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."
Questions remain about new drug for hot flashes
In May, a new drug, Fezolinetant, was approved by the FDA to treat hot flashes associated with menopause.
Vascomotor symptoms (VMS) is the medical term for hot flashes associated with menopause. You are going to hear a lot more about it because a company has a new drug to sell. Here is what you need to know.
Menopause marks the end of a woman’s reproductive capacity. Normal hormonal production associated with that monthly cycle becomes erratic and finally ceases. For some women the transition can be relatively brief with only modest symptoms, while for others the body's “thermostat” in the brain is disrupted and they experience hot flashes and other symptoms that can disrupt daily activity. Lifestyle modification and drugs such as hormone therapy can provide some relief, but women at risk for cancer are advised not to use them and other women choose not to do so.
Fezolinetant, sold by Astellas Pharma Inc. under the product name Veozah™, was approved by the Food and Drug Administration (FDA) on May 12 to treat hot flashes associated with menopause. It is the first in a new class of drugs called neurokinin 3 receptor antagonists, which block specific neurons in the brain “thermostat” that trigger VMS. It does not appear to affect other symptoms of menopause. As with many drugs targeting a brain cell receptor, it must be taken continuously for a few days to build up a good therapeutic response, rather than working as a rescue product such as an asthma inhaler to immediately treat that condition.
Hot flashes vary greatly and naturally get better or resolve completely with time. That contributes to a placebo effect and makes it more difficult to judge the outcome of any intervention. Early this year, a meta analysis of 17 studies of drug trials for hot flashes found an unusually large placebo response in those types of studies; the placebo groups had an average of 5.44 fewer hot flashes and a 36 percent reduction in their severity.
In studies of fezolinetant, the drug recently approved by the FDA, the placebo benefit was strong and persistent. The drug group bested the placebo response to a statistically significant degree but, “If people have gone from 11 hot flashes a day to eight or seven in the placebo group and down to a couple fewer ones in the drug groups, how meaningful is that? Having six hot flashes a day is still pretty unpleasant,” says Diana Zuckerman, president of the National Center for Health Research (NCHR), a health oriented think tank.
“Is a reduction compared to placebo of 2-3 hot flashes per day, in a population of women experiencing 10-11 moderate to severe hot flashes daily, enough relief to be clinically meaningful?” Andrea LaCroix asked a commentary published in Nature Medicine. She is an epidemiologist at the University of California San Diego and a leader of the MsFlash network that has conducted a handful of NIH-funded studies on menopause.
Questions Remain
LaCroix and others have raised questions about how Astellas, the company that makes the new drug, handled missing data from patients who dropped out of the clinical trials. “The lack of detailed information about important parameters such as adherence and missing data raises concerns that the reported benefits of fezolinetant very likely overestimate those that will be observed in clinical practice," LaCroix wrote.
In response to this concern, Anna Criddle, director of global portfolio communications at Astellas, wrote in an email to Leaps.org: “…a full analysis of data, including adherence data and any impact of missing data, was submitted for assessment by [the FDA].”
The company ran the studies at more than 300 sites around the world. Curiously, none appear to have been at academic medical centers, which are known for higher quality research. Zuckerman says, "When somebody is paid to do a study, if they want to get paid to do another study by the same company, they will try to make sure that the results are the results that the company wants.”
Criddle said that Astellas picked the sites “that would allow us to reach a diverse population of women, including race and ethnicity.”
A trial of a lower dose of the drug was conducted in Asia. In March 2022, Astellas issued a press release saying it had failed to prove effectiveness. No further data has been released. Astellas still plans to submit the data, according to Criddle. Results from clinical trials funded by the U.S. goverment must be reported on clinicaltrials.gov within one year of the study's completion - a deadline that, in this case, has expired.
The measurement scale for hot flashes used in the studies, mild-moderate-severe, also came in for criticism. “It is really not good scale, there probably isn’t a broad enough range of things going on or descriptors,” says David Rind. He is chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit authority on new drugs. It conducted a thorough review and analysis of fezolinestant using then existing data gathered from conference abstracts, posters and presentations and included a public stakeholder meeting in December. A 252-page report was published in January, finding “considerable uncertainty about the comparative net health benefits of fezolinetant” versus hormone therapy.
Questions surrounding some of these issues might have been answered if the FDA had chosen to hold a public advisory committee meeting on fezolinetant, which it regularly does for first in class medicines. But the agency decided such a meeting was unnecessary.
Cost
There was little surprise when Astellas announced a list price for fezolinetant of $550 a month ($6000 annually) and a program of patient assistance to ease out of pocket expenses. The company had already incurred large expenses.
