From Crap to Cure: The Story of Fecal Transplants
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."
Some hospitals are pioneers in ditching plastic, turning green
This is part 2 of a three part series on a new generation of doctors leading the charge to make the health care industry more sustainable - for the benefit of their patients and the planet. Read part 1 here and part 3 here.
After graduating from her studies as an engineer, Nora Stroetzel ticked off the top item on her bucket list and traveled the world for a year. She loved remote places like the Indonesian rain forest she reached only by hiking for several days on foot, mountain villages in the Himalayas, and diving at reefs that were only accessible by local fishing boats.
“But no matter how far from civilization I ventured, one thing was already there: plastic,” Stroetzel says. “Plastic that would stay there for centuries, on 12,000 foot peaks and on beaches several hundred miles from the nearest city.” She saw “wild orangutans that could be lured by rustling plastic and hermit crabs that used plastic lids as dwellings instead of shells.”
While traveling she started volunteering for beach cleanups and helped build a recycling station in Indonesia. But the pivotal moment for her came after she returned to her hometown Kiel in Germany. “At the dentist, they gave me a plastic cup to rinse my mouth. I used it for maybe ten seconds before it was tossed out,” Stroetzel says. “That made me really angry.”
She decided to research alternatives for plastic in the medical sector and learned that cups could be reused and easily disinfected. All dentists routinely disinfect their tools anyway and, Stroetzel reasoned, it wouldn’t be too hard to extend that practice to cups.
It's a good example for how often plastic is used unnecessarily in medical practice, she says. The health care sector is the fifth biggest source of pollution and trash in industrialized countries. In the U.S., hospitals generate an estimated 6,000 tons of waste per day, including an average of 400 grams of plastic per patient per day, and this sector produces 8.5 percent of greenhouse gas emissions nationwide.
“Sustainable alternatives exist,” Stroetzel says, “but you have to painstakingly look for them; they are often not offered by the big manufacturers, and all of this takes way too much time [that] medical staff simply does not have during their hectic days.”
When Stroetzel spoke with medical staff in Germany, she found they were often frustrated by all of this waste, especially as they took care to avoid single-use plastic at home. Doctors in other countries share this frustration. In a recent poll, nine out of ten doctors in Germany said they’re aware of the urgency to find sustainable solutions in the health industry but don’t know how to achieve this goal.
After a year of researching more sustainable alternatives, Stroetzel founded a social enterprise startup called POP, short for Practice Without Plastic, together with IT expert Nicolai Niethe, to offer well-researched solutions. “Sustainable alternatives exist,” she says, “but you have to painstakingly look for them; they are often not offered by the big manufacturers, and all of this takes way too much time [that] medical staff simply does not have during their hectic days.”
In addition to reusable dentist cups, other good options for the heath care sector include washable N95 face masks and gloves made from nitrile, which waste less water and energy in their production. But Stroetzel admits that truly making a medical facility more sustainable is a complex task. “This includes negotiating with manufacturers who often package medical materials in double and triple layers of extra plastic.”
While initiatives such as Stroetzel’s provide much needed information, other experts reason that a wholesale rethinking of healthcare is needed. Voluntary action won’t be enough, and government should set the right example. Kari Nadeau, a Stanford physician who has spent 30 years researching the effects of environmental pollution on the immune system, and Kenneth Kizer, the former undersecretary for health in the U.S. Department of Veterans Affairs, wrote in JAMA last year that the medical industry and federal agencies that provide health care should be required to measure and make public their carbon footprints. “Government health systems do not disclose these data (and very rarely do private health care organizations), unlike more than 90% of the Standard & Poor’s top 500 companies and many nongovernment entities," they explained. "This could constitute a substantial step toward better equipping health professionals to confront climate change and other planetary health problems.”
Compared to the U.K., the U.S. healthcare industry lags behind in terms of measuring and managing its carbon footprint, and hospitals are the second highest energy user of any sector in the U.S.
Kizer and Nadeau look to the U.K. National Health Service (NHS), which created a Sustainable Development Unit in 2008 and began that year to conduct assessments of the NHS’s carbon footprint. The NHS also identified its biggest culprits: Of the 2019 footprint, with emissions totaling 25 megatons of carbon dioxide equivalent, 62 percent came from the supply chain, 24 percent from the direct delivery of care, 10 percent from staff commute and patient and visitor travel, and 4 percent from private health and care services commissioned by the NHS. From 1990 to 2019, the NHS has reduced its emission of carbon dioxide equivalents by 26 percent, mostly due to the switch to renewable energy for heat and power. Meanwhile, the NHS has encouraged health clinics in the U.K. to install wind generators or photovoltaics that convert light to electricity -- relatively quick ways to decarbonize buildings in the health sector.
Compared to the U.K., the U.S. healthcare industry lags behind in terms of measuring and managing its carbon footprint, and hospitals are the second highest energy user of any sector in the U.S. “We are already seeing patients with symptoms from climate change, such as worsened respiratory symptoms from increased wildfires and poor air quality in California,” write Thomas B. Newman, a pediatrist at the University of California, San Francisco, and UCSF clinical research coordinator Daisy Valdivieso. “Because of the enormous health threat posed by climate change, health professionals should mobilize support for climate mitigation and adaptation efforts.” They believe “the most direct place to start is to approach the low-lying fruit: reducing healthcare waste and overuse.”
