Modulating the gut microbiome could represent a new frontier for cancer medicine

Faecal transplants can boost the immune systems of patients with advanced cancer, improving their response to immunotherapy. Could this experimental treatment play a major role in the future?

Fecal transplant or fecal matter transplant (FMT). A laboratory tube with with fecal microbiota to cure persistent digestive diseases such as infection by Clostridium bacteria

In early 2022, the MD Anderson Cancer Center in Houston began enrolling patients with late-stage disease for a unique clinical trial. 

With a matter of months to live, and all other treatment options exhausted, the centre’s oncologists offered these patients a chance to see whether manipulating their gut microbiome via a faecal transplant into the colon could improve their body’s response to immunotherapy.

It came with various risks, but in the eyes of Fergus Shanahan, a professor at University College Cork and one of the world’s leading experts on the gut, modulating the microbiome could represent an entirely new frontier for cancer medicine.

A few years earlier, he had been invited to a talk at Memorial Sloan Kettering Cancer Hospital in New York City, where oncologists presented data showing that the prognosis of patients with blood cancers following a bone marrow transplant depended greatly on the diversity of their gut microbiome.

“They had hard data,” says Shanahan.

“The people with high microbial diversity in their gut did far better than those with low diversity. It was a dramatic difference.”

Now, the Houston trial would demonstrate what could be achieved by boosting the diversity of the microbiome.

Fifteen patients would receive stool samples, freeze-dried into capsules, containing the gut microbes of a so-called “super donor,” a woman who had been cured of her cancer with immunotherapy.

The theory was that the mixture of bacteria in her intestines had enhanced her treatment response and might do so in others.

In two of the patients, the capsules would succeed. One 53-year-old man with small bowel cancer that had metastasised to multiple organs was cured when oncologists resumed immunotherapy treatment following the faecal transplant. Another patient went into long-term remission.

According to Michael Overman, the oncologist who led the trial, this indicates that the gut microbiome is capable of sensitising the body’s immune system to immunotherapy, helping dial up its ability to then recognise and attack cancer cells. 

“The interplay between what’s in your gut and the immune system is incredible,” he says.

Such transplants are still highly experimental in cancer medicine, but Shanahan believes they could play a major role in future.

“Numerous cancers exploit the fact that the immune system has some switches that can turn itself off, and cancer cells can access those switches,” he says.

“We now have these newer immunotherapies which can fight back and prevent them doing this, and this is where boosting your immune system via the microbiome can make a substantial difference.”

Cancer therapy is just one of many areas of medicine where faecal transplants are being explored as a new therapeutic option, however.

Yellow soup

In the past decade, the concept of transferring one person’s stool into another’s colon for medical purposes has experienced a surge of interest, but Shanahan explains that it actually has thousands of years of history, originating as part of ancient Chinese medicine.

“People are kind of titillated by the idea of a faecal transplant, that poo could be therapeutic,” he says. “But there are records of this being used going all the way back to the Ming dynasty. They used to call it yellow soup.”

More recently, such transplants have found more of a defined medical niche as a vital therapy for severe clostridioides difficile (C. difficile) infections, a known hospital superbug that can take over the guts of elderly patients following antibiotic treatment, which can to life-threatening complications.

Faecal transplants are now approved by regulators as a mainstream therapy for C. difficile infections.

For the past five years, Irish microbiologists have been trying to establish a nationwide “stool bank” to make it easier to carry out these transplants in Irish hospitals.

“Faecal transplantation has proven over and over again to work in the vast majority of these cases,” says Shanahan.

“You can get this very serious disease in elderly people with C. difficile because they have little reserve in their guts to combat it.”

Jens Walter, Professor of Ecology, Food and the Microbiome at University College Cork's APC Microbiome Ireland research centre.

Given the gut microbiome’s role in innumerable chronic diseases, various researchers worldwide have been exploring the potential of faecal transplants in other conditions, ranging from neurological disorders to metabolic and immune system complications. Clinical trials have been carried out in multiple sclerosis, irritable bowel syndrome and even Parkinson’s disease, although none so far have taken place in Ireland.

