Drugs vs. Bugs

Harnessing the microbiome to improve treatments

From ibuprofen to chemotherapy, everyone has taken medication at some point in their life. But why do some people respond differently than others? Could our microbiome play a role?

The human microbiome consists of all the microorganisms on the inside and outside of our bodies, including bacteria, viruses and yeasts. While the majority of microbes reside in our gut, research is revealing their presence in other areas such as the skin, urogenital tract and breast.

“It’s no surprise that the human microbiome has huge potential to influence our health,” says Dr. Jeremy Burton, Lawson Scientist and Research Chair in Human Microbiome and Probiotics. “It outnumbers other cells in our body 10 to one.”

Interest in the human microbiome has been growing and researchers are now starting to learn its importance in relation to pharmaceutical drugs.

With potential to modify everything from immune reaction to properties of the drug itself, it may be the key to improving a patient’s response to therapy.

The majority of drugs are taken orally, making their way through the intestinal tract where they often spend a long time in contact with billions of microorganisms. Even those that are administered in other ways, such as intravenously, may come into contact with microbes at other sites.

“Our microbes have huge potential to metabolize drugs and therefore modify their activity and alter their effects,” explains Dr. Burton.

Since everyone has a different microbiome, drug responses may vary drastically by individual.

In their lab located at St. Joseph’s Hospital, part of St. Joseph’s Health Care London, Dr. Burton and his team are working to learn more about microbiome-drug interactions and how the microbiome can be harnessed to make drugs safe and effective for every patient.

An unexpected consequence

In one study, the team partnered with Dr. Joseph Chin, Associate Scientist at Lawson and Urologist at London Health Sciences Centre (LHSC), to examine how a prostate cancer drug called abiraterone interacts with the gut microbiome.

Prostate cancer growth is stimulated by testosterone, which belongs to a group of hormones called androgens. Abiraterone decreases androgen production in an effort to stop the growth of prostate cancer. It is used in combination with another drug called prednisone which helps to reduce side effects.

“Abiraterone works for many patients, but not all,” says Dr. Burton. “We studied the drug’s interaction with the microbiome to see whether it provided any new insights.”

They discovered that patients’ microbiome changed drastically after taking abiraterone.

Bacteria in the gut were metabolizing the drug and, while androgen-producing organisms decreased, an organism called Akkermasia began to thrive. Akkermasia is a microbe associated with positive metabolic control and better health.

“We know that abiraterone turns off androgen production, but it has other positive effects that we couldn’t explain,” adds Dr. Burton. “Are these positive effects influenced by the microbiome?”

The team also examined the interaction of prednisone with the gut microbiome and found something very surprising. Bacteria can utilize prednisone and turn it into androgen-like compounds.

“This is an important finding as it may explain why treatment fails for some patients. With the body being starved of androgen, is the bacterial population stepping up to produce it and driving the growth of prostate cancer?”

Using poop to make drugs more effective

Another way the microbiome impacts our response to medication is through its influence on our immune system.

With the rise of immunotherapy drugs in cancer treatment, Lawson researchers are conducting Phase I clinical trials to see whether the microbiome can be modified through fecal microbial transplants (FMT) to improve treatment outcomes and prevent side effects.

Immunotherapy drugs stimulate the immune system to attack cancer. While they can significantly improve survival outcomes, they are not always effective and can cause severe immune reactions.

“We know the gut microbiome influences immunity from an early age. It makes sense that a healthy gut could improve response to immunotherapy and prevent side effects,” explains Dr. Burton.

He is collaborating with a team of researchers that includes Dr. Michael Silverman, a pioneer in the field of FMT. Fecal transplants involve collecting stool from a healthy donor, preparing it in a lab and transplanting it to a patient. The donor’s microbiome is transplanted so that healthy bacteria can colonize in the patient’s gut.

We know the gut microbiome influences immunity from an early age. It makes sense that a healthy gut could improve response to immunotherapy and prevent side effects,

The team is the first in Canada to study fecal transplants to improve outcomes in melanoma patients treated with anti-PD1 immunotherapy drugs. Dr. John Lenehan, Associate Scientist at Lawson and Oncologist at LHSC, hopes that fecal transplants can alter the microbiome and ensure more patients respond.

In another trial, the team is studying fecal transplants with stage IV renal cell carcinoma patients who are treated with a combination of two immunotherapy drugs called ipilimumab and nivolumab. These drugs have significantly improved survival outcomes, but approximately half of patients experience severe immune-related side effects like inflammation of the bowel, lungs and skin. Side effects can become so severe that patients need to stop treatment.

Study participants will undergo a fecal transplant before their first immunotherapy treatment and two supportive fecal transplants with smaller dosing before their second and third treatments. Dr. Ricardo Fernandes, Lawson Associate Scientist and LHSC Oncologist, hopes this will bolster the microbiome and reduce immune-related side effects so patients can stay on treatment.

“We’re one of the first in the world to study fecal transplants in cancer patients. These studies are as cutting-edge as it gets,” notes Dr. Saman Maleki, Lawson Scientist specializing in cancer immunotherapy.

 

The future of microbiome therapy

For Dr. Burton, these studies are just the beginning of exploring the relationship between pharmaceuticals and the microbiome.

In the future, highly-specific antibiotics could be developed that only target bacteria involved in the growth of cancer. Instead of using fecal transplants, the growth of beneficial organisms could be boosted by powerful prebiotics and probiotics.

“We need to undertake one of the largest paradigm shifts to ever occur in medicine. Every drug needs to be reevaluated for its effects after interaction with the microbiome.”

Imaging the microbiome

There’s growing interest in analyzing a person’s microbiome using their poop, but researchers suspect this is not representative of what happens further up the digestive tract. Instead, Dr. Jeremy Burton is collaborating with Dr. Donna Goldhawk, Lawson Imaging Scientist, and her graduate trainee, Sarah Donnelly, to visualize a person’s gut microbiome using magnetic resonance imaging (MRI). This is based on unique MRI signals emitted by gut bacteria.

 

 

“Some microbes in the gut send very interesting signals. We’re working to develop targeted imaging agents to see bacteria in real-time,” says Dr. Burton.

 

Eventually, MRI could be used to see how a person’s microbiome changes after taking a probiotic or having a fecal transplant.

 

 

The potential of poop

Dr. Michael Silverman, Lawson Associate Scientist and Chair/Chief of Infectious Diseases at Western University, St. Joseph’s and LHSC, is a pioneer in the field of fecal transplants. He was one of the first in the country to use fecal transplants in the treatment of patients with Clostridium difficile (C. diff). His team is also one of few delivering fecal transplants for select conditions using specially-prepared oral capsules.

 

 

“Fecal transplants have saved the lives of countless patients with recurrent C. diff,” says Dr. Silverman. “We’re now starting to see its potential for the treatment of other diseases.”

In addition to cancer immunotherapy, Drs. Silverman and Burton are studying fecal transplant for multiple other conditions including non-alcoholic fatty liver disease and multiple sclerosis (MS).