Nav: Home

A protein's surprising role offers clues to limit graft-vs.-host disease

March 22, 2019

ANN ARBOR, Michigan -- A protein that protects people with inflammatory bowel disease has quite a different effect in graft-vs.-host disease, a common and challenging side effect of bone marrow transplants.

In a surprising finding, researchers at the University of Michigan Rogel Cancer Center showed the protein NLRP6 aggravated the difficult symptoms of gastrointestinal graft-vs.-host disease. Knocking out this protein in mice led to significantly better survival and less severe GVHD.

Graft-vs.-host disease, a response to the donor bone marrow, causes symptoms similar to ulcerative colitis, including diarrhea and abdominal pain. Generally, the mechanisms that cause colitis overlap with those that cause GVHD, and many of the treatments are similar.

Studies have shown NLRP6 lessens symptoms in colitis. So when researchers looked at NLRP6's impact on graft-vs.-host disease, they assumed it would also be protective.

"There are a lot of reasons NLRP6 seemed to work well in those other diseases, but in the case of GVHD, it seemed to do the opposite. In mice where we knocked out NLRP6, instead of doing worse, they did better. That was a big surprise," says co-senior study authors, Pavan Reddy, M.D., deputy director of the Rogel Cancer Center and division chief of hematology/oncology at Michigan Medicine.

In their study, published in Nature Microbiology, the team compared mouse models expressing NLRP6 and those in which the protein was eliminated. In both models, the mice had undergone a bone marrow transplant.

The second surprise was that NLRP6 played a role that was not dependent on microbiome composition. Previous data had suggested NLRP6's protective role is directly related to the microbes within the intestinal tract: the more good microbes, the more protective effect.

In this study, researchers measured the levels of various microbes, then worked to alter the microbiome, wiping out certain microbes or breeding mice together to share their microbiome. They developed mice in a germ-free environment and then exposed them to a microbiome with and without NLRP6. Each time, those without NLRP6 had better outcomes.

"Even when we did all of those manipulations, the protection was still there in the NLRP6-knockout mice. The composition of the microbiome does not seem to matter, unlike with other disease processes," says study author Hideaki Fujiwara, M.D., Ph.D., a post-doctoral researcher in Reddy's lab.

Digging deeper, researchers found a metabolite called taurine that appears to be, in part, responsible for turning on NLRP6 and ultimately making GVHD worse. Changes in the microbiome can lead to excess taurine, which signals NLRP6, which in turn triggers GVHD.

"Just measuring changes in the microbiome is not always sufficient. We have to look at what specifically changes and the consequences of those changes. A change that leads to the generation of metabolites like taurine or other proteins or enzymes will need to be understood to comprehend the effects of the microbiome on GVHD," says co-senior author Grace Chen, M.D., Ph.D., associate professor of hematology/oncology at Michigan Medicine.

"Conceptually, if we can target this protein and block NLRP6, we can mitigate intestinal GVHD. Or, if you look at it the other way, changing the diet or microbiome to avoid an excessive amount of taurine could be another way to reduce GVHD," Reddy says.

NLRP6 is expressed in gut cells but not in the tumor cells the researchers studied. This means the bone marrow transplant could do its job to eliminate the tumor. In principle, blocking NLRP6 could limit GVHD without limiting the transplant's anti-tumor effect.

Reddy notes that no blocker currently exists against NLRP6 and any potential clinical benefit still needs to be explored. His lab plans to follow up with more study of taurine and other metabolites, including how modifying them impacts NLRP6 and GVHD.
-end-
Additional authors: Tomomi Toubai, Corinne Rossi, Mary Riwes, Hiroya Tamaki, Cynthia Zajac, Chen Liu, Anna V. Mathew, Jaeman Byun, Katherine Oravecz-Wilson, Ikuo Matsuda, Yaping Sun, Daniel Peltier, Julia Wu, Jiachen Chen, Sergey Seregin, Israel Henig, Stephanie Kim, Stuart Brabbs, Subramaniam Pennathur

Funding: National Institutes of Health grants AI-075284, HL-090775; the American Society of Blood and Marrow Transplantation New Investigator Award; the JSPS Postdoctoral Fellowships for Research Abroad; the YASUDA Medical Foundation Grants for Research Abroad; University of Michigan Microbial Systems Molecular Biology Laboratory

Disclosure: None

Reference: Nature Microbiology, doi: 10.1038/s41564-019-0373-1, published online March 11, 2019

Resources:
University of Michigan Rogel Cancer Center, http://www.rogelcancercenter.org
Michigan Health Lab, http://www.MichiganHealthLab.org
Michigan Medicine Cancer AnswerLine, 800-865-1125

Michigan Medicine - University of Michigan

Related Microbes Articles:

A new look at deep-sea microbes
Microbes found deeper in the ocean are believed to have slow population turnover rates and low amounts of available energy.
Microbes might manage your cholesterol
Researchers discover a link between human blood cholesterol levels and a gene in the microbiome that could one day help people manage their cholesterol through diet, probiotics, or entirely new types of treatment.
Can your gut microbes tell you how old you really are?
Harvard longevity researchers in collaboration with Insilico Medicine develop the first AI-powered microbiomic aging clock
What can be learned from the microbes on a turtle's shell?
Research published in the journal Microbiology has found that a unique type of algae, usually only seen on the shells of turtles, affects the surrounding microbial communities.
Life, liberty -- and access to microbes?
Poverty increases the risk for numerous diseases by limiting people's access to healthy food, environments and stress-free conditions.
Rye is healthy, thanks to an interplay of microbes
Eating rye comes with a variety of health benefits. A new study from the University of Eastern Finland now shows that both lactic acid bacteria and gut bacteria contribute to the health benefits of rye.
Gut microbes may affect the course of ALS
Researchers isolated a molecule that may be under-produced in the guts of patients.
Gut microbes associated with temperament traits in children
Scientists in the FinnBrain research project of the University of Turku discovered that the gut microbes of a 2.5-month-old infant are associated with the temperament traits manifested at six months of age.
Gut microbes eat our medication
Researchers have discovered one of the first concrete examples of how the microbiome can interfere with a drug's intended path through the body.
Microbes can grow on nitric oxide
Nitric oxide (NO) is a central molecule of the global nitrogen cycle.
More Microbes News and Microbes Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.