Newly started insulin production with microbial diversity wins the NOSTER & Science Microbiome Prize

Newly started insulin production with microbial diversity wins the NOSTER & Science Microbiome Prize

Irina Leonardi

image: Irina Leonardi Headshot
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Credit: Irina Leonardi

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), Dr. Jennifer Hampton Hill winner of this year’s NOSTER & Science The microbiome price.

“When we started this work, virtually nothing was known about the role of the microbiota in type 1 diabetes,” Hill said. Although it had been established that individuals with T1D had reduced microbiotadiversity – indicating that they had lost, or never colonized with, specific bacteria that played important disease-protective roles – her work goes a step further and shows a certain bacterial protein found in rodents and Human gut microbes can help restore insulin production.

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

NOSTER & Science The Microbiome Prize awarded to Hill for her diabetes-focused work aims to reward innovative research from young researchers working on the functional properties of the microbiota of all organisms that have the potential to contribute to our understanding of human or veterinary health and disease, or to guide therapeutic interventions .

Submissions for 2022 NOSTER /Science The award has been outstanding “, says Caroline Ash, senior editor at Science. “It is a great privilege to get a glimpse of the fascinating, sophisticated and important research that today’s generation of researchers is helping to understand the interactions of microbiota with its hosts.”

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

Treatment methods for T1D focus on either restoring endogenous insulin or tempering autoimmunity. Although remarkable progress has been made in the previous approach – insulin recovery – the field has not yet been very successful in stimulating endogenous insulin renewal. One reason for this is the inconsistency in beta cell physiology between rodents and humans.

“While mice and rats are very similar to us, there are important differences,” Hill said. “These differences often become apparent when researchers test whether an exciting find from a museum is translated into a human islet.”

Hill explained that many in the field have found that human beta cells are repeatedly reluctant to signal strongly stimulated rodent cells. But she and colleagues identified a way to restore insulin that stimulates rodent cells and promises human beta cells.

Hill and colleagues hypothesized that because animals evolved in a microbial world, it is likely that they used microbial clues to gather information about the environment, such as local nutrient availability, and set their metabolism to match. They set out to investigate whether animals set the number of cells that produce insulin by incorporating information from their native microbiomes.

To test this idea, Hill and her team used the zebrafish model to study the evolution of pancreatic beta cells with or without the microbiota. When comparing larvae grown in environments without microbes with their conventionally bred, microbial-bearing counterparts, they found that the latter larvae had significantly more beta cells than the microbial-free ones.

“We systematically put back individual zebrafish gut bacteria and their secreted products until we identified a single protein that was sufficient to restore GF-beta cell mass,” 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 sufficient to increase the growing beta-cell mass of these animals, they showed.

“Because our discovery of BefA is very much preserved [across vertebrates]”said Hill,” we are optimistic about the potential of our discovery to overcome [existing] barriers to translation. “

Why BefA was developed as a microbial product is still a question, she noted.

“We know that BefA can bind to and disrupt cell membranes, