Bacteria can help or hinder GVHD
“We knew that the microbiome was important in causing GVHD via MHCII, but we didn’t know which bacterial species were involved,” Koyama said.
To help her uncover the bacterial players in GVHD, Koyama took advantage of the fact that the gut microbiome is shaped by environmental factors like food and water.
Over the long term, changing these factors changes the microbiome’s makeup. The team surveyed genetically identical lab mice grown by different vendors and found that mice raised in different locations have different microbiomes and different levels of MHCII in their gut epithelium, and that mice with higher levels of gut MHCII get more severe GVHD.
To narrow down which bacterial species were involved in generating acute GVHD through MHCII, the researchers tackled the problem from both sides: by adding bacteria and taking them away.
First, Koyama and Hill teamed up with microbiome expert Sujatha Srinivasan, PhD, in Fred Hutch's Fredricks Lab. The collaborators used genetic sequencing to analyze the bacterial species present in mice from different vendors. Koyama collaborated with computational biologist Daniel Hippe, PhD, in Fred Hutch’s Randolph Lab, to breakdown the correlations between bacterial groups and MHCII. They saw that certain bacterial genera — a taxonomic grouping broader than species — appeared to induce MHCII expression, while others suppressed it.
Then, Koyama put mice with different levels of gut MHCII in the same cages.
“This transfers the bacteria [between the mice] and we can see how this changes MHCII expression,” Koyama said.
After four weeks, the MHCII-low mice had transformed into MHCII-high mice, and Koyama and Hippe saw that MHCII-inducing bacteria had moved into their gut microbiomes. She was also able to kill off “inducer” bacteria — and tamp down MHCII and GVHD — using certain antibiotics prior to transplant.
Unfortunately, Koyama also saw that treating mice with these antibiotics also reduced GVL, the ability of the donor cells to attack residual leukemia cells, although less severely than GVHD. In patients, GVL helps keep their cancers from recurring, so treatment strategies must balance the benefit of reducing GVHD with the risk of reducing GVL and enhancing recurrence.
“Another group had already shown that certain bacteria increase MHCII expression on gut epithelial cells,” Koyama said. “We needed to know, do the suppressor bacteria have a functional effect?”
Working with Hutch colleague and microbiome expert Neelendu Dey, MD, the team grew two types of suppressor bacteria. Koyama pretreated two groups of MHCII-high mice with antibiotics to wipe out most of the “inducer” bacteria.
Two weeks of daily dosing with the suppressor bacteria ramped down their gut epithelial MHCII, while MHCII levels bounced back in mice that received antibiotics but no suppressor bacteria. Mice that received the suppressor bacteria after antibiotic treatment also survived better after transplant.
Koyama then collaborated with another Fred Hutch microbiome scientist, Kate Markey, PhD, MClin, to see if the human data supported her findings in mice.
They analyzed a cohort of microbiome data taken from bone marrow transplant patients prior to transplant at Memorial Sloan Kettering Cancer Center in New York City. While individual species differed a great deal between mice and human gut microbiomes, the researchers saw distinct overlap between GVHD-associated bacterial genera in mice and humans.
“This suggests that before transplant, humans also have different bacteria in their gut microbiota that can influence GVHD outcomes,” Koyama said.
A window of opportunity
While the team's findings highlight the power of the microbiome in promoting GVHD, it will likely be some time before doctors will be able to modulate this complex ecosystem to improve transplant outcomes, she said.
But by further clarifying how interactions between the microbiome and donor and host immune cells precipitate GVHD, the researchers' work reveals the key interactions and players that can then become the focus of further research into therapeutic targets and new treatment strategies.
“There is still a lot to understand about how to manipulate the microbiome, but our work shows that the pre-transplant microbiome is an important place to focus future research,” Koyama said.
This work was funded by the National Institutes of Health, the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute on Aging, the Susan and Peter Solomon Family Fund, the Solomon Microbiome Nutrition and Cancer Program, Cycle for Survival, the Parker Institute for Cancer Immunotherapy, the Paula and Rodger Riney Multiple Myeloma Research Initiative, the Starr Cancer Consortium, the American Society of Clinical Oncology, Hyundai Hope on Wheels, Cycle for Survival, the Rally Foundation for Childhood Cancer Research, the Tow Center for Developmental Oncology and Seres Therapeutics.