence by week 4 post-FMT.

Am going to taste or smell poop?

No! This is a common misconception. Patients who undergo an FMT via colonoscopy will eventually pass the material that is indistinguishable from their own stool. Anecdotally, patients have reported noticing a different odor to their gas post-FMT.
Capsule formulations are frozen and have no odor or taste when swallowed. Newer microbiome therapeutic formulations are lyophilized or freeze-dried capsules that are shelf-stable, have no odor or taste, and eliminate any indication that the material was derived from human stool.

Am I going to get fat?

There has been a single high-publicity case report of weight gain after FMT from a donor who is overweight. Importantly, a large cohort study (N = 173) refuted the case report’s finding and suggested that a stool donor’s body mass index did not affect a recipient’s weight after a single FMT for CDI. Regardless, out of an abundance of caution, donors must be normal weight, and therefore it is unlikely for patients who receive FMT to become obese.
It is important to counsel patient about healthy weight gain post-FMT. Most patients lose weight during their CDI course; therefore, a healthy weight regain is expected. This has been shown to not exceed their pre-CDI baseline.

Would you recommend at-home fecal microbiota transplantation?

No. Using unscreened material at home via a do-it-yourself (DIY) FMT can be dangerous and may lead to transmission of an infection or a microbiome-mediated condition. We would always recommend consultation with a physician and the use of well-screened donor material that is compliant with manufacturing and quality best practices.
Additionally, many patients interested in DIY FMT are using them to treat diseases other than CDI, and this is not recommended.

Can I do fecal microbiota transplantation if I don’t have Clostridioides difficile infection?

FMT is currently only recommended for patients with recurrent or refractory CDI following SOC antibiotics for CDI (see Chapter 4: “Decision: Which Patients with Clostridioides difficile Infection Are Appropriate for Fecal Microbiota Transplantation?”).
There are many ongoing clinical trials exploring the use of FMT for other indications. If patients are interested, refer them to www.clinicaltrials.gov or an equivalent trial website to look for clinical trials in your area (see Chapter 10 “Discovery: Emerging Indications”).

I don’t want to take antibiotics. Can I start with fecal microbiota transplantation to treat my Clostridioides difficile infection?

FMT is only recommended for recurrent or refractory CDI following SOC antibiotics for CDI (see Chapter 4: “Decision: Which Patients With Clostridioides difficile Infection Are Appropriate for Fecal Microbiota Transplantation?”).
At this time, FMT is not indicated for a first episode of CDI or primary CDI. We would recommend counseling your patients that approximately 80% of patients will have a clinical cure without further recurrence with an initial treatment course of antibiotics.

Do I need to be on a special diet after my fecal microbiota transplantation?

No. There are no data to suggest that a specific diet will improve the efficacy the FMT or improve engraftment profiles. The most important consideration post-FMT is limiting the use of unnecessary systemic antibiotics.

Can the transplant reject?

This procedure, although referred to as a transplant, does not carry the same requirements for organ matching that is conducted in solid organ transplantation (SOT), and traditional immunological rejection is not a concern.
Engraftment is used to determine whether the FMT took. Engraftment generally means that microbes were absent in the patient pre-FMT, found in the donor, and detected in the patient after FMT.
Engraftment is not used in clinical practice. Instead, clinical cure is used to determine the success of FMT among patients with CDI.

Provider FAQs: Common Questions From Clinicians Considering Performing a Fecal Microbiota Transplantation or Referring a Patient for a Fecal Microbiota Transplantation

Should patients be banking their own stool for later use?

Currently, this process is generally not done in clinical practice. However, there has been preliminary proof-of-concept work in self-banking, and there may be future utility to a process similar to that of banking cord blood.

Is it safe to do colonoscopy in patients with Clostridioides difficile infection?