In addition to resulting in waste, the plastic in hospitals ultimately harms patients, who may be even more vulnerable to the effects due to their health conditions. Microplastics have been detected in most humans, and on average, a human ingests five grams of microplastic per week. Newman and Valdivieso refer to the American Board of Internal Medicine's Choosing Wisely program as one of many initiatives that identify and publicize options for “safely doing less” as a strategy to reduce unnecessary healthcare practices, and in turn, reduce cost, resource use, and ultimately reduce medical harm.
A few U.S. clinics are pioneers in transitioning to clean energy sources. In Wisconsin, the nonprofit Gundersen Health network became the first hospital to cut its reliance on petroleum by switching to locally produced green energy in 2015, and it saved $1.2 million per year in the process. Kaiser Permanente eliminated its 800,000 ton carbon footprint through energy efficiency and purchasing carbon offsets, reaching a balance between carbon emissions and removing carbon from the atmosphere in 2020, the first U.S. health system to do so.
Cleveland Clinic has pledged to join Kaiser in becoming carbon neutral by 2027. Realizing that 80 percent of its 2008 carbon emissions came from electricity consumption, the Clinic started switching to renewable energy and installing solar panels, and it has invested in researching recyclable products and packaging. The Clinic’s sustainability report outlines several strategies for producing less waste, such as reusing cases for sterilizing instruments, cutting back on materials that can’t be recycled, and putting pressure on vendors to reduce product packaging.
The Charité Berlin, Europe’s biggest university hospital, has also announced its goal to become carbon neutral. Its sustainability managers have begun to identify the biggest carbon culprits in its operations. “We’ve already reduced CO2 emissions by 21 percent since 2016,” says Simon Batt-Nauerz, the director of infrastructure and sustainability.
The hospital still emits 100,000 tons of CO2 every year, as much as a city with 10,000 residents, but it’s making progress through ride share and bicycle programs for its staff of 20,000 employees, who can get their bikes repaired for free in one of the Charité-operated bike workshops. Another program targets doctors’ and nurses’ scrubs, which cause more than 200 tons of CO2 during manufacturing and cleaning. The staff is currently testing lighter, more sustainable scrubs made from recycled cellulose that is grown regionally and requires 80 percent less land use and 30 percent less water.
The Charité hospital in Berlin still emits 100,000 tons of CO2 every year, but it’s making progress through ride share and bicycle programs for its staff of 20,000 employees.
Wiebke Peitz | Specific to Charité
Anesthesiologist Susanne Koch spearheads sustainability efforts in anesthesiology at the Charité. She says that up to a third of hospital waste comes from surgery rooms. To reduce medical waste, she recommends what she calls the 5 Rs: Reduce, Reuse, Recycle, Rethink, Research. “In medicine, people don’t question the use of plastic because of safety concerns,” she says. “Nobody wants to be sued because something is reused. However, it is possible to reduce plastic and other materials safely.”
For instance, she says, typical surgery kits are single-use and contain more supplies than are actually needed, and the entire kit is routinely thrown out after the surgery. “Up to 20 percent of materials in a surgery room aren’t used but will be discarded,” Koch says. One solution could be smaller kits, she explains, and another would be to recycle the plastic. Another example is breathing tubes. “When they became scarce during the pandemic, studies showed that they can be used seven days instead of 24 hours without increased bacteria load when we change the filters regularly,” Koch says, and wonders, “What else can we reuse?”
In the Netherlands, TU Delft researchers Tim Horeman and Bart van Straten designed a method to melt down the blue polypropylene wrapping paper that keeps medical instruments sterile, so that the material can be turned it into new medical devices. Currently, more than a million kilos of the blue paper are used in Dutch hospitals every year. A growing number of Dutch hospitals are adopting this approach.
Another common practice that’s ripe for improvement is the use of a certain plastic, called PVC, in hospital equipment such as blood bags, tubes and masks. Because of its toxic components, PVC is almost never recycled in the U.S., but University of Michigan researchers Danielle Fagnani and Anne McNeil have discovered a chemical process that can break it down into material that could be incorporated back into production. This could be a step toward a circular economy “that accounts for resource inputs and emissions throughout a product’s life cycle, including extraction of raw materials, manufacturing, transport, use and reuse, and disposal,” as medical experts have proposed. “It’s a failure of humanity to have created these amazing materials which have improved our lives in many ways, but at the same time to be so shortsighted that we didn’t think about what to do with the waste,” McNeil said in a press release.
Susanne Koch puts it more succinctly: “What’s the point if we save patients while killing the planet?”
The Friday Five: A surprising health benefit for people who have kids
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
Here are the promising studies covered in this week's Friday Five:
- Kids stressing you out? They could be protecting your health.
- A new device unlocks the heart's secrets
- Super-ager gene transplants
- Surgeons could 3D print your organs before operations
- A skull cap looks into the brain like an fMRI