Q&A with Dr. Alexander Khoruts, Director of the Microbiota Therapeutics Program, UMN
OpenDialog May 2026 – Issue Two
Patient outcomes may depend on science that’s moving faster than any of us can track. OpenBiome Foundation’s monthly newsletter cuts through the noise – delivering focused conversations in Q&A format with leading researchers and clinicians on the microbiome discoveries most relevant to your practice. No jargon, no fluff. Just the insights worth your time.
This second edition features an innovative leader in microbiome discoveries and for C. difficile and its treatments. He is Dr. Alexander Khoruts, Director of the Microbiota Therapeutics Program, UMN.
Q&A
Dr. Khoruts is the Director of the Microbiota Therapeutics Program. His group has made several seminal contributions to the development of FMT, including the first demonstration of engraftment of donor microbiota in a patient (Khoruts et al., J Clin Gastroenterol, 2010) and the first description of standardized preparation of purified and cryopreserved microbiota (Hamilton et al., Am J Gastroenterol, 2012). Dr. Khoruts holds IND 15071, which details the donor program and manufacturing of several FMT formulations. UMN Microbiota Therapeutics Program manufactures all FMT products in a GMP facility in accordance with the FDA approved protocols. The Program was a partner with OpenBiome between 2022 and 2024 as the manufacturer of FMT products. It continues with the OpenBiome Foundation to rally the FDA to reinstate enforcement discretion for FMT for severe/fulminant C. diff patients.
Q: What motivated you to focus on C. diff in your research and practice, and expand your therapeutic efforts from patient care to a manufacturer of FMT products?
A: “Chance favors the prepared mind,” Scientist Louis Pasteur, 1854
This quote captures how I came to focus on C. difficile and microbiome therapeutics. Trained as a physician–scientist—a gastroenterologist and an immunologist—I was drawn to Jeffrey Gordon’s pioneering work showing the gut microbiome as a newly recognized human organ within my field of specialty. I was convinced that I was witnessing the discovery of a new organ in the human body – the gut microbiome.
While searching for a way to enter this emerging field, I encountered a patient with recurrent C. difficile infection who failed months of antibiotics. Inspired by early reports of fecal bacteriotherapy, I partnered with microbial ecologist Michael Sadowsky to analyze donor and patient samples before and after treatment.
Using the patient’s husband as a donor, we showed for the first time that donor microbes could engraft and restore a healthy microbiome, a result that made international news in in 2010, helping to define the modern concept of fecal microbiota transplantation (FMT).
As cases grew and the need for scalable therapy became more urgent, my team developed standardized, cryopreserved microbial preparations, published our protocols in 2012, and launched the University of Minnesota Microbiota Therapeutics program. We continue to provide treatments to patients suffering from C. diff infections and to develop the next- generation formulations that target the gut microbiome for various indications.
Q: For clinicians who don’t specialize in CDI, can you walk us through some of the most difficult scenarios that providers may encounter in treating CDI?
A: The first challenge is the diagnosis. C. difficile colonization is associate with the extent of healthcare burden. Mere colonization does not cause symptoms. However, treatment of C. difficile colonization with antibiotics markedly increases the risk of progression to symptomatic infection. An early placebo-controlled randomized clinical trial comparing vancomycin and metronidazole in attempts to eradicate asymptomatic C. difficile carriage (Johnson et al., Ann Intern Med, 1992) found neither antibiotic to be effective. However, antibiotic treatment increased C. difficile carriage relative to the placebo. Multiple recent studies have since demonstrated that antibiotics can facilitate the progression of C. difficile colonization to infection.
Diagnosis of C. difficile infection requires both laboratory evidence and clinical judgment. First, the diagnosis of C. difficile infection should only be considered in patients thought to have underlying gut dysbiosis with increased diarrheal symptoms. The most common cause of ‘dysbiosis’ is treatment with antibiotics. If someone presents with chronic IBS-D symptoms without recent antibiotics and worsening of their symptoms, the pre-test probability of C. difficile infection is very low. The best laboratory practice is a 2-step testing protocol. The first step is a highly sensitive step, typically a PCR test for C. difficile toxin B gene. If positive, it indicates the presence of toxigenic C. difficile bacteria. However, the presence of a gene does not mean it is being expressed. Therefore, the second test is an EIA test for the actual toxin. Hospitals that have adopted a two-step protocol have seen a ~50% drop in the rate of C. difficile infection diagnosis compared with using PCR alone. Of course, there are caveats. The EIA test may be false negative, especially if the sample sits outside too long before testing. Also, a positive EIA test does not automatically equate with infection. There may be certain mechanisms, e.g., anti-toxin antibodies that neutralize toxins. For example, high levels of anti-toxin antibodies protect patients with cystic fibrosis from symptomatic C. difficile infection despite extraordinarily high C. difficile carriage rates (~50%). Bottom line, accurate diagnosis also requires taking careful patient history and considering pre-test probability.
