Kick-starting insulin production with microbial diversity wins award

for her work showing that restoring lost bacterial signals in the gut can stimulate the development of insulin-producing cells, potentially protecting against the autoimmune destruction associated with type 1 diabetes (T1D), Jennifer Hampton Hill is the winner of the NOSTER award & Science Microbiome Award.

“When we started this work, virtually nothing was known about the role of the microbiota in type 1 diabetes,” Hill said. Although it has been established that people with T1D have reduced microbiota diversity – suggesting that they have lost or never been colonized by specific bacteria that play an important role in protecting against the disease – his The work goes even further, showing a particular bacterial protein found in rodents and human gut microbes can help restore insulin production.

“If we can continue to learn more about the mechanisms behind specific microbiota effects,” she said, “I think we can … hopefully use this knowledge to treat many autoimmune diseases. “

The NOSTER & Science Microbiome Award aims to reward innovative research by young researchers working on the functional attributes of the microbiota of any organism likely to contribute to our understanding of human or veterinary health and disease, or to guide therapeutic interventions.

“Submissions for the NOSTER 2022/Science awards have been exceptional,” said Caroline Ash, editor at Science. “It is a great privilege to gain insight into the fascinating, sophisticated and important research that the current generation of scientists contribute to understanding the interactions of microbiota with their hosts.”

insulin in humans

One hundred years ago, Frederick Banting and Charles Best transformed the prognosis of type 1 diabetes with the discovery of the hormone insulin. But while scientists have made great strides in understanding diabetes, now known to be an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas, no cure exists.

Treatment approaches for T1D either focus on restoring the body’s insulin or improving autoimmunity. Although there has been notable progress in restoring insulin, the field has not yet had much luck in adjusting the immune response to stimulate insulin production. One of the reasons for this is the inconsistency of beta cell physiology between rodents and humans.

“Although mice and rats have a lot of similarities to us, there are also some important differences,” Hill said. “These differences often become apparent when researchers test whether an exciting discovery of a mouse islet [pancreatic cell] translates into a human island.”

Hill explained that many people in the field have found that human beta cells are repeatedly recalcitrant to signals that strongly stimulate rodent cells. But she and her colleagues have identified an insulin-restoring pathway that stimulates rodent cells and shows promise for human beta cells.

Jennifer Hampton Hill | Photo courtesy of Rachel Merrill

Hill and his colleagues had hypothesized that because animals lived in a microbial world, it is plausible that they used microbial signals to gather information about the environment, such as the local availability of nutrients, and adjust their metabolisms accordingly. The researchers investigated whether the animals adapt the number of insulin-producing cells by incorporating information from their resident microbiomes.

To test this idea, Hill and his team used the zebrafish model to study the development of pancreatic beta cells with or without the microbiota. By comparing larvae cultured in microbial-free environments to their conventionally raised, microbial-carrying counterparts, they found that the latter larvae had significantly more beta cells than those without microbes.

“We systematically added individual zebrafish gut bacteria and their secreted products until we identified a single protein sufficient to restore [germ-free] mass of beta cells,” Hill said. She and her teammates named this previously unknown protein beta-cell expansion factor A (BefA).

To test whether BefA elicited similar responses in mammalian species, they analyzed beta cell development in microbial-free mouse models. Adding purified BefA was enough to increase the mass of developing beta cells in these animals, they showed.

Since the discovery of BefA means that this protein is similar in all vertebrates, Hill said “we are optimistic about the potential of our discovery to overcome [existing] impediments to translation.”

Importance of the microbiome

Why BefA evolved as a microbial product remains a question, she noted.

“We know that BefA can bind and disrupt cell membranes, which is a hallmark of antimicrobial proteins. [AMP]and bacteria tend to use AMPs as tiny weapons against other microbes… But we still don’t fully understand the benefits that BefA production offers in the context of a complex microbial community,” Hill said. “These are important questions to think about because if we can understand the circumstances that lead bacteria to produce BefA, we may be able to use this knowledge to stimulate natural BefA production in more disease-susceptible hosts.

Knowing BefA’s mechanism for impacting beta cells could pave the way for researchers to restore or increase beta cell production, Hill said, though she noted that her own work has focused on developing of cells – and that there are important differences between the beta cells of infants and mature adults. .

“We are currently working on experiments to assess the effects of BefA later in life and on mature beta cells,” Hill said. “If BefA can promote the renewal or regeneration of mature adult beta cells, it would show promise as a potential beta cell replacement therapy.”

The hygiene hypothesis that is often discussed today posits that the apparent increase in certain diseases, such as T1D, is the result of changing societal practices that have reduced microbial exposures and microbiome diversity. Hill and his team suggest in their trial that spiking these microbial activities in children who are genetically more at risk for T1D could be a strategy to prevent or delay the disease.

Hill was first drawn to microbiology research through an inspiring undergraduate professor, Patty Siering, at Humboldt State University in California. “Working in his lab has really revealed to me all the hidden potential in the uncharted space of bacterial genomes.”

Hill then completed a fellowship at the University of California, San Francisco in Didier Stainier’s lab working on zebrafish beta cell regeneration, creating the unique research pathway that would lead to his award-winning research.

“[W]When I started my thesis in the lab of Karen Guillemin in Oregon, who was an emerging leader in studying the effects of microbiota during development, it was somewhat fortuitous to espouse the only experiments previous research I had had in microbiology and beta cell development. And to our surprise, it was an idea with real legs!” Hill said.

Hill reflected on the importance of winning this award in his field of research. “There is incredible and fascinating work going on in the whole area of ​​the microbiome,” she said, “and to be selected is a huge honor. I’m thrilled to be recognized, especially as a young scientist trying to establish my own niche. . My work has been supported by amazing mentors and colleagues, and this certainly wouldn’t be possible without them. I’m extremely grateful. It’s a very exciting time to study the microbiota, and this award helps to draw attention to the innovation this field has to offer.”

“Controlling the microbiome is expected to contribute to the prevention and treatment of many chronic diseases,” said Kohey Kitao, CEO of NOSTER Inc. “I sincerely hope that the award will motivate young scientists to pursue their research with passion to develop microbiome-based therapies. medicines for the benefit of human health and that the children of the world who will be the architects of our Earth’s future will be inspired by the wonders of scientific discovery.”

Finalists

portrait of Apollo Stacy
Apollo Stacy

Apollo Stacy is a finalist for his writing “Host-derived metabolite causes microbiota to develop resistance to colonization,” which focused on analyzing the gut microbiota of previously infected mice, finding that transient infection can enhance resistance to colonization and finding that microbiota can be “formed” by host metabolites induced by infection. Stacy earned her undergraduate degree from Washington University in St. Louis and her Ph.D. from the University of Texas at Austin. He is currently a postdoctoral fellow at the National Institutes of Health, starting his lab at the Cleveland Clinic Lerner Research Institute in 2022. His research investigates how host-derived metabolites shape ecological balance and therefore host susceptibility to inflammatory diseases .

portrait of Irina Leonardi
Irina Leonardi

Irina Leonardi is a finalist for her writing “Mycobiota Modulate Immunity and Behaviour”, which focused on fungal communities as an integral part of the gut microbiota and worked to demonstrate that mucosa-associated fungi are associated with host protective immunity . Leonardi earned undergraduate degrees from ETH Zürich and a Ph.D. from the University of Zurich. She did her postdoctoral work at Weill Cornell Medicine. His research focused on the cellular mechanisms of fungal recognition in the intestine and the local and systemic consequences of intestinal fungal colonization. She is currently the Scientific Communications Manager at Immunai in New York.

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