Jens Walter, a microbiology professor at University College Cork, recently collaborated with researchers at the University of Alberta in Canada on a trial that tested a combination of faecal transplants and fibre supplements in patients with severe obesity and metabolic syndrome.

However, while the study yielded some improvements in insulin sensitivity, Walter questions whether faecal transplants in their current form can be a viable therapy for non-life-threatening chronic illnesses.

“The effects on insulin were very small and probably temporary,” he says. “You would likely have to keep repeating it every four to eight weeks to maintain them.”

While this could be done, Walter’s reticence stems from some of the known safety concerns with faecal transplants. For while modulating the gut with another person’s bacteria can yield benefits, it comes with its own dangers as well.

Risk factors

For a long time, the primary concern associated with faecal transplants has been the risk of accidentally transferring a novel and potentially harmful pathogen to another person’s gut.

However, Shanahan and others believe this is now less of a concern, due to modern technologies for screening faecal samples and precisely assessing the microbes within.

According to professor Liam O’Mahony, a microbiologist at UCC and APC Microbiome Ireland, the far bigger risk is modulating a vulnerable person’s microbiome in a way that inadvertently makes them prone to developing another chronic illness.

“You can transfer risk of cardiometabolic disorders, immune dysfunction, anxiety, depression, central nervous system problems, allergies, the list is nearly endless because the microbiome contributes to all of these,” says O’Mahony.

Liam O’Mahony, Principal Investigator at APC Microbiome Ireland SFI Research Centre & Professor of Immunology, University College Cork. Picture:  Gerard McCarthy.

“We know from animal studies that there are transferable traits that pass on risk.

“For example, if you do a faecal transplant from a food allergic child into a mouse, you can induce a food allergy in that animal.”

Shanahan also points out that there’s a real danger of taking someone already living with multiple sclerosis or irritable bowel syndrome and giving them a greater risk of developing a particular cancer. For example, he says that a faecal transplant may contain species of Helicobacter, a bacteria which is a known cause of stomach cancer. 

“Not just that, but the evidence that certain groups of gut bacteria contribute to the risk of colon cancer is quite strong."

Faecal transplants for C. difficile infections are a lifesaving breakthrough, and they have potential in treating patients not responding to existing treatments. 

However, to take the field forward and make it safer and applicable to a broader range of conditions, both Shanahan and O’Mahony believe a more sophisticated approach is needed.

New technology

In the wake of its trial, MD Anderson Cancer Center has partnered with a startup called Kanvas Biosciences. The startup has developed a new technology called HiPR-FISH, capable of pinpointing important relationships between different collections of gut microbes. Using this to identify the key populations of bacteria within the super donor’s stool, and enabling the powerful response to immunotherapy, Kanvas Biosciences has now isolated these strains and put them into a single pill.

This will now be used in further clinical trials at the centre and other hospitals across North America, to see whether it can enhance responses to immunotherapy treatment on a larger scale.

Shanahan says that this kind of approach represents the future.

“I don’t think the way in which we currently practise faecal transplantation is likely to have a long-term future,” he says. “It’s too crude. It’s giving yellow soup to people without knowing the constituents of the soup.”

Instead, Shanahan says that we need to study faecal samples where transplants have proved successful, identify relevant microbes, and conduct experiments to understand exactly how they’re achieving these transformational changes.

“At the moment, a faecal sample can vary hugely from one bowel movement to the next, even if it’s coming from the same person,” he says.

“We need to be giving defined consortia of microbes so that a faecal transplant on a Monday is the same as on a Tuesday.”

Until recently, this would have been technically difficult, but with science’s growing ability to analyse gut bacteria and understand their functions, Shanahan predicts that it won’t be long before we’re able to give cancer patients, or even those with immunological or metabolic disorders, a specific cocktail of microbes in the same way in which we offer drugs and vaccines.

“It’s going to involve isolating the important organisms, growing them in a lab, studying them, and putting them back together in a combination where we know precisely what they can and can’t do, instead of just a crude soup.

“There are still logistical hurdles to be overcome, but we’ve got academic and commercial groups which are very much along the road to doing that, and I don’t think it’ll take long at all."