Yes! This procedure is meant to be performed for the prevention of CDI recurrence. Accordingly, patients will be on SOC C. difficile antibiotics, followed by an FMT. The colons of rCDI patients are generally not inflamed and usually appear endoscopically normal on luminal visualization.
Procedurally, no special considerations are required during FMT; however, you may consider using carbon dioxide instead of oxygen for insufflation because there will be minimal or no suctioning upon the withdrawal of the endoscope.
Standard infection control measures should be implemented in the endoscopy unit

Is bowel preparation required prior to fecal microbiota transplantation?

Although there is speculation on the role of bowel preparation on decreasing residual C. difficile spores in the colon and/or removing residual C. difficile antibiotics (eg, vancomycin), there are limited data on the use of standard bowel preparation prior to FMT regardless of delivery modality.
Bowel preparation is recommended prior to FMT via colonoscopy for luminal visualization and ruling out colonic pathology that may mimic clinical CDI (eg, microscopic colitis, ulcerative colitis, Crohn’s disease).
Generally, bowel preparation is not administered prior to upper GI administration (eg, nasogastric tube [NGT]) or FMT capsules.

How do I refer a patient for a fecal microbiota transplantation if I’m not comfortable doing it myself?

Stool banks often have a provider list of health care facilities they supply.

National gastroenterology or infectious disease medical societies may also have clinician contacts for FMT or ongoing national FMT registries. For example, the American Gastroenterological Association has sponsored the US FMT Registry, and a list of all participating sites appears on www.clinicaltrials.gov

If the fecal microbiota transplantation doesn’t work, what should I do next?

In the context of suspected FMT failure, it is important to confirm that the diagnosis of rCDI and to rule out mimics such as post-infection irritable bowel syndrome with C. difficile colonization (see Chapter 4: “Decision: Which Patients With Clostridioides difficile Infection Are Appropriate for Fecal Microbiota Transplantation?”).
Clinically, there are several factors that increase the risk for FMT failure. These include severe or fulminant CDI at the time of FMT, the presence of pseudomembranes, ongoing use of systemic antibiotics post-FMT, and certain comorbidities or immunocompromised states, including SOT and inflammatory bowel disease (IBD). Counseling patients about the risk of FMT failure must be done during the informed consent process (see Chapter 7: “Discussion: How Do You Discuss the Risks and Benefits of Fecal Microbiota Transplantation?”).
There are generally 3 categories of FMT failure:
1. Primary nonresponse: This is defined as ongoing diarrhea with laboratory-confirmed C. difficile testing immediately after or within 7 days of the FMT. The patient never experiences sustained relief. In this case, it is appropriate to start an abbreviated course of SOC C. difficile antibiotics and bring the patient back quickly for a repeat FMT (typically 1 week later).
2. Secondary nonresponse: This is defined as a patient who experiences resolution of his or her diarrhea after FMT; however, the diarrhea returns with laboratory-confirmed C. difficile testing between 1 and 8 weeks after the FMT. Early secondary nonresponse is between weeks 1 and 4, and late secondary nonresponse is between weeks 4 and 8. It is important to confirm CDI recurrence with a 2-stage testing algorithm (see Chapter 4: “Decision: Which Patients With Clostridioides difficile Infection Are Appropriate for Fecal Microbiota Transplantation?”). If CDI recurrence is confirmed, it is appropriate to repeat FMT. It is appropriate to restart vancomycin for a minimum of 4 days to help improve symptoms and reduce colonic inflammation prior to FMT, although longer courses are also reasonable.
3. Reinfection: If the patient experiences a CDI recurrence after 8 weeks post-FMT, this should be considered a new primary CDI episode. Repeat FMT does not need to be performed, and treatment with SOC C. difficile antibiotics is appropriate.
Overall, data suggest that FMT failure rates are higher with nasoenteric administration and enema. Therefore, if your patients experience FMT failure after FMT, you should consider administration with colonoscopy or high-efficacy FMT capsules.
Some experts suggest FMT administration into both the jejunum and colon by combined push enteroscopy and colonoscopy for patients with multiple confirmed FMT failures.

Should I test my patient for cure after the fecal microbiota transplantation? What test should I be using?