An especially difficult diagnostic challenge is often encountered in patients with underlying inflammatory bowel diseases. These patients have an increased healthcare burden and consequently higher rates of C. difficile colonization. They may also have significant dysbiosis driven by the underlying disease, even in the absence of antibiotic exposure. Patients with IBD should be tested for C. difficile when they present with a flare. However, PCR+/toxin- patients are much less likely to respond to antibiotic treatment and more likely to respond to optimization of their immunosuppressive regimens (Gupta et al., Dig Dis Sci, 2021).
In addition to diagnostic challenges, the two major therapeutic challenges associated with C. difficile remain recurrent infections and severe/fulminant disease. Restorative microbiome therapies have a role in both conditions, although the two problems are quite distinct.
Q: Why do some patients develop severe/fulminant disease and what’s actually at stake for them? Related to this question, what are some of the common clinical missteps you see in management of patients with fulminant C. diff?
A: Severe/fulminant C. difficile infection is characterized by systemic inflammation. At the extreme end of the spectrum, which is fulminant disease, the clinical presentation is characterized by shock, end-organ compromise, and toxic megacolon. This is potentially a highly lethal condition, and this form of the infection is a major driver of C. difficile-associated mortality.
It is common that before it is appreciated that the patient has severe/fulminant form of the disease, there is a delay in making a diagnosis of C. difficile infection or therapeutic steps are taken that accelerate its progression. For example, a patient may believe that they are having a transient upset stomach and do not seek timely medical care. Once they arrive to the Emergency Department, they look septic, and they are given broad-spectrum antibiotics. They are commonly also given opioid medications to control abdominal pain. In the meantime, the broad-spectrum antibiotics may not be discontinued as the physicians search for the ‘cause of sepsis’; in fact, they may find bacteria in the urine or an infiltrate on a chest X-ray, but these are typically not the prime offenders. It is the colon that is driving the patient’s deteriorating state. Timely diagnosis and appropriate treatment can be a matter of life and death.
It is important to appreciate that C. difficile bacteria do not go systemic. The sepsis-like state is driven by microbial products that are entering the circulation because the gut barrier is damaged by C. difficile toxins in the colon. Antibiotics against C. difficile bacteria, vancomycin and fidaxomicin, do work. Once these anti-C. difficile antibiotics are given, the toxin production stops. However, if the colon lining has already been severely damaged, the systemic inflammation will continue. Additional antibiotics may only increase the burden of microbes that drive inflammation because the microbes that are best at evading antibiotics are best at invading the host. Opioid medications will slow down the diarrhea and increase the burden of hostile microbes in the colon.
Bottom line, C. difficile infection is potentially a very serious complication of antibiotic therapies. Ideally, it is promptly recognized, and steps are taken to minimize its progression to a severe form.
Q: Why do C. diff therapies fail to address the high unmet need in severe/fulminant C. diff specifically? Is there a role for microbiome therapeutics in this condition?
A: Remarkably, many researchers do not recognize that the challenge in severe/fulminant C. difficile infection is not a failure to kill C. difficile bacteria. Providers are generally surprised that C. difficile quickly becomes undetectable in stool of patients with severe/fulminant C. difficile infection once they are started on anti-C. difficile antibiotics. The clinical presentation is driven by leakage of non-C. difficile microbial products from the colon into circulation, and the goal of therapy should be to mitigate this leakage.
C. difficile infections can be prevented if the native colon microbiota can be spared during antibiotic treatments. However, as long as we use the antibiotics that we have for various infections, we can expect C. difficile infections as a complication. Once the patient has a C. difficile infection, it is likely that their gut microbiome has been depleted and a highly specific anti-C. difficile treatment, e.g., phage therapy, is not obviously going to make a huge difference at this point.
However, there is absolutely a role for microbiome therapeutics in severe/fulminant C. difficile infection. In fact, this was the original indication described by Ben Eiseman and colleagues (Eiseman et al., Surgery, 1958). His team successfully used fecal enemas to treat patients with post-antibiotic enterocolitis, not yet recognized at the time as C. difficile infection. Back then the predicted mortality for this complication was 75%. Sadly, today’s standard therapies with all the intensive and surgical care that we have are not that much better, and 30-day mortality of fulminant C. difficile infection can be as high as 50%. We and others have since also published remarkably rapid improvements in case series of the sickest patients who were no longer considered surgical candidates.
