Additional research may lead to precision medicine FMT treatments for patients with specific cancers
Research continues to show that the human gut microbiome plays a significant role in a person’s health and longevity. One recent example is a clinical trial study conducted by scientists at MD Anderson Cancer Center in Houston which demonstrated that fecal microbiota transplants (FMTs) can help in the eradication of some cancers.
If approved for clinical treatment of cancer, the use of FMT may increase the demand for diagnostic tests to verify that the approach worked in a patient.
Our guts are home to trillions of microorganisms (aka, microbiota), known as the gut microbiome, which serve many important functions in the body. The microbiome is a delicate ecosystem that can be pushed out of balance when unfavorable microbes outnumber advantageous ones.
An FMT is an uncomplicated and powerful method of repopulating the microbiome with beneficial microbes. The researchers at MD Anderson administered FMTs from donors with advanced cancers that had been completely cured by immunotherapy into the guts of patients whose cancers were not improving.
“[Early reports] demonstrate that gut microbiota is contributing to immunotherapy resistance in at least some patients and provide hope that by changing the microbiome, some will respond,” Jonathan Jacobs, MD, PhD, a gastroenterologist at the Fielding School of Public Health at the University of California, Los Angeles (UCLA), told NBC News. Jacobs was not involved in the MD Anderson research.
“These early reports of patients who were previously immunotherapy-resistant but experienced clinical response after receiving FMT [fecal transplants] and immunotherapy retreatment are very exciting,” said Jonathan Jacobs, MD, PhD (above), a gastroenterologist at the Fielding School of Public Health at the University of California, Los Angeles, in an interview with NBC News. (Photo copyright: UCLA.)
‘Miraculous’ Treatment for Cancer
Fecal microbiota transplant is a procedure where stool from a healthy donor is transplanted into the microbiome of a patient plagued by a certain medical condition. The procedure has been used as a standard treatment for recurrent Clostridioides difficile for years and is currently being studied as a potential cure for illnesses such as Parkinson’s disease, autism, obesity, and inflammatory bowel disease.
The premise of the MD Anderson clinical trial study was that gut bacteria from the now cancer-free individuals may assist the immune systems of the current patients to recognize and fight their cancers. The scientists focused their efforts on PD-1 immune checkpoint inhibitors that help keep white blood cell lymphocytes (T cells) from attacking other cells in the body.
PD-1 inhibitors are especially effective in treating tumors known as microsatellite instability-high cancer tumors. This type of tumor has an unusually large numbers of DNA mutations. PD-1 inhibitors help pinpoint these mutations and attack the cancerous tumors.
“They’re miraculous drugs,” Timothy Yeatman, MD, PhD, associate director of translational research at the Tampa General Hospital Cancer Institute, told NBC News. “They’ve been able to cure people with no chemotherapy, no radiotherapy, or no surgery.”
Yeatman also said that some patients “experience improvements that are barely believable: people with mere months to live who are then cured of their disease. In medical parlance, this is referred to as a complete response.”
FMT Treatment Brings Fast Results
Yinghong Wang, MD, PhD, a gastroenterology specialist and professor in the department of gastroenterology, hepatology and nutrition at MD Anderson, said in a news release that positive results for cancer patients undergoing the FMT treatment can appear expeditiously.
“The quickest response can be seen within 24 hours. Patients have reported having much better energy and appetite the next day. Some say they feel like a new person,” she said. “Usually, though, I’d recommend giving it at least a week. If two weeks pass by without any discernable benefit, it probably wasn’t effective.”
According to Wang, FMTs can be delivered by several methods that fall into two categories:
Lower GI tract: The colonoscopy method is used very frequently since it allows more thorough coverage of the colon’s interior walls and reduces the chance of leakage after the procedure. However, liquid donor stool can also be delivered via enema.
Upper GI tract: These include frozen or freeze-dried capsules that can be swallowed, as well as liquids that can be placed directly in the GI tract via a feeding tube or upper endoscopy procedure.
This ongoing pilot study at MD Anderson could aid in the advancement of using the gut microbiome to help the immune system fight all sorts of diseases.
Future Developments of FMT Research
MD Anderson has partnered with biotechnology startup Kanvas Biosciences, which developed a technology known as HiPR-FISH (high-phylogenetic-resolution microbiome mapping by fluorescence in situ hybridization) to examine the relationships between gut bacteria and the immune system. This tool enables scientists to identify key microbial strains and place those strains in a pill that MD Anderson will use in further research to determine if PD-1 inhibitors can help the immune system on a larger scale.