No, testing for cure post-FMT is not required. In the absence of CDI symptoms, repeat C. difficile laboratory testing to assess to confirm cure or to assess for ongoing colonization is not needed. In fact, > 95% of patients will be decolonized after a successful FMT.
Should persistent diarrhea (Bristol stool score [BSS] 6-7) return and there is clinical suspicion for CDI, laboratory testing should be done to confirm CDI recurrence. If testing is negative in the setting of diarrhea, alternative diagnoses should be explored (see Chapter 9: “Discharge: How Should You Follow and Care for Patients After Fecal Microbiota Transplantation?”).

Does a patient have to fail a vancomycin taper in order to qualify for a fecal microbiota transplantation?

No. Indication for FMT is determined by the number of confirmed episodes of CDI or disease severity, not by prior treatment courses (see Chapter 4: “Decision: Which Patients With Clostridioides difficile Infection Are Appropriate for Fecal Microbiota Transplantation?”).

Is it safe to do biopsies or take out polyps during fecal microbiota transplantation?

Yes. If there is any concern about potential other causes of the patient’s diarrhea that need to be explored (eg, microscopic colitis or IBD), obtaining random or targeted biopsies at the time of FMT is appropriate.
Most experts believe that removing polyps is generally safe at the time of FMT.
It is important to counsel patients that FMT via colonoscopy does not count as a standard screening colonoscopy. Visualization of the lumen is obscured upon the withdrawal of the scope due to administration of the donor material. If you feel that a screening colonoscopy must be done at the time of FMT, you will need to perform a full colonoscopy with appropriate withdrawal and inspection and then reenter the colon to deliver the material, preferably in the cecum. If this is not possible or you do not feel comfortable, the patient should come back at a later date to have a full screening colonoscopy.

How fast do you infuse the fecal microbiota transplantation material?

In endoscopic administration (eg, upper endoscopy, colonoscopy, flexible sigmoidoscopy), there is no preferred speed of infusion. The material can either be drawn up into 60-cc syringes and manually pushed through the biopsy cap, similar to a water flush, or the bottle can be hooked up to the water foot pedal and pumped through the endoscope.

In enema administration, the 250 mL of material can be transferred to an enema bag and infused over 1 hour to patients in the left lateral decubitus position. Patients should attempt retention of the material for 1 hour, although there is a paucity of data on the timing. Preferably, patients should be asked to periodically rotate 180 degrees to the right side and back to help distribute the material throughout the colon. However, if the patient has mobility issues, the rotation step may be omitted from the procedure.

In NGT administration, patients should be positioned upright during administration. Smaller-volume material is used in the upper GI tract (see Chapter 8: “Delivery: How Do You Select the Most Appropriate Delivery Modality for Fecal Microbiota Transplantation?”). Material can be infused over 2 to 3 minutes. Once complete, the NGT can be removed 30 minutes after the infusion is complete, and patients should remain upright to reduce risk of aspiration. Patients should be observed post-procedure for between 30 minutes and 2 hours to ensure no aspiration-related adverse events.

For fulminant Clostridioides difficile infection patients, is it safe to do a flexible sigmoidoscopy at the bedside? Am I going to cause a perforation?

Unlike patients with rCDI, fulminant CDI patients will have acutely inflamed colons. However, gentle flexible sigmoidoscopy by a skilled endoscopist can still be safely performed. The aim is to assess the colon for pseudomembranes and deliver the material to the most proximal part of the colon that can be reached safely. Carbon dioxide is highly recommended in these patients to minimize distention, and light insufflation should be employed.

An upper endoscope can be used for the procedure; gentle insertion and direct visualization is recommended.

Enema administration in this population has been considered. A drawback to enema administration in fulminant CDI patients is the lack of direct visualization to assess for pseudomembranes, which is often needed for sequential FMT protocols (see Chapter 10.1.2: “The Role of Fecal Microbiota Transplantation in the Treatment of Severe and Fulminant Clostridioides difficile Infection”). Additionally, lower efficacy has been reported with enema in fulminant patients. If performing multiple flexible sigmoidoscopies is not feasible, you can consider administering of the first FMT via flexible sigmoidoscopy and subsequent FMTs via enema.

