From Crap to Cure: The Story of Fecal Transplants
Meg Newman, who suffered from C. difficile, underwent a fecal transplant that helped restore her to health.
C. difficile had Meg Newman's number; it had struck her 18 different times beginning in 1985. The bacterial infection takes over the gut bringing explosive diarrhea, dehydration, weight loss, and at its worst depletes blood platelets. It causes nearly 30,000 deaths each year in the U.S. alone.
"I was one sick puppy as that point and literally three days after the transplant I was doing pretty well, day four even better."
Meg knew these statistics not just from personal experience but also because she was a doctor at San Francisco General Hospital. Antibiotics had sometimes helped to treat the infection, but it never quite seemed to go away. Now, "It felt like part of my colon was sort of sliding off as I had the bowel movement." On her worst day she counted 33 bowel movements. It was 2005 and she knew she was at the end of her rope.
Medical training had taught Meg to look at the data. So when antibiotics failed, she searched the literature for other options. One was a seemingly off-the-wall treatment called fecal transplants, which essentially gives poop from a healthy person to one who is sick.
Its roots stretch back to "yellow soup" used to treat dysentery in China nearly two thousand years ago, in which ancient Chinese treaters would combine stool with liquid, mash it up, and administer it. The approach also is commonly used in veterinary medicine today. However, there were only about three papers on its use in humans in the medical literature at that time, she recalls. Still, the logic of the intervention appealed to her.
The gut microbiome as a concept and even a word were not widely known fifteen years ago. But the idea that the microbial community in her gut was in disarray, and a transplant of organisms from a healthy gut might help restore a more normal ecology made sense. And besides, the failure of standard medicine left her few options.
Meg spoke with a colleague, gastroenterologist Neil Stollman, about a possible fecal microbial transplant (FMT). Only a handful of doctors in the U.S. had ever done the procedure; Stollman had tried it just once before. After conversation with Newman, he agreed to do it.
They decided on Meg's partner Sherry as the donor. "I try very hard to use intimate sexual partners as the donor," explains Stollman. The reason is to reduce disease risk: "The logic there is pretty straightforward. If you have unprotected sex with this individual, in a monogamous way for a period of time, you have assumed pretty much any infectious risk," like hepatitis, HIV, and syphilis, he says. Other donors would be screened using the same criteria used to screen blood donations, plus screening for parasites that can live in stool but not blood.
The procedure
Martini aficionados fall into two camps, fans of shaken or stirred. In the early days the options for producing of fecal transplants were a blender or hand shaken. Stollman took the hands-on approach, mixing Sherry's fecal donation with saline to create "a milkshake in essence." He filtered it several times through gauze to get out the lumps.
Then he inserted a colonoscope, a long flexible tube, through the anus into Meg's colon. Generally a camera goes through the tube to look for polyps and cancers, while other tools can snip off polyps and retrieve tissue samples. Today he used it to insert the fecal "milkshake" as high up the colon as he could go. Imodium and bed rest were the final pieces. It works about 90 percent of the time today.
Meg went home with fingers crossed. "And within about two weeks things just slowed down; the diarrhea just stopped. I felt better so my appetite was better." The tide had turned, though it would take months to slowly repair the toll taken on her body from disease and antibiotics.
Then in 2011 another serious medical challenge required heavy use of antibiotics and Meg's C. difficile came roaring back; she needed a second FMT. Sherry had a bad sinus infection and had been on antibiotics, so that ruled her out as a donor. Red, Meg's godson, volunteered. He was twenty-one and had little or no exposure to antibiotics, which can harm friendly bacteria living in the gut.
"I was one sick puppy as that point," Meg recalls, "and literally three days after the transplant [from Red] I was doing pretty well, day four even better. It was unbelievable." It illustrated that donors are not the same, and that while an intimate partner may be the safest option, it also may not be the most efficacious donation in terms of providing missing parts of the microbial ecosystem.
Going mainstream
By then, FMTs were starting to come out of the shadows as more than just a medical oddity. One gigantic milestone in changing perceptions was a Dutch study on using the procedure to treat C. difficile that was published in January 2013 in the New England Journal of Medicine. "That was the first trial where people said, look this isn't voodoo. This wasn't made up; it really worked," says Colleen Kelly, another pioneer in using FMTs to treat C. difficile and a researcher at Brown University. A single dose was successful more than 80 percent of the time in resolving disease in patients who had failed multiple regimens of antibiotics.
Charlatans pounced on the growing interest in the microbiome, promoting FMT as a cure for all sorts of ailments for which there was no scientific evidence. The FDA stepped in, announcing it would regulate the procedure as a drug, and essentially banned use of FMTs until it wrote regulations. But the outcry from physicians and patients was so great it was forced to retreat and has allowed continued use in treating C. difficile albeit on an interim regulatory basis that has continued since 2013.
Another major change was the emergence of stool banks, modeled on blood banks. The most widely know is OpenBiome, established in 2012 as a nonprofit by young researchers at Harvard and MIT. It aimed to standardize donation of stool and screening for disease, and package them in frozen form for colonoscopic delivery, or pill form. It greatly simplified the process and more doctors became willing to use FMTs to treat C. difficile. Today, some gastroenterologists specialize in administering the transplants as a feature of their practice.
To be sure, there have been some setbacks, including a transplant between family members where the recipient became obese, likely in part because of bacteria in the material she received. The same thing has occurred in studies in mice. And last year, an elderly man died from a toxic strain of E. coli that was in material provided by a stool bank. That caused the FDA to add that pathogen to the list of those one must screen for in products designed for use as fecal transplants.