In 2017 Astellas purchased the company that originally developed fezolinetant for $534 million plus several hundred million in potential royalties. The drug company ran a "disease awareness” ad, Heat on the Street, hat aired during the Super Bowl in February, where 30 second ads cost about $7 million. Industry analysts have projected sales to be $1.9 billion by 2028.
ICER’s pre-approval evaluation said fezolinetant might "be considered cost-effective if priced around $2,000 annually. ... [It]will depend upon its price and whether it is considered an alternative to MHT [menopause hormone treatment] for all women or whether it will primarily be used by women who cannot or will not take MHT."
Criddle wrote that Astellas set the price based on the novelty of the science, the quality of evidence for the drug and its uniqueness compared to the rest of the market. She noted that an individual’s payment will depend on how much their insurance company decides to cover. “[W]e expect insurance coverage to increase over the course of the year and to achieve widespread coverage in the U.S. over time.”
Leaps.org wrote to and followed up with nine of the largest health insurers/providers asking basic questions about their coverage of fezolinetant. Only two responded. Jennifer Martin, the deputy chief consultant for pharmacy benefits management at the Department of Veterans Affairs, said the agency “covers all drugs from the date that they are launched.” Decisions on whether it will be included in the drug formulary and what if any copays might be required are under review.
“[Fezolinetant] will go through our standard P&T Committee [patient and treatment] review process in the next few months, including a review of available efficacy data, safety data, clinical practice guidelines, and comparison with other agents used for vasomotor symptoms of menopause," said Phil Blando, executive director of corporate communications for CVS Health.
Other insurers likely are going through a similar process to decide issues such as limiting coverage to women who are advised not to use hormones, how much copay will be required, and whether women will be required to first try other options or obtain approvals before getting a prescription.
Rind wants to see a few years of use before he prescribes fezolinetant broadly, and believes most doctors share his view. Nor will they be eager to fill out the additional paperwork required for women to participate in the Astellas patient assistance program, he added.
Safety
Astellas is marketing its drug by pointing out risks of hormone therapy, such as a recent paper in The BMJ, which noted that women who took hormones for even a short period of time had a 24 percent increased risk of dementia. While the percentage was scary, the combined number of women both on and off hormones who developed dementia was small. And it is unclear whether hormones are causing dementia or if more severe hot flashes are a marker for higher risk of developing dementia. This information is emerging only after 80 years of hundreds of millions of women using hormones.
In contrast, the label for fezolinetant prohibits “concomitant use with CYP1A2 inhibitors” and requires testing for liver and kidney function prior to initiating the drug and every three months thereafter. There is no human or animal data on use in a geriatric population, defined as 65 or older, a group that is likely to use the drug. Only a few thousand women have ever taken fezolinetant and most have used it for just a few months.
Options
A woman seeking relief from symptoms of menopause would like to see how fezolintant compares with other available treatment options. But Astellas did not conduct such a study and Andrea LaCroix says it is unlikely that anyone ever will.
ICER has come the closest, with a side-by-side analysis of evidence-based treatments and found that fezolinetant performed quite similarly and modestly as the others in providing relief from hot flashes. Some treatments also help with other symptoms of menopause, which fezolinetant does not.
There are many coping strategies that women can adopt to deal with hot flashes; one of the most common is dressing in layers (such as a sleeveless blouse with a sweater) that can be added or subtracted as conditions require. Avoiding caffeine, hot liquids, and spicy foods is another common strategy. “I stopped drinking hot caffeinated drinks…for several years, and you get out of the habit of drinking them,” says Zuckerman.
LaCroix curates those options at My Meno Plan, which includes a search function where you can enter your symptoms and identify which treatments might work best for you. It also links to published research papers. She says the goal is to empower women with information to make informed decisions about menopause.
A company in England has made a test that picks out the compounds from breath that reveal if people have liver disease.
Every year, around two million people worldwide die of liver disease. While some people inherit the disease, it’s most commonly caused by hepatitis, obesity and alcoholism. These underlying conditions kill liver cells, causing scar tissue to form until eventually the liver cannot function properly. Since 1979, deaths due to liver disease have increased by 400 percent.
The sooner the disease is detected, the more effective treatment can be. But once symptoms appear, the liver is already damaged. Around 50 percent of cases are diagnosed only after the disease has reached the final stages, when treatment is largely ineffective.
To address this problem, Owlstone Medical, a biotech company in England, has developed a breath test that can detect liver disease earlier than conventional approaches. Human breath contains volatile organic compounds (VOCs) that change in the first stages of liver disease. Owlstone’s breath test can reliably collect, store and detect VOCs, while picking out the specific compounds that reveal liver disease.
“There’s a need to screen more broadly for people with early-stage liver disease,” says Owlstone’s CEO Billy Boyle. “Equally important is having a test that's non-invasive, cost effective and can be deployed in a primary care setting.”