How does fecal microbiota transplantation work?

The mechanism of FMT for the prevention of rCDI has not been fully elucidated; however, there are 2 primary hypotheses linked to the restoration of the gut microbiome. First, patients with rCDI have a lower microbiome diversity than healthy individuals or those with primary CDI. A high-diversity environment restored by FMT is thought to provide colonization resistance and prevent C. difficile from colonizing and subsequently producing toxin. Second, patients with rCDI have a decrease in secondary bile acids compared with healthy individuals or those with primary CDI. This is thought to be due to disruption of the healthy gut microbiome, which impacts bile acid ratios (primary vs secondary bile acids). Secondary bile acids prevent C. difficile spores from transforming into an active vegetative state capable of producing toxin. FMT helps restore a healthy gut microbiome, and in turn restore a healthy bile acid profile.

Do you have to match donors?

This procedure, although referred to as a transplant, does not carry the same requirements for matching that is done in SOT.
We do not currently match donors and recipient based on age, gender, or other immune factors, such as human leukocyte antigen matching.
In fact, the efficacy of FMT for the prevention of CDI recurrence is so high, there are no specific donor factors that have been found that directly correlate with higher efficacy rates. This includes microbiome profiles, donor diet, donor short-chain fatty acid profiles, BSS of donation, and donor stool processing time.

Are we still calling this fecal microbiota transplantation?

This therapy has several names, including fecal microbiota transplantation, stool transplant, stool transfer, fecal transplant, intestinal microbiota transplant or transfer, and intestinal microbiome restoration, among others. These all refer to the same therapeutic intervention.
Fecal microbiota transplantation, or FMT, is currently the most commonly used term. However, many clinicians feel that it is not patient-centric and that having the term fecal or stool in the title is not appropriate because the engraftment of intestinal microbiota is the critical component of this procedure. Therefore, intestinal microbiota transfer may be more appropriate.

Is there any role for fecal microbiota transplantation in oncology?

Graft vs host disease (GvHD) in the gut: There are emerging data on the role of the microbiome in hematology-oncology patients who have undergone stem cell transplantations. An international study of 1362 patients undergoing allogeneic hematopoietic cell transplantation demonstrated that these patients were characterized by a loss of microbiome diversity and that high diversity was associated with a lower risk of death.1 Clinician-scientists have also specifically applied FMT to increase microbiome diversity for GI GvHD, with encouraging preliminary results. A systematic review and meta-analysis of 37 GvHD patients who underwent FMT reported a 74% response rate with a well-tolerated safety profile.² Well-designed controlled studies are required, but microbiome diagnostics and therapeutics may have a role in the future care of hematology-oncology patients.
Combination therapy with immune checkpoint inhibitors (ICIs): Immunotherapy has revolutionized oncology care; however, programmed cell death protein 1/programmed death-ligand 1 and cytotoxic T-lymphocyte–associated protein 4 inhibitors are not effective in all patients. Landmark preclinical data suggest that the gut microbiome plays a key critical role in the efficacy of immunotherapies for cancer.³ Accordingly, there are ongoing studies that are assessing the role of FMT in combination with ICI in a number of different cancer types, as well as ICI nonresponders.
ICI colitis: ICI colitis is a common immune-related adverse event associated with ICIs used in oncology. Typically, it occurs after weeks after the second or third dose, and, endoscopically and histologically, the presentation is nearly identical to IBD. Recent reports suggest that FMT may have a role in steroid-refractory cases by reconstituting the microbiome and increasing the proportion of regulatory T-cells in the colonic mucosa.⁴ Further research is needed, but FMT remains a promising option for ICI colitis.

References

1. Peled JU, Gomes ALC, Devlin SM, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl J Med. 2020;382:822-834.

2. Tariq R, Furqan F, Pardi D, Khanna S. Efficacy of fecal microbiota transplantation for acute graft versus host disease in the gut: a systematic review and meta-analysis. Am J Gastroenterol. 2019;114:S123.

3. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018;359:91-97.

4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808.

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