Gut health research may help the fight against infections and cancer

Dr. Andrew Koh, Director of Pediatric Hematopoietic Stem Cell Transplantation at Children’s Health℠ and Associate Professor of Pediatrics and Microbiology at UT Southwestern, is on a mission to unravel how the gut microbiome shapes immune responses in pediatric cancer patients.

His team’s discoveries are reshaping our understanding of the links between gut bacteria, cancer treatment and the life-threatening infections and complications that go with it. And their research is paving the way toward a new wave of probiotic therapies that could reduce infections in pediatric stem cell transplant patients, modulate graft-versus-host-disease (GVHD) and make cancer immunotherapies, such as checkpoint inhibitors and CAR T-cell therapy, more effective for more patients.

“The trillions of bugs in our gut educate, activate and prime our immune system. By discovering how these bugs affect kids with cancer, we can potentially solve some of cancer treatment’s thorniest challenges,” says Dr. Koh.

How probiotics could prevent infections in immunocompromised patients

When cancer treatment leaves patients immunocompromised, it opens the door to life-threatening infections that originate in the gut. One arm of research in Dr. Koh’s lab investigates how the pathogens that cause these infections proliferate – and how to maintain or restore gut health to prevent these infections.

“In a healthy microbiome, ‘good guy’ bugs signal our immune system to make antibiotics that suppress the ‘bad guy’ bugs that cause infections,” Dr. Koh says. “When cancer treatment wipes out the good guy bugs, the bad guy bugs can take over.”

Dr. Koh received an RO1 grant from the National Institute of Allergy and Infectious Diseases to support his work in this area. His team achieved a key milestone when they published a 2015 study in Nature Medicine that identified how two bacteria (Bacteroides thetaiotamicron and Blautia producta) stimulate production of an antimicrobial peptide, a naturally produced antibiotic in the gut, that kills infection-causing bugs like Candida albicans.

The study showed that an existing medicine, mimosine, can stimulate production of this infection-fighting peptide. This technique reduced fatal infections in mouse models by 50%.

C. albicans is one of the main culprits behind infections in cancer patients,” Dr. Koh says. “If we can find a way to keep it in check, it could help more patients avoid those infections.”

Now Dr. Koh’s lab is at the forefront of investigating how to restore or maintain a healthy gut in patients undergoing cancer therapy or stem cell transplantation.

One promising strategy is to use probiotics to reintroduce infection-fighting bacteria that get depleted during cancer treatment; another is to stimulate the body to suppress the bacteria that cause infections. Dr. Koh’s team is working to translate these strategies into real-world treatments – but there are significant challenges.

“Most of the bugs that are important in restoring balance to the gut microbiome are obligate anaerobes, which means any bit of oxygen will kill them,” Dr. Koh says. “That makes working with them and manufacturing them difficult. But I hope the various strategies we are developing to modulate the gut microbiome could be ready in five to 10 years.”

Investigating ways to modulate or prevent GVHD

Dr. Koh’s team is also investigating how the gut microbiome can be harnessed to prevent one of transplantation’s most intractable problems: GVHD.

Several years ago, researchers at Memorial Sloan Kettering Cancer Center published a paper that drew a direct link between GVHD and the microbiome. They showed that adult patients with gut GVHD lacked key anti-inflammatory bacteria in their gut and had unusually large populations of pro-inflammatory bacteria. Dr. Koh’s team was the first to show that the same is true in children.

Dr. Koh and his colleagues also identified six gut bacteria that seem to protect against GVHD. Now they’re honing in on a specific combination of these gut microbiota to develop a probiotic cocktail that could modulate or prevent GVHD.

“There’s emerging literature that suggests different strains of bacteria differ in their ability to produce the short chain fatty acids that keep inflammation in check,” Dr. Koh says. “We’re trying to find specific strains of these short-chain fatty acid producing gut bacteria that can do the best job and potentially dampen GVHD.”

How does the microbiome influence immunotherapy response?

An exciting direction in Dr. Koh’s research was spurred several years ago by two Science papers that showed that a novel form of cancer immunotherapy (immune checkpoint inhibitor therapy) was less effective in preclinical mouse cancer models that were germ-free or had been treated with antibiotics. Intrigued, Dr. Koh set out to uncover out how the gut microbiome influences the response to immunotherapy.

As a first step, his team used shotgun sequencing to get a high-resolution profile of the gut microbiota in melanoma patients receiving immune checkpoint inhibitor therapy. This enabled Koh’s group to be one of the first to show that those who responded well to checkpoint inhibitors had a completely different microbiome signature than those who didn’t. From there, the team showed that checkpoint inhibitors worked better in a melanoma model when supplemented with a precision probiotic of Bacteroidetes thetaiotamicron and Faecalibacterium prausnitzii (BT/FP).

The insights from Dr. Koh’s melanoma study led to a recent NIH R01 grant. His team is also working with a major pharmaceutical company to study whether BT/FP precision probiotics can improve response to a broad array of checkpoint inhibitors.

“In humans, B. theta and F. prausnitzii are prevalent and part of the gut microbiota repertoire that’s needed to activate the immune system, and our early results suggest that giving these bugs to patients could potentially help checkpoint inhibitor therapy work better,” Dr. Koh says.

Working to make CAR T-cell therapy more effective

Dr. Koh’s checkpoint inhibitor work led to another insight: Since the microbiota they studied influence lymphocyte immune function, they could potentially influence response to CAR T-cell therapy, which are genetically engineered lymphocytes. Now they’re partnering with a pharmaceutical company to investigate whether a microbiotic approach could modulate the effect of CAR T-cells after they’re infused into patients.

Investigating CAR-T was a natural step for Dr. Koh, in part because Children’s Health and UT Southwestern are global leaders of research on pediatric CAR T-cell therapy. Children’s Health was among 25 sites that participated in late-stage clinical trials of KYMRIAH®, and has the world’s second-highest volume of KYMRIAH® patients.

“Even though our initial discoveries were in the melanoma context, we think these findings are tumor agnostic and immunotherapy agnostic,” Dr. Koh says. “We’re excited to harness the power of the bugs in and around our bodies to make cancer immunotherapy more effective for more people.”

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