Can the gut microbiome alleviate cancer treatment side effects?

As a child, Hannah Wardill, PhD, often found herself engrossed in television programs that showed surgical procedures; it almost seemed predestined that she would pursue a career in medical research, she says. 

In 2013, while Wardill was still a doctoral student at the University of Adelaide in Australia, she became captivated by the gut microbiome. Nestled within the intricate folds of the digestive tract are trillions of microscopic inhabitants – a bustling metropolis of bacteria, fungi, and viruses that live symbiotically with their hosts. At the time, researchers had been finding links between people’s gut microbiome and various diseases, including inflammatory bowel diseases, obesity and autoimmune disorders such as diabetes. 

Intrigued by this flurry of research, for her doctoral thesis Wardill chose to study how chemotherapy affects the gut microbiome of people with cancer. Might modulating it in some way prevent cancer patients from developing diarrhea and other side effects? It’s a central question that remains at the root of her research today. 

That chemotherapy can cause such dreaded side effects as nausea, diarrhea, fatigue and brain fog is widely known. What’s become increasingly apparent in recent years is that a person’s gut microbiome is a contributing factor, says Wardill, who is now a lab head at the University of Adelaide. Not everyone undergoing chemotherapy develops the same side effects and some people experience none at all.

Gut microbes and health 

“We have been looking at how a person’s unique microbiome impacts their response to chemotherapy and whether it can predict which side effects they will develop,” she explains. Cancer treatments can also disrupt the microbiome, so Wardill is also studying ways to salvage the damage to promote better patient health. 

Over the last decade, studies have shown that a person’s gut microbiome plays an essential physiological role. Gut microbes aid digestion and produce metabolites that influence a person’s metabolism and overall health; they even modulate the immune system. 

“Every one of us has a unique composition of microbes in our gut, it’s like a fingerprint,” explains Wardill.  This composition, including the abundance or lack of specific bacterial species – has been linked to such varied conditions as diabetes, Parkinson’s disease, anxiety, and depression. 

It can also influence the efficacy of drugs. Mycoplasma bacteria, for example, can break down the chemotherapy drug gemcitabine, reducing or even negating efficacy (1). 

Some studies have also found that variations in the composition of the gut microbiome influence the effectiveness of immunotherapy (2).

Predicting side effects?

“One of the big challenges in cancer treatment,” says Wardill, “is that the side effects are really unpredictable, which makes it difficult to prepare patients for what’s going to come next.” 

While cancer outcomes have improved dramatically over the past decades, people still suffer through treatment, she adds. Wardill’s goal is to be able to spare people the debilitating side effects of treatment. 

Could sampling a person’s microbiome before cancer treatment predict which side effects will develop?  In head and neck cancer, Wardill has found the unique composition of the microbiome – a so-called microbial signature – appears to distinguish people who will develop mouth sores as a side effect of radiotherapy.  

The study is ongoing and Wardill is continuing to collect data in a range of patient populations. But this predictive ability would help improve care. “Both patients and doctors want clarity. It allows them to make the best and most informed decisions about a person’s treatment in a highly personalized way.”

Wardill is also interested in understanding what happens to the microbiome after cancer treatment – many studies have shown that it becomes damaged, but few have found ways to protect good gut bacteria during cancer treatment. 

To support a healthy microbiome during cancer treatment, there are a number of different strategies, she says. One major focus in her lab is to treat patients with healthy microbes in pill form.

As part of a placebo-controlled clinical trial, people scheduled to receive a stem cell transplant for blood cancer will receive a fecal transplant in pill form – a “crapsule,” as Wardill calls it – to see if it will reduce side effects from the stem cell transplant.

The future is fecal 

A more ideal treatment would be an autologous fecal transplant – collecting a fecal sample from people before treatment begins and then transplanting it back into them after treatment. 

Because each one us carries a unique microbiome, crapsules that contain microbes collected from the patient may be more effective. “We may be more tolerant of our own microbes,” Wardill says. 

Her team had recently completed a feasibility study of autologous fecal transplant but unfortunately found the logistics of collecting and storing a fecal sample from patients before treatment too challenging. For now, they are focusing on supplying healthy microbes, collected from healthy donors, in pill form.  

Yet another strategy would be to provide patients undergoing a stem cell transplant a fecal transplant prepared using microbes collected from their stem cell donor. 

The gut microbiome and the immune system develop to tolerate one another, explains Wardill. She and her colleagues have been exploring whether mice that receive a stem cell transplant have better outcomes if they also receive a fecal transplant from the same donor. 

“We hope that by matching both immune cells and microbes, we might have a more tolerant immune system and fewer side effects that occur when the donated stem cells behave aggressively.”

Technology fuels microbiome research 

Much of the explosion of research on the gut microbiome can be attributed to advances in DNA sequencing technologies, particularly high-throughput sequencing, which allowed researchers to study the microbial communities in the gut in much greater detail.

In Wardill’s lab, the QIAcube has become an essential workhorse for all nucleic acid extraction. Before switching to the system, all nucleic acid extraction was done manually, she says. 

The fully automated system saves precious time. “We also use QIAGEN kits to extract RNA from dorsal root ganglia from mice, which is about the size of a pin head, to analyze the expression of inflammatory genes and get reliably good yield.” 

She also uses QIAGEN CLC software to analyze sequence data. “It’s a great analysis tool for a non-specialist bioinformatics scientist like me. It has very good built-in pipelines to analyze sequencing data in a user-friendly manner.”  

Wardill has trained 10 people on the software, none of whom are statisticians or biostatisticians, who can now do a first pass on their data, “which is hugely beneficial for people who are just looking for an initial analysis and who don’t want to outsource it,” she says.  

Asked if her research on the microbiome has changed her own diet or lifestyle habits, Wardill stops to think. “I have always been vegetarian and lived a healthy lifestyle, so it hasn’t changed anything in that regard. But I have become a big believer in minimizing antibiotic use.”  

She has also found herself becoming much more involved in patient advocacy work, something she never anticipated. “I have been working to increase the visibility of the side effects of chemotherapy. Many people view them as just something they are stuck with, that they have to suck it up. Many patients are hesitant to even discuss them, either because it concerns bowel habits or because they feel ungrateful.

“I want to shine a light on these concerns and help people understand that the side effects are something that should be thoroughly discussed and that there are options available to reduce their impact.”