Importantly, the FMT protocols for treatment of severe/fulminant C. difficile infection are different from prevention of C. difficile infection recurrence. The latter is generally done on an outpatient basis, when the colon is fully healed, and the goal is merely to repopulate a severely depleted microbiota. The initial purpose of FMT in treatment of severe/fulminant C. difficile infection is reduction in systemic inflammation. Infusion of donor microbiota does achieve a rapid response. We just published our latest series of patients with severe/fulminant C. difficile infections (majority were fulminant), where we documented rapid reduction in the levels of C-reactive protein and WBC counts following colonoscopic infusion of standardized, high dose FMT preparations (Khoruts et al., Clin Gastroenterol Hepatol, 2026). These changes were accompanied by improvements in hemodynamics and seemed as remarkable as the patients vividly described by Dr. Eiseman. The mechanism of FMT in these situations requires further investigations. It is possible that infusion of healthy donor microbiota decreases the burden of gut microbes prone to translocation. It is also possible that the donor microbiota delivers a direct anti-inflammatory signal. It is clear, however, that C. difficile bacteria are not the target of FMT during treatment of severe/fulminant infection.
Q: What are the practical barriers, whether financial, institutional, or logistical for patients with severe/fulminant C. diff to receive microbiome-based therapies?
A: Once the patient develops severe/fulminant C. difficile infection, progression to a surgical emergency can be very fast. It is critical that the provider has ready access to FMT material. This is the case at our center because our program manufactures standardized FMT preparations, which we always have on site in our cryobank. Unfortunately, this is not the case in most hospitals, and access to such material via a stool bank is no longer possible, as the FDA updated its enforcement discretion policy to limit distribution of stool bank material to IND protocols only. Commercially available microbiota-based therapeutics are not yet proven here. There is no mechanistic reason why the fecal spore preparation (live-brpk, Vowst) should be effective since the clinical benefits cannot wait for spore germination and expansion of donor bacteria. It is possible that live-jslm (Rebyota) could be helpful; however, it is not approved for this indication, it may not be dosed appropriately, and obtaining the product in a timely manner can be a problem.
Of course, provider awareness about FMT as a potentially colon- and/or life-saving option for patients with severe/fulminant C. difficile infection is also a barrier. This is even the case at our center, where we have been frustrated over the years by being consulted late in the course of the disease. Over the past year, we have set up an early alert system within six participating hospitals, academic and community-based. Our team is notified by our electronic medical record system about inpatients with positive C. difficile tests and clinical indicators predictive of severe/fulminant disease (ATLAS score ≥ 4). After reviewing the cases, we offer our recommendations to the primary teams.
Q: Are there any protocol differences in how one may use FMT or FDA-approved microbiome therapies as a treatment of severe/fulminant C. diff?
A: First, as already noted, there is no reason to expect the fecal microbial spore preparation (live-brpk, Vowst) to be effective. Rebyota may be an option if it is readily available. However, it has not been approved for severe/fulminant C. difficile infection or formulated in an appropriate dose.
We view several stages in the use of FMT as a treatment for severe/fulminant C. difficile infection. In our current protocol (Khoruts et al., Clin Gastroenterol Hepatol, 2026), we first stop all antibiotics and administer 2 liters of a polyethylene glycol-based purgative to wash out the antibiotics and allow colonoscopic FMT. The objective of this ‘induction FMT’ is to reduce systemic inflammation. We use a high dose preparation, standardized for the number of bacteria. The CRP and WBC counts can be tracked daily to measure response. We generally see a reduction in these indicators over 24 hours, and the decline continues over the next 3 days. We restart the antibiotics on day 4 after induction FMT. If the response is insufficient, the induction FMT can be repeated. This protocol is very similar to the one published by Dr. Monica Fischer (Fischer et al., Gut Microbes, 2017), although her antibiotic-free periods were shorter, and we rely more on systemic markers of inflammation to aid clinical decisions.
Importantly, the full treatment ultimately requires a consolidation FMT to prevent further recurrence. Severe/fulminant C. difficile infection is a major risk factor for recurrence, and all patients recovering from this disease should be considered high-risk for recurrence. We typically perform our consolidation FMT using oral capsules manufactured in our program. However, it is likely that commercial products (Vowst or Rebyota) can also be used to punctuate the antibiotic treatment course at this stage.
Tools & Resources
Our mission: Expand patient access to microbiome therapies and drive scientific discoveries that shape the future of health. We build partnerships, fund innovation, and share open-access tools, so that the impact of microbiome science lives on, long after our mission is complete.