Cost remains an issue. OpenBiome charges $1500-$2000 per transplant dose, depending on whether a frozen or pill form of the product is used. And that is likely to go up as the FDA increases the number of diseases that must be screened for, such as the virus that causes COVID-19, which is present in feces and likely can be transmitted through feces. Most insurance companies do not cover FMTs because no product has been formally approved for use by the FDA.
One of the greatest treatment challenges is making the correct diagnosis, says physician Robin Patel, who initially treated patients at the Mayo Clinic in Rochester, Minnesota but now spends most of her time there developing new diagnostics. Many things can cause diarrhea and the simple presence of the organism does not mean that C. difficile is causing it. In addition, many people are colonized with the bug but never develop symptoms of the disease.
Patel used the expensive tool of whole genome sequencing to look in great detail at C. difficile in patients who were treated with antibiotics for the infection and had recurrent diarrhea. "Some of them, as you might predict, were getting their symptoms with the same exact strain [of C. difficile] but others were not, it was a different strain," suggesting that they had been reinfected.
If it is a different strain, you might want to try antibiotics, she says, but if the same strain is present, then you might want to try a different approach such as FMT. Whole genome sequencing is still too slow and expensive to use in regularly treating patients today, but Patel hopes to develop a rapid, cost-effective test to help doctors make those types of decisions.
Biotech companies are trying to develop alternatives to poop as a source for transplant to treat C. difficile. They are picking and choosing different bacteria that they can grow and then combine into a product, to varying degrees of success, but none have yet crossed the finish line of FDA approval.
"I think [the future of FMTs] is going to be targeted, even custom-made."
The FDA would like such a product because it is used to dealing with small molecule drugs that are standardized and produced in batches. Companies are pursing it because, as Kelly says, they are like sharks "smelling money in the water." Approval of such a product might cause the FDA to shut down existing stool banks that now exist in a regulatory limbo, leaving the company with a monopoly of exclusive rights to the treatment.
Back when Meg received her first fecal transplant, the procedure was so obscure that the guidelines for treating C. difficile put out by the American College of Gastroenterology didn't even mention FMT. The procedure crept into the 2013 revision of those guidelines as a treatment of last resort. Guidance under review for release later this year or early next year will ease use further but stop short of making it a first option.
Stollman imagines a future holy grail in treating C. difficile: "You give me a stool specimen and I run it through a scanner that tells me you have too much of this and too little of that. I have a sense of what normal [microbial composition of the gut] should be and add some of this and subtract some of that. Maybe I even give you some antibiotics to get rid of some of the bad guys, give you some probiotics. I think it is going to be targeted, even custom-made."
His complete vision for treating C. difficile won't arrive tomorrow, but given how rapidly FMTs have become part of medicine, it is likely to arrive in pieces and more quickly than one might think.
About five years ago Meg discovered she had an antibody deficiency that contributed to her health problems, including vulnerability to C. difficile. She began supplementation with immunoglobulin and "that has made a huge difference in my health. It is just unbelievable how much better I am." She is grateful that fecal transplants gave her the time to figure that out. She believes "there's every reason to consider it [FMT] as a first-line treatment and do the studies, ASAP."
Urinary tract infections account for more than 8 million trips to the doctor each year.
Few things are more painful than a urinary tract infection (UTI). Common in men and women, these infections account for more than 8 million trips to the doctor each year and can cause an array of uncomfortable symptoms, from a burning feeling during urination to fever, vomiting, and chills. For an unlucky few, UTIs can be chronic—meaning that, despite treatment, they just keep coming back.
But new research, presented at the European Association of Urology (EAU) Congress in Paris this week, brings some hope to people who suffer from UTIs.
Clinicians from the Royal Berkshire Hospital presented the results of a long-term, nine-year clinical trial where 89 men and women who suffered from recurrent UTIs were given an oral vaccine called MV140, designed to prevent the infections. Every day for three months, the participants were given two sprays of the vaccine (flavored to taste like pineapple) and then followed over the course of nine years. Clinicians analyzed medical records and asked the study participants about symptoms to check whether any experienced UTIs or had any adverse reactions from taking the vaccine.
The results showed that across nine years, 48 of the participants (about 54%) remained completely infection-free. On average, the study participants remained infection free for 54.7 months—four and a half years.
“While we need to be pragmatic, this vaccine is a potential breakthrough in preventing UTIs and could offer a safe and effective alternative to conventional treatments,” said Gernot Bonita, Professor of Urology at the Alta Bro Medical Centre for Urology in Switzerland, who is also the EAU Chairman of Guidelines on Urological Infections.
The news comes as a relief not only for people who suffer chronic UTIs, but also to doctors who have seen an uptick in antibiotic-resistant UTIs in the past several years. Because UTIs usually require antibiotics, patients run the risk of developing a resistance to the antibiotics, making infections more difficult to treat. A preventative vaccine could mean less infections, less antibiotics, and less drug resistance overall.
“Many of our participants told us that having the vaccine restored their quality of life,” said Dr. Bob Yang, Consultant Urologist at the Royal Berkshire NHS Foundation Trust, who helped lead the research. “While we’re yet to look at the effect of this vaccine in different patient groups, this follow-up data suggests it could be a game-changer for UTI prevention if it’s offered widely, reducing the need for antibiotic treatments.”
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
A surgeon at Massachusetts General Hospital prepares a pig organ for transplant.
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.