“We have essentially made a synthetic version of the superdonor stool and then optimized and immortalized it so that it can be reproduced and used in the treatment of cancer patients worldwide,” Matthew Cheng, MD, a trained medical microbiologist and co-founder and CEO of Kanvas, told NBC News.
More research and clinical trials are needed before fecal microbiota transplants can be used on a mainstream basis in the treatment of cancer. However, the MD Anderson research is promising in foreseeing the possibility that cancer patients who do not respond well to immunotherapy may have better luck through a personalized medicine approach geared to specific patients.
As such, the research is of interest to pathologists who want to learn more about the potential role of the human microbiome in precision medicine and clinical laboratory testing.
“It’s possible that even better outcomes could be obtained with a more precise understanding of the recipient’s microbiome, genetics, type of cancer, and antitumor immune responses, to select the optimal combinations,” said Jacobs in the NBC News interview.
Is it possible that there is a connection between an individual’s gut microbiota and the ability to fight off gastrointestinal (GI) cancer? Findings from a preliminary research study performed by researchers in South Korea suggest that a link between the two may exist and that fecal microbiota transplants (FMTs) may enhance the efficacy of immunotherapies for GI cancer patients.
The proof-of-concept clinical trial, conducted at the Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea, analyzed how an FMT could help 13 patients with metastatic solid tumors that were resistant to the anti-PD-1 antibody drug known as nivolumab (Opdivo). Anti-PD-1 drugs are immunotherapies that help treat cancer by improving an individual’s immune response against cancer cells.
Four of the trial participants had gastric cancer, five had esophageal cancer, and the remaining four had hepatocellular carcinoma. The patients were given a colonoscopy to implant the FMTs. The recipients also received antibiotics to reduce the response of their existing microbiotas.
The FMT donors also had gastric cancer, esophageal cancer, or hepatocellular carcinoma. Prior to donating their fecal matter, the donors experienced complete or partial response to the anti-PD-1 drugs nivolumab or pembrolizumab (Keytruda) for at least six months after receiving initial treatments.
“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” co-senior study author Hansoo Park, MD, PhD, Assistant Professor, Biomedical Science and Engineering, Gwangju Institute of Science and Technology, told The ASCO Post. “While the connection between gut microbiota and immune response to cancer therapy has been a growing area of interest, our study provides concrete evidence and new avenues for improving treatment outcomes in a broader range of cancers,” he added. Further studies may confirm the need for microbiome testing by clinical laboratories to guide clinicians treating patients with colon cancers. (Photo copyright: Gwangju Institute of Science and Technology.)
Surprising Results
Fecal material for an FMT procedure combines donated fecal matter with a sterile saline solution which is then filtered to produce a liquid solution. That solution is then administered to the recipient via colonoscopy, upper GI endoscopy, enema, or an oral capsule. The solution may also be frozen for later use.
Upon analyzing the recipients, the scientists found that six of the patients (46.2%) who had experienced resistance to immunotherapies for their cancers, benefitted from the FMTs.
“Both donors were long-lasting, good responders to anti-PD-1 inhibitors, but because we did not yet know the causative bacteria responsible for the [FMT] response, we could not predict whether the treatment would be effective,” she added.
The researchers also determined that the presence of a bacterial strain known as Prevotella merdae helped to improve the effectiveness of the FMTs, while two strains of bacteria—Lactobacillus salivarius and Bacteroides plebeius (aka, Phocaeicola plebeius)—had a detrimental impact on the transplants.
Challenges to Widespread Adoption of FMTs
The researchers acknowledge there are challenges in widespread acceptance and use of FMTs in treating cancers but remain optimistic about the possibilities.
“Developing efficient and cost-effective methods for production and distribution is necessary for widespread adoption,” Sook Ryun Park told The ASCO Post. “Addressing these challenges through comprehensive research and careful planning will be essential for integrating FMT into the standard of care for cancer treatment.”
More research and clinical trials are needed before this use of FMTs can be utilized in clinical settings. However, the study does demonstrate that the potential benefits of FMTs may improve outcomes in patients with certain cancers. As this happens, microbiologists may gain a new role in analyzing the microbiomes of patients with gastrointestinal cancers.
“By examining the complex interactions within the microbiome, we hope to identify optimal microbial communities that can be used to enhance cancer treatment outcomes,” Hansoo Park told The ASCO Post. “This comprehensive approach will help us understand how the microbial ecosystem as a whole contributes to therapeutic success.”
Clinical laboratory scientists and microbiologists could play a role in helping doctors explain to patients the potential dangers of do-it-yourself medical treatments
Be careful what you wish for when you perform do-it-yourself (DIY) medical treatments. That’s the lesson learned by a woman who was seeking relief for irritable bowel syndrome (IBS). When college student Daniell Koepke did her own fecal transplant using poop from her brother and her boyfriend as donors her IBS symptoms improved, but she began to experience medical conditions that afflicted both fecal donors.
“It’s possible that the bacteria in the stool can influence inflammation in the recipient’s body, by affecting their metabolism and activating their immune response,” microbial ecologist Jack Gilbert, PhD, Professor and Associate Vice Chancellor at University of California San Diego (UC San Diego) told Business Insider. “This would cause shifts in their hormonal activity, which could promote the bacteria that can cause acne on the skin. We nearly all have this bacterium on skin, but it is often dormant,” he added.
A Fecal Microbiota Transplant (FMT) is a procedure where stool from a healthy donor is transplanted into the microbiome of a patient plagued by a certain medical condition.
Our guts are home to trillions of microorganisms (aka, microbes), known as the gut microbiota, that serve many important functions in the body. The microbiome is a delicate ecosystem which can be pushed out of balance when advantageous microbes are outnumbered by unfavorable ones. An FMT is an uncomplicated and powerful method of repopulating the microbiome with beneficial microbes.
“With fecal microbiome transplants there is really compelling evidence, but the science is still developing. We’re still working on if it actually has benefits for wider populations and if the benefit is long-lasting,” said Gilbert in a Netflix documentary titled, “Hack Your Health: The Secrets of Your Gut.”
“The microbial community inside our gut can have surprising influences on different parts of our body,” microbial ecologist Jack Gilbert, PhD (above), of the Gilbert Lab at University of California San Diego told Business Insider. “Stools are screened before clinical FMTs, and anything that could cause major problems, such as certain pathogens, would be detected. When you do this at home, you don’t get that kind of screening.” Doctors and clinical laboratories screening patients for IBS understand the dangers of DIY medical treatments. (Photo copyright: University of California San Diego.)
Changing Poop Donors
When Koepke began experiencing symptoms of IBS including indigestion, stabbing pains from trapped gas and severe constipation, she initially turned to physicians for help.
In the Netflix documentary, Koepke stated that she was being prescribed antibiotics “like candy.” Over the course of five years, she completed six rounds of antibiotics per year, but to no avail.
She also changed her diet, removing foods that were making her symptoms worse. This caused her to lose weight and she eventually reached a point where she could only eat 10 to 15 foods.
“It’s really hard for me to remember what it was like to eat food before it became associated with anxiety and pain and discomfort,” she said.
In an attempt to relieve her IBS symptoms, Koepke made her own homemade fecal transplant pills using donated stool from her brother. After taking them her IBS symptoms subsided and she slowly gained weight. But she developed hormonal acne just like her brother.
Koepke then changed donors, using her boyfriend’s poop to make new fecal transplant pills. After she took the new pills, her acne dissipated but she developed depression, just like her boyfriend.
“Over time, I realized my depression was worse than it’s ever been in my life,” Koepke stated in the documentary.
She believes the microbes that were contributing to her boyfriend’s depression were also transplanted into her via the fecal transplant pills. When she reverted to using her brother’s poop, her depression abated within a week.
Gilbert told Business Insider his research illustrates that people who suffer from depression are lacking certain bacteria in their gut microbiome.
“She may have had the ‘anti-depressant’ bacteria in her gut, but when she swapped her microbiome with his, her anti-depressant bacteria got wiped out,” he said.
FDA Approves FMT Therapy for Certain Conditions
Typically, the fecal material for an FMT procedure performed by a doctor comes from fecal donors who have been rigorously screened for infections and diseases. The donations are mixed with a sterile saline solution and filtered which produces a liquid solution. That solution is then administered to a recipient or frozen for later use.
On November 30, 2022, the US Food and Drug Administration (FDA) approved the first FMT therapy, called Rebyota, for the prevention of Clostridioides difficile (C. diff.) in adults whose symptoms do not respond to antibiotic therapies. Rebyota is a single-dose treatment that is administered rectally into the gut microbiome at a doctor’s office.
Then, in April of 2023, the FDA approved the use of a medicine called Vowst, which is the first oral FMT approved by the FDA.
According to the Cleveland Clinic, scientists are exploring the possibility that fecal transplants may be used as a possible treatment for many health conditions, including:
Doctors and clinical laboratories know that do-it-yourself medicine is typically not a good idea for obvious reasons. Patients seldom appreciate all the implications of the symptoms of an illness, nor do they fully understand the potentially dangerous consequences of self-treatment. Scientists are still researching the benefits of fecal microbiota transplants and hope to discover more uses for this treatment.
