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.
Findings could lead to new therapies and clinical laboratory biomarkers for detecting and defeating antibiotic-resistant bacteria
Once again, new research shows that human gut bacteria (microbiota) may be useful in fighting antibiotic-resistant bacterial infections. The study findings could provide new therapeutics and clinical laboratory biomarkers for diagnosing and treating severe gastrointestinal disorders.
Antibiotic-resistant bacterial infections often appear in patients with chronic intestinal conditions and in those with long-term antibiotic use. Enterobacteriaceae is a large family of gram-negative bacteria that includes more than 30 genera and over 100 species.
“Despite two decades of microbiome research, we are just beginning to understand how to define health-promoting features of the gut microbiome,” said Marie-Madlen Pust, PhD, a computational postdoctoral researcher at the Broad Institute and co-first author of the paper, in the news release.
“Part of the challenge is that each person’s microbiome is unique. This collaborative effort allowed us to functionally characterize the different mechanisms of action these bacteria use to reduce pathogen load and gut inflammation,” she added.
The researchers identified a way to treat patients infected by antibiotic-resistant strains of bacteria that does not involve antibiotics. Should further research validate these early findings, this could be a viable approach to treating patients with this condition.
“Microbiome studies can often consist of analyzing collections of genetic sequences, without understanding what each gene does or why certain microbes are beneficial,” said Ramnik Xavier, MD (above), director of Broad Institute’s immunology program, co-director of the infectious disease and microbiome program, and co-senior author on the study, in a news release. “Trying to uncover that function is the next frontier, and this is a nice first step towards figuring out how microbial metabolites influence health and inflammation.” Clinical laboratories that test for intestinal conditions caused by antibiotic resistance will want to follow the Broad Institute’s research. (Photo copyright: Broad Institute.)
Suppressing Growth of Antibiotic-resistant Bacteria
To perform their research, the scientists isolated about 40 strains of bacteria from the stools of five healthy fecal donors. They then used those stool samples in fecal microbiota transplants to treat mice that had been infected with either Escherichia coli (E. coli) or Klebsiella, both forms of Enterobacteriaceae. The scientists tested different combinations of the 40 strains and identified 18 that suppressed the growth of Enterobacteriaceae.
“Antibiotic-resistant Enterobacteriaceae such as E. coli and Klebsiella bacteria are common in hospitals, where they can proliferate in the gut of patients and cause dangerous systemic infections that are difficult to treat. Some research suggests that Enterobacteriaceae also perpetuates inflammation in the intestine and infection by other microbes,” the Broad Institute news release notes.
The researchers discovered that Klebsiella changed the gene expression in carbohydrate uptake and metabolism in the Klebsiella-infected mice that were treated with the 18 beneficial strains. The gene expression included the downregulating of gluconate kinase and transporter genes, which revealed there is increased competition among gut bacteria for nutrients.
When combined, these 18 strains alleviated inflammation in the guts of the treated mice by depriving the harmful gut bacteria of carbohydrates. This non-antibiotic approach also prevented harmful bacteria from colonizing in the gut.
“In partnership with the Broad’s Metabolomics Platform, led by senior director and study co-author Clary Clish, PhD, they analyzed samples from pediatric patients with ulcerative colitis, looking for the presence of alternate gluconate pathway genes of gut microbes and fecal gluconate levels. They found higher levels of gluconate linked to more gluconate-consuming Enterobacteriaceae in samples from pediatric patients with ongoing inflammation, indicated by high levels of the protein calprotectin,” the study authors wrote in Nature.
“Together, the findings suggest that Enterobacteriaceae processes gluconate as a key nutrient and contributes to inflammation in patients. But when a gut microbiome includes the 18 helpful strains, they likely compete with Enterobacteriaceae for gluconate and other nutrient sources, limiting the proliferation of the harmful bacteria,” the scientists concluded.
Promising New Bacterial Therapies
This research could ultimately lead to the development of fecal microbiota transplants for individuals to eradicate antibiotic-resistant bacteria in a more objective and specific manner, with fewer side effects than current treatments.
“Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection,” the scientists wrote in Nature.
According to the news release, they plan to continue research to “uncover the identity and function of unknown metabolites that contribute to gut health and inflammation.” The team hopes to discover how different bacteria compete with each other, and to develop microbial therapeutics that improve gut microbiome and curb bacterial infections.
More studies are needed to prove the efficacy of this type of fecal bacterial treatment. However, this research demonstrates how using nano processes enabled by new technologies to identify the actual work of proteins, RNA, and DNA in the body cheaply, faster, and with greater precision, will open doors to both therapeutic and diagnostic clinical laboratory biomarkers.
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.”
