How Poop Transplants Battle Multidrug-Resistant Bacteria

In hospital settings, multidrug-resistant organisms (MDRO) are a major threat to patient safety. MDRO are microbes, like bacteria, that have become evolutionarily battle-hardened, developing traits that enable them to shrug off most conventional antimicrobial interventions. Vulnerable patients infected with MDROs are at increased risk of serious illness.

A new study has taken a different approach to eradicating MDROs. They’ve developed a method that fights microbes with other microbes. The paper is published in Science Translational Medicine.

The risk of MDROs

Michael Woodworth, an infectious disease physician and an assistant professor of medicine at Emory University School of Medicine, has made it his mission to find ways to overcome the spread of MDROs. In the new work, Woodworth – the study’s first author – worked with a group of patients at huge risk from MDROs – kidney transplant patients.

“Kidney transplant patients have a lot of experience with the health care system, and they’ve had a lot of surgery,” says Woodworth in an interview with Technology Networks. “They're all committed to get long courses of antibiotics after getting their organ transplant.” All these factors increase the risk of exposure to MDROs.

While antibiotics are intended to kill harmful bacteria, long use of these drugs can have the opposite effect. By wiping out more vulnerable bacteria, over a long period of time, antibiotics create a biological niche that can be filled by a growing population of colonizing MDROs. Even worse for these patients, the last-line antibiotics used to tame a growing MDRO population can cause kidney damage. “They have more to lose if they get one of these infections,” says Woodworth.

Woodworth doesn’t develop potent antibiotics or other antimicrobial agents but instead leverages a substance usually kept to a minimum in sterile clinical settings: human feces.

The power of poo

Fecal microbiota transplants (FMT) are a far cry from the toilet bowl. These are highly regulated and thoroughly screened medical products, where donors are chosen to minimize the risk of any transmittable infection and go through similar tests to potential blood donors.

FMTs are usually administered during a colonoscopy. Woodworth’s trial, PREMIX, based its approach on previous successful interventions for patients with recurring Clostridium difficile (C. difficile)infection. A single donor provided the FMT for 11 kidney transplant patients studied in the small trial, all of whom had struggled with MDRO colonization since their operations. Colonization, says Woodworth, is an intermediate step on the road to a full bacterial infection. By stamping out MDRO at this stage, physicians can prevent their patients from becoming ill and infectious to others.

Half of the cohort in the trial received an FMT at the start of the study, while the other half were asked to undergo a 36-day observation period beforehand. At the end of this waiting period, none of the patients in this latter group had become decolonized, while four of the FMT group had become MDRO-free.

All of the patients in the trial were offered up to two FMTs. At the end of this treatment, nine patients fully completed the FMT protocol. Eight were free of MDRO. The whole cohort was then compared to a control group, made up of other patients in the hospital system who would have qualified for the trial, but were unable or unwilling to enroll.

In the six months after receiving an FMT, patients were far more likely to stay MDRO-free than those who didn’t receive one. “This provides some evidence that FMT may not only reduce colonization but may also reduce infections in these patients that are treated,” sums up Woodworth.

The new study is not the first to leverage FMT to decolonize the gut. But research up until now has been unable to explain exactly how FMT helps. Woodworth and his colleagues believe they have identified a potential mechanism.

Competition can help the gut

Some patients in the trial had lived for a long period with a single MDRO in their bodies. After FMT, the researchers noted that the MDRO had been joined by another strain of bacteria from the same species. But this new strain was a naïve rookie in comparison to the veteran MDRO – it wasn’t resistant to conventional antimicrobials.

Over time, to the team’s surprise, the “weaker” strain actually outcompeted the MDRO, replacing it in the gut. “It looked like there was some potential competition going on where the resistant strain was more strongly detected beforehand,” said Woodworth. The researchers confirmed these findings by plating both strains together in a dish. Once again, the non-MDRO organism held its own, putting up a fight against the resistant strain, rather than being overwhelmed. Strangely, the new competitor didn’t come from the donor, but in one case was seen to be present in the recipient’s gut prior to FMT. “Something about the FMT appears to be more favorable for selecting for a more susceptible strain,” says Woodworth.

Woodworth suggests the findings have opened the door for further research. He highlights that larger studies will be needed to confirm their findings. One key takeaway, he says, is that microbiota research might need to move away from focusing just on MDRO bacteria: “Antibiotic resistance is such a strong feature that is so often selected for in our patients. It’s such a prominent focus in many of these studies. But what we're seeing is that it's important to look at the more antibiotic-susceptible strains to better understand what are the features that can make it more fit for them to become dominant.”

Reference: Woodworth MH, Conrad RE, Haldopoulos M et al. Fecal microbiota transplantation promotes reduction of antimicrobial resistance by strain replacement. Sci Trans Med. 2023; 15: eabo2750. doi: 10.1126/scitranslmed.abo2750.