Findings could lead to clinical laboratory tests that help physicians identify microbes lacking in the microbiomes of their Parkinson patients
Microbiologists and clinical laboratory scientists know that gut microbiome can be involved in the development of Parkinson’s disease, a progressive neurological disorder that affects the nervous system due to damage caused to nerve cells in the brain. There is no cure for the illness. But a new treatment developed by researchers at the VIB Center for Inflammation Research at the University of Ghent in Belgium, may help to alleviate the symptoms.
During a clinical trial, VIB Center for Inflammation Research (VIB-IRC) scientists discovered that fecal microbiota transplantation (FMT), also known as a stool transplant, can improve motor skills in some Parkinson’s patients, according to Neuroscience News.
Parkinson’s disease (PD) develops when a protein called alpha-synuclein misfolds and forms into bundled clusters damaging nerve cells in the brain that produce dopamine. These formations, which are believed to appear in the gastrointestinal wall in the early stages of PD, then reach the brain via the vagus nerve leading to typical PD symptoms in patients.
“Our study provides promising hints that FMT can be a valuable new treatment for Parkinson’s disease,” Roosmarijn Vandenbroucke, PhD (above), Principal Investigator, VIB-UGent Center for Inflammation Research and full professor, UGent Department of Biomedical molecular biology, Faculty of Sciences, told Neuroscience News. “More research is needed, but it offers a potentially safe, effective, and cost-effective way to improve symptoms and quality of life for millions of people with Parkinson’s disease worldwide.” Clinical laboratories will likely be involved in identifying the best microbes for the FMT treatments. (Photo copyright: University of Ghent.)
Correlation between Gut Microbiome and Neurogenerative Disease
To perform their clinical study—referred to as GUT-PARFECT—the IRC researchers first recruited patients with early-stage PD and healthy donors who provided stool samples to the Ghent Stool Bank. The PD patients received the healthy stool via a tube inserted into the nose which led directly into the small intestine.
The FMT procedures were performed on 46 patients with PD between December 2020 and December 2021. The participants in this group ranged in ages from 50 to 65. There were 24 PD patients in the placebo group, and a total of 22 donors provided the healthy stool. Clinical evaluations were performed at baseline, three, six, and 12 months.
After 12 months, the group that received the transplants showed a reduction in symptoms compared to the placebo group. Their motor score on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) improved by a mean of 5.8 points. The improvement registered on the same scale for the placebo group was 2.7 points.
Developed in the 1980s, the MDS-UPDRS is a scale utilized to evaluate various aspects of PD by measuring patient responses via a questionnaire rating several issues (such as cognitive impairment, apathy, depression, and anxiousness) common in PD patients from normal to severe. It is divided into four parts:
Part I: Non-motor experiences of daily living.
Part II: Motor experiences of daily living.
Part III: Motor examination.
Part IV: Motor complications.
During the final six months of the research, the improvement in motor symptoms became even greater. To the VIB-IRC researchers this implied that an FMT may have long-lasting effects on PD patients. The FMT study group also experienced less constipation, a condition that can be bothersome for some PD patients.
“Our results are really encouraging!” said the study’s first author, Arnout Bruggeman, MD, PhD student, VIB-UGent Center for Inflammation Research, in a UGent News release. “After twelve months, participants who received the healthy donor stool transplant showed a significant improvement in their motor score, the most important measure for Parkinson’s symptoms.”
Findings Could Lead to Other Targeted Therapies for PD
The VIB-IRC researchers believe there is a correlation between the gut microbiome and Parkinson’s disease.
“Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages,” the IRC researchers wrote in eClinicalMedicine.
“Our next step is to obtain funding to determine which bacteria have a positive influence. This could lead to the development of a ‘bacterial pill’ or other targeted therapy that could replace FMT in the future,” Debby Laukens, PhD, Associate Professor, Ghent University, told Neuroscience News.
According to the Parkinson’s Foundation website, nearly one million people in the US live with PD. It is second only to Alzheimer’s disease in the category of neurodegenerative diseases.
More research and studies are needed before the VIB-IRC’s stool transplant treatment can be used in clinical care. As researchers learn more about which specific strains of bacteria are doing the beneficial work in PD patients, that data could eventually lead to clinical laboratory tests performed to help physicians identify which microbes are lacking in the microbiomes of their PD patients, and if fecal transplants could help those patients.
Is gut microbiota the fabled fountain of youth? Researchers at Valenzano Research Lab in Germany found it works for killifish. Could it work for other vertebrates as well?
Research into the microbiomes of humans and other animals is uncovering tantalizing insights as to how different microbes can be beneficial or destructive to the host. It is reasonable to expect ongoing research will eventually give microbiologists and clinical laboratories useful new medical laboratory tests that assess an individual’s microbiome for diagnostic and therapeutic purposes.
Human microbiota (AKA, microbiome) have been identified as having a key role in several different health conditions. In previous ebriefings, Dark Daily reported on several breakthroughs involving the microbiome that bring the promise of precision medicine ever closer. Research and clinical studies are contributing to more accurate diagnoses, identification of best drugs for specific patients, and, enhanced information for physician decision-making, to name just a few benefits.
Valenzano Lab published its study online in August. The team of scientists and researchers led by Dario Valenzano, PhD, focused on the longevity of the turquoise killifish (Nothobranchius furzeri), a tiny fish native to the African countries of Mozambique and Zimbabwe. They found that when older killifish ate the fecal matter of younger killifish they lived longer. The fecal matter carried the microbiota to the older fish and extended their lifespans.
Moving Microbiome from One Gut to Another
To perform the research, Valenzano and his team first treated killifish that were nine and a half weeks old (considered middle-aged) with antibiotics to cleanse their gut flora. The fish were then placed in a sterile aquarium containing the gut contents of young adult killifish that were just six weeks old. Although killifish won’t typically eat feces, they would nip at the gut contents in the water and swallow some of the microbes from the younger fish in the process. The researchers discovered that the transplanted microbes were able to successfully colonize the stomachs of the older fish.
Dario Valenzano, PhD (above), gazes at an older Killifish, the subject in his research into increased aging at the Valenzano Research Lab in Cologne, Germany. Studies of the microbiomes of different species is expected to eventually give microbiologists new and useful clinical laboratory tests. (Photo copyright: Max Planck Institute for Biology of Aging.)
When the middle-aged killifish reached the age of 16 weeks—considered elderly—their gut microbiomes were still similar to that of a six-week-old fish. The process had a noticeable effect on the lifespan of the killifish that received the microbiome transplants from the young fish. They lived 41% longer than killifish that received microbes from middle-aged fish and their longevity increased by 37% over fish that were not exposed to any treatment at all. In addition, at 16 weeks, the killifish who had received the transplants were much more active than fish of the same age who had not received the transplants.
“These results suggest that controlling the composition of the gut microbes can improve health and increase life span,” the study paper noted. “The model system used in this study could provide new ways to manipulate the gut microbial community and gain key insights into how the gut microbes affect aging. Manipulating gut microbes to resemble a community found in young individuals could be a strategy to delay the onset of age-related diseases.”
Transferring Fecal Microbiota to Save/Extend Human Lives
Previous research has indicated there may be a connection between microbiomes and aging in some animals, and that the diversity of gut microbes decreases with age. This study proved that this same pattern is true in turquoise killifish.
However, Valenzano does not know how the microbes are affecting the lifespans of the older killifish. “It is possible that an aging immune system is less effective at protecting the micro-organisms in the intestines, with the result that there is a higher prevalence of pathogens in older guts. The gut microbiota in a young organism could help to counter this and therefore support the immune system and prevent inflammation. This could lead to longer life expectancy and better health,” he stated in a press release.
“You can really tell whether a fish is young or old based on its gut microbiota,” Valenzano told Nature. He noted, however, that it is too early to determine if fecal transplants can be used in humans to extend life. “I wouldn’t go that far. This is really early evidence that this has a potential positive effect.”
There is, however, a similar procedure used in humans called Fecal Microbiota Transplant or FMT that has demonstrated promising results in treating certain illnesses.
In a fecal transplant, fecal matter is collected from an approved donor, treated, and placed in a patient during a colonoscopy, endoscopy, sigmoidoscopy, or enema. The purpose of the transplant is to replace good bacteria in a colon that has undergone an event that caused the colon to be inundated with bad bacteria, such as Clostridium difficile, resulting in C. diff. infection, a life-threatening illness that, according to the Centers for Disease Control and Prevention (CDC), kills tens of thousands of people each year.
“The challenge with all of these experiments is going to be to dissect the mechanism. I expect it will be very complex,” stated Heinrich Jasper, PhD, in the Nature article. Jasper is a professor at the Buck Institute for Research on Aging in Novato, California. His lab is working on similar research with microbiome transplants in fruit flies. He predicts this type of longevity research will be performed on other animals in the future.
Valenzano’s and Jasper’s research may eventually create new diagnostic tools for microbiologists to assess the microbiome of individual patients. This technology may also enable microbiologists to advise pathologists and clinical laboratories regarding what specific microbes may be harmful and what microbes may be therapeutically beneficial to patients.