The standard tool for detection is a biopsy. It is invasive and expensive, making it impractical to use for people who aren't yet symptomatic. Meanwhile, blood tests are less invasive, but they can be inaccurate and can’t discriminate between different stages of the disease.
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
The team is testing patients in the early stages of advanced liver disease, or cirrhosis, to identify and detect these biomarkers. In an initial study, Owlstone’s breathalyzer was able to pick out patients who had early cirrhosis with 83 percent sensitivity.
Boyle’s work is personally motivated. His wife died of colorectal cancer after she was diagnosed with a progressed form of the disease. “That was a big impetus for me to see if this technology could work in early detection,” he says. “As a company, Owlstone is interested in early detection across a range of diseases because we think that's a way to save lives and a way to save costs.”
How it works
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
Study participants breathe into a mouthpiece attached to a breath sampler developed by Owlstone. It has cartridges are designed and optimized to collect gases. The sampler specifically targets VOCs, extracting them from atmospheric gases in breath, to ensure that even low levels of these compounds are captured.
The sampler can store compounds stably before they are assessed through a method called mass spectrometry, in which compounds are converted into charged atoms, before electromagnetic fields filter and identify even the tiniest amounts of charged atoms according to their weight and charge.
The top four compounds in our breath
In an initial study, Owlstone captured VOCs in breath to see which ones could help them tell the difference between people with and without liver disease. They tested the breath of 46 patients with liver disease - most of them in the earlier stages of cirrhosis - and 42 healthy people. Using this data, they were able to create a diagnostic model. Individually, compounds like 2-Pentanone and limonene performed well as markers for liver disease. Owlstone achieved even better performance by examining the levels of the top four compounds together, distinguishing between liver disease cases and controls with 95 percent accuracy.
“It was a good proof of principle since it looks like there are breath biomarkers that can discriminate between diseases,” Boyle says. “That was a bit of a stepping stone for us to say, taking those identified, let’s try and dose with specific concentrations of probes. It's part of building the evidence and steering the clinical trials to get to liver disease sensitivity.”
Sabine Szunerits, a professor of chemistry in Institute of Electronics at the University of Lille, sees the potential of Owlstone’s technology.
“Breath analysis is showing real promise as a clinical diagnostic tool,” says Szunerits, who has no ties with the company. “Owlstone Medical’s technology is extremely effective in collecting small volatile organic biomarkers in the breath. In combination with pattern recognition it can give an answer on liver disease severity. I see it as a very promising way to give patients novel chances to be cured.”
Improving the breath sampling process
Challenges remain. With more than one thousand VOCs found in the breath, it can be difficult to identify markers for liver disease that are consistent across many patients.
Julian Gardner is a professor of electrical engineering at Warwick University who researches electronic sensing devices. “Everyone’s breath has different levels of VOCs and different ones according to gender, diet, age etc,” Gardner says. “It is indeed very challenging to selectively detect the biomarkers in the breath for liver disease.”
So Owlstone is putting chemicals in the body that they know interact differently with patients with liver disease, and then using the breath sampler to measure these specific VOCs. The chemicals they administer are called Exogenous Volatile Organic Compound) probes, or EVOCs.
Most recently, they used limonene as an EVOC probe, testing 29 patients with early cirrhosis and 29 controls. They gave the limonene to subjects at specific doses to measure how its concentrations change in breath. The aim was to try and see what was happening in their livers.
“They are proposing to use drugs to enhance the signal as they are concerned about the sensitivity and selectivity of their method,” Gardner says. “The approach of EVOC probes is probably necessary as you can then eliminate the person-to-person variation that will be considerable in the soup of VOCs in our breath.”
Through these probes, Owlstone could identify patients with liver disease with 83 percent sensitivity. By targeting what they knew was a disease mechanism, they were able to amplify the signal. The company is starting a larger clinical trial, and the plan is to eventually use a panel of EVOC probes to make sure they can see diverging VOCs more clearly.
“I think the approach of using probes to amplify the VOC signal will ultimately increase the specificity of any VOC breath tests, and improve their practical usability,” says Roger Yazbek, who leads the South Australian Breath Analysis Research (SABAR) laboratory in Flinders University. “Whilst the findings are interesting, it still is only a small cohort of patients in one location.”
The future of breath diagnosis
Owlstone wants to partner with pharmaceutical companies looking to learn if their drugs have an effect on liver disease. They’ve also developed a microchip, a miniaturized version of mass spectrometry instruments, that can be used with the breathalyzer. It is less sensitive but will enable faster detection.
Boyle says the company's mission is for their tests to save 100,000 lives. "There are lots of risks and lots of challenges. I think there's an opportunity to really establish breath as a new diagnostic class.”