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.”
These new findings may affect how microbiology labs and physicians diagnose and treat several gastrointestinal conditions
Once again, a research effort has teased out new insights into the role the human microbiome plays in our digestive processes. Microbiologist and medical laboratory managers will be interested to learn that, according to the study team, specific microbes have a role in regulating how fast food moves through the digestive tract.
Researchers at the Dey Laboratory in Seattle recently examined the function of microbial bile acid metabolism in gut motility. They determined that “metabolites generated by the gut microbiome regulate gut transit,” according to a new paper published by the Fred Hutchinson Cancer Research Center (Fred Hutch).
“These findings have potential implications for the treatment of gastrointestinal conditions,” noted a Fred Hutch news release. This may mean new clinical laboratory tests to identify these strains of bacteria, along with new therapies for treating patients.
Gut motility (aka, Peristalsis) is the term used to describe the movement of food from the time it enters via the mouth until it leaves the body. This movement, the researchers found, is regulated by interactions between diet, the enteric nervous system (ENS) and the gut microbiota via processes that include bile acid metabolism.
Sex, Diet, and Lifestyle All Affect Treatment for Gastrointestinal Diseases
The Dey Laboratory researchers also discovered that sex was a significant variable in determining transit times with males having larger pro-motility effects.
“Our results suggest that strategies for treating or preventing gastrointestinal diseases may need to be tailored to sex and to biogeography of the gut,” they wrote. “While targeting the microbiome and the ENS is justified, our observation of significant transcriptional responses to defined interventions in a highly controlled gnotobiotic setting also highlights challenges to clinical translation.”
The researchers concluded that:
Gut microbiome-generated bile acids regulate colonic transit via TGR5 protein.
Lithocholic acid (LCA) had the largest colonic pro-motility effect.
Bile acids exert sex-biased effects on gut transit times.
Enteric nervous system (ENS) transcriptional responses are regional- and microbiome-specific.
“The human experience—which reflects the aggregate effects of the innumerable dietary ingredients that we consume daily, the hugely diverse metabolically dynamic microbes that inhabit our guts, our own digestive processes, and the interactions of all of the above that result in thousands of gut metabolites—entails significantly more complex and variable transcriptional responses to environmental cues,” the Dey Laboratory scientists concluded.
To perform their research, the scientists developed both high and low BSH (bile salt hydrolase) bacterial communities for germ-free mice, which are known to exhibit slower gut motility and less complex bile acid profiles than colonized animals. (See graphic above taken from the Dey Laboratory published paper.)
The spice turmeric and dyes were added to the diets of the mice to track gut motility. The mice that were given the BSH-high microbiota had higher fecal concentrations of unconjugated bile acids than those given the BSH-low form of the microbiota. The mice given the BSH-high version also experienced faster transit times, according to the researchers’ iScience paper.
The researchers also concluded that the BSH-high group had greater fecal concentrations of lithocholic acid (LCA) which indicates variations in bile acid metabolism might affect gut transit.
When the scientists infused bile acids directly into mouse colons, variable acids reacted differently with LCA having the fastest transit times. The researchers hypothesized that LCA might signal through a bile receptor known as TGR5 which blocked the effects of LCA on colonic transit times. TGR5, also called G protein-coupled bile acid receptor, functions as a cell surface receptor for bile acids.
The Dey Laboratory team developed a method to measure expression changes in ENS genes and found that neither BSH activity nor gut transit phenotypes were major drivers of gene expression changes. They found that the location of the gut segment, or biogeography, was the leading contributor to ENS signature variance between samples.
“We expected to see shared host transcriptional responses in mice harboring communities with similar metabolic profiles. However, we did not see this for the most part,” explained gastroenterologist Neelendu Dey, MD (above), a physician/scientist and Assistant Professor, Clinical Research Division, at Fred Hutchinson Cancer Research Center, in the press release. “If anything, shared responses were regional, and these signatures did not cluster by BSH/motility phenotypes.” (Photo copyright: Seattle Cancer Care Alliance.)
The scientists “identified consortium-specific transcriptional changes in genes involved in ENS signaling, development, maintenance, and bile acid metabolism, and these differed across regions of the GI tract. Together these findings indicate that ENS transcriptional responses are regional and microbiome-specific,” according to the Fred Hutch press release.
“This remains a confusing part of the story for us—how is it that we can see predictable host motility responses when colonizing the guts of gnotobiotic mice with phenotypically defined communities, but the middle-man (the host enteric nervous system) appears to have such varied responses?” the Dey Laboratory researchers noted in the press release.
“It suggests that gut motility phenotypes that appear similar may in fact represent (when we look under the hood) diverse host physiologic phenotypes that we are just beginning to understand,” they added.
The results of this study could have potential implications for the precision medicine diagnosis and treatment of gastrointestinal illnesses.
Blue Poop Challenge
Earlier this year, people were encouraged to participate in the “blue poop challenge” conducted by research company ZOE Global Limited (ZOE) to determine how long it takes food to travel through the body.
For the Blue Poop Challenge, individuals are asked to eat blue muffins and then report on the company’s website as to how long it took for the blue dye to appear in their stools.
