Gut microbiomes as a cancer therapy

“It’s very glamorous,” says Dr. Hannah Wardill with a laugh, after the biomedical research fellow is asked about the details of her work at the University Medical Center Groningen (UMCG). “We collect fecal samples from both patients and animals, isolate specific bacteria from the microbiome and analyze the reactions before and after exposure to chemotherapy.”

While the gut microbiome may not seem alluring, it has been a recent hot topic. These ecological communities of commensal, symbiotic, and pathogenic microorganisms within our bodies act as a sort of microbiological fingerprint, unique to each individual. “Within each of us are billions of microbes, including bacteria, fungi, and viruses. The majority live in our gut and collectively can weigh up to two kilos. They have very complex and bi-directional communications, with us, their host, as well as with each other,” says Wardill with enthusiasm.

Changing developments in life science

Each species is directly affected by diet, medication, living conditions – and even life events, such as if one was born by Caesarian section. Searching for certain bacterial or fungal species that may influence the side effects of a particular cancer treatment within this vast and complex ecosystem is no easy task, and Wardill spends much of her time researching the millions of microbiological entities at UMCG, one of the biggest healthcare institutes in the Netherlands.

Wardill arrived here from Australia for a two year research program centered on the microbiome, and is currently focusing on how the various species that live within the human body affect how we respond to different cancer therapies: “There always has been a large focus on the outcomes of cancer therapy but very little emphasis placed on the complications that might occur as a result of treatment.”

Current oncological treatments, including chemotherapy, radiotherapy, immunotherapy, and stem cell transplantation, while effective, are also associated with a broad range of complications. Patients can often experience side effects like hair loss, infections, diarrhea, bleeding and even cognitive changes during their treatment. “My aim is to prevent that burden for patients,” says Wardill. “By looking at all aspects of an individual, from genetics, to their microbiome and immune function, as well as the myriad of cofactors like age, sex, and smoking status, we can come up with a very personalized approach to both achieve greatest efficacy on anti-cancer outcomes and minimize or alleviate toxicities associated with the therapy.”

It is an ambitious goal but an important one. Especially when focusing on pediatric cancer patients. "The survival rates of cancer therapies in children are fortunately very high today. But it makes it even more vital that we avoid chronic or traumatic side-effects." Daan van Wessel, a physician at the of the UMCG Pediatric Surgery Department, shares this view. He works closely with Dr. Wardill saying that “we as doctors are focused more and more on the holistic approach towards the patients, not only treating them but also making sure that the possible side effects are limited to a certain extent in any way possible."

The protective gut

One candidate of interest to Wardill and other scientists is the Blautia bacterium. The gram-negative, anaerobic bacterium appears to wield a positive effect in reducing the side effects of cancer treatments in children. "We find extensive colonization of these bacteria in healthy people, but they are rare in sick people," says Wardill. Blautia bacteria live mainly in epithelial cells, which also help them to renew themselves more quickly. They produce a metabolite called acetate, a short-chain-fatty-acid. “We think that this factor is very important in providing protection to patients before chemotherapy, and making it less likely that they will go on to develop serious side effects during that round of treatment.” Microorganisms such as Blautia can be administered as a powder, which then grows in the intestine. “What we are interested in doing is trying to identify the specific metabolite or product of this Blautia genus to then be able to administer that.”

Getting results

Wardill uses QIAGEN kits to extract DNA from her samples to hunt down the elusive microbiotic entities that could potentially influence treatment. She also relies on bioinformatic solutions like CLC Workbench. “We often work with very small biopsies that have been collected from patients, which means isolating the DNA from the bacteria covering a surface of just one square-millimeter,” explains Wardill. “We get really good results using the QIAGEN DNA kits, with high DNA yields, which can be used for sequencing.”

Analyzing the microbiome requires huge amounts of data, because of the relative abundance of the species. Wardill works closely with bioinformatics specialists who help to tease apart that data. “We start with larger-scale outcome measures, so we can look at large signals and phenomena that may be happening. Once we identify those, we work down to isolate a more specific mechanism that may be at play.”

Microbial transplants

Probiotics have their uses, but researching general probiotics was a scientific disappointment in Wardill’s young career. "I was always very convinced about probiotics," she says. But when testing the efficacy of these supplements in a large study, the result was sobering. "Effects could not be proven – that was incredibly devastating," she says. But an important conviction stemming from her previous research work was: "Every negative result also contains helpful information."

In this case, the result led Wardill to consider that probiotics might not have a specific effect per se, but instead have different effects on individuals. "The probiotics administered so far were simply not sufficient in quantitative terms to produce a large culture of the corresponding microorganisms,” Wardill explains. “I’m now much more interested in looking at things like fecal-microbiome transplantation, because you can deliver a whole microbial community along with all of their metabolic factors and metabolites and products that they produce in a very large yield.“ This treatment, while not the most glamorous, has been quite effective for patients.