Dennis Kasper, MD, William Ellery Channing Professor of Medicine and Professor of Immunology at HMS; Jun Huh, PhD, associate professor of immunology at HMS; and Sloan Devlin, AB ’06, PhD, associate professor of biological chemistry and molecular pharmacology at HMS, are pursuing research that suggests the microbiome’s medical significance extends beyond gastrointestinal conditions to the immune system, metabolism, and brain.

Focusing on Microbes 

Kasper has spent more than five decades at HMS studying how gut bacteria interact with the immune system. He found that specific molecules produced by gut bacteria can act like teachers for the host’s immune system, helping it strike the right balance between inflammation and tolerance—with implications for inflammatory diseases, autoimmune conditions, and cancer treatment. “The immune system was previously thought to be only genetically influenced,” Kasper says. “But in fact, so many parameters of the immune system depend on the microbiome to develop. Without the microbiome, we really are immunodeficient.” More recently, in collaboration with Arlene Sharpe, Kasper found that microbial molecules shape immune cell responses to cancer treatment, which may help explain why some cancer patients don’t respond well to certain immunotherapies. When they blocked the activity of these microbiome-derived molecules in mice, the mice’s response to PD-1 checkpoint immunotherapy improved.

Bridging Gut and Mind 

Huh’s lab explores mechanisms through which microbial signals travel from the gut to the brain — including microbe-produced molecules that corral immune cells to migrate from the gut to the meninges, where they emit signals to the nervous system. His research has found that removing gut bacteria from mice that carry Alzheimer’s or ALS-related gene mutations changes their behavior and likelihood of developing neurological diseases, and that removing the gut microbiome can mitigate autism-like behaviors in mice with a genetic predisposition to autism. Huh says the microbiome could potentially help researchers target neurodevelopmental and mental disorders in humans. “There is data suggesting that the microbiome not only influences inflammatory diseases like IBD but also neurological disorders like Alzheimer’s, Parkinson’s, and even autism,” Huh says. He and Kasper co-direct a germ-free mouse facility at HMS that allows researchers to study these links with a level of control and precision very few facilities worldwide can match.

Decoding Molecules 

Devlin’s research has revealed that while gut microbes vary between individuals, different strains of bacteria often share common genes that encode proteins and enzymes that produce the same core molecules. Her lab has shown that gut microbes chemically modify bile acids into compounds that act like hormones to regulate metabolism, and that gut bacteria can transform human steroid hormones into allopregnanolone—the molecule used in an FDA-approved drug for postpartum depression. The findings point toward a new approach to drug development based not on microbes themselves but on the molecules they make.

These findings are really exciting. There are data suggesting that the microbiome not only influences inflammatory diseases like IBD but also neurological disorders like Alzheimer’s, Parkinson’s, and even autism.

—Jun Huh, PhD