The purpose of this ongoing study is to reveal pertinent information about an individual’s gut health and microbiome.
Since 2010, Dark Daily has reported on dozens of research studies and innovative developments involving human microbiome and gut bacteria and their critical importance in the development of clinical laboratory testing, drug therapies, and precision medicine.
These studies’ findings could lead to improved immune system therapeutics and associated clinical laboratory tests.
“All of this suggests the potential in the future for clinical laboratories and microbiologists to do microbiome testing in support of clinical care,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
More research is needed in these areas. But gut bacteria and the human microbiome are an integral part of our health and wellbeing. It is worth keeping an eye on new developments in those fields of study.
Advancements in genetic sequencing continue to enable microbiologists and genetic scientists to explore the origins and mutations of deadly diseases
Microbiologists and researchers can now study the gene sequence of 5,000-year-old bubonic plague bacteria. The scientific team that achieved this feat of gene sequencing believes this is the oldest case of the ancient strain of the plague found to date.
For microbiologists, this demonstrates how advances in gene sequencing technologies are allowing scientists to go further back in time to look at how the genomes of bacteria and viruses have evolved and mutated. This helps science understand the process of genetic mutation, as well as learning which mutations survived because they could more easily infect humans.
Missing Gene has ‘Dramatic Influence on Virulence’ of Plague
To conduct their study, the researchers sequenced the genomes of samples from the teeth and bones of four hunter-gatherers and tested the remains for bacterial and viral pathogens. They found evidence of Yersinia pestis (Y. pestis) in the dental remains of a 20- to 30-year-old male dubbed RV 2039.
The jaw bones used for the research were discovered in the late 1800s in the Rinnukalns, a stone age settlement unearthed in present-day Republic of Latvia in the late 19th century.
Missing Genetic Element in Ancient Bacterium
The scientists were surprised to find evidence of Y. pestis in the remains and noted that the analysis of the microbe lacked a crucial genetic element observed in later strains of the bacteria. Missing was the gene that allows biting fleas to act as vectors to spread the plague to humans.
“What’s so surprising is that we see already in this early strain more or less the complete genetic set of Y. pestis, and only a few genes are lacking,” said biochemist and archeologist Ben Krause-Kyora, Professor and head of the Ancient DNA (aDNA) Laboratory at the University of Kiel in Germany, and one of the authors of the study, in a press release.
“But even a small shift in genetic settings can have a dramatic influence on virulence,” he added.
This absent gene also is responsible for creating the pus-filled buboes associated with the Black Death (bubonic plague) that occurred in the 1300s. The Black Death killed 75 million to 200 million people worldwide, mostly in Eurasia and North Africa. It is to date the most fatal pandemic recorded in human history.
“Different pathogens and the human genome have always evolved together,” said Professor Ben Krause-Kyora (above left with and Steve Zäuner at center and Dr. Silvia Codreanu-Windauer at right), in the press release. “We know Y. pestis most likely killed half of the European population in a short time frame, so it should have a big impact on the human genome. But even before that, we see major turnover in our immune genes at the end of the Neolithic Age, and it could be that we were seeing a significant change in the pathogen landscape at that time as well,” he added. (Photo copyright: Mittelbayerische.)
A Less Lethal Bubonic Plague?
Although RV 2039 most likely perished from the bubonic plague, the researchers believe his strain of the infection was more mild, less contagious, and not as lethal as the later genetic mutations of the bacteria that caused the Black Death pandemic. The researchers concluded that the man most likely contracted the disease through a bite from an infected rodent or other animal, the press release notes.
“Isolated cases of transmission from animals to people could explain the different social environments where these ancient diseased humans are discovered,” Krause-Kyora said in the press release. “We see it in societies that are herders in the steppe, hunter-gatherers who are fishing, and in farmer communities—totally different social settings but always spontaneous occurrence of Y. pestis cases.”
From Animal Bite to Flea Infection in 7,000 Years’ Worth of Mutations
The Y. pestis bacteria that infected RV 2039, the researchers surmised, most likely split from its predecessor, Yersinia pseudotuberculosis, which first appeared on Earth about 7,000 years ago. It most likely took Y. pestis over a thousand years to acquire all the mutations necessary for flea-based transmission of the bacteria to humans, the researchers noted.
“What’s most astonishing is that we can push back the appearance of Y. pestis 2,000 years farther than previously published studies suggested,” Krause-Kyora said. “It seems that we are really close to the origin of the bacteria.”
It is unknown how many cases still occur worldwide due to unreliable diagnoses and poor reporting in developing countries. However, data from the World Health Organization (WHO) states that there were 3,248 cases of plague reported worldwide between 2010 and 2015, including 584 deaths. Currently, the three most endemic countries for plague are the Democratic Republic of the Congo, Madagascar, and Peru.
The researchers’ findings illustrate how advances in gene sequencing technologies are helping microbiologists, virologists, and genetic scientists understand the affect mutations have on diseases that have plagued humans since the beginning of humanity itself.
Will this lead to new genomic diagnostics? Perhaps. The research is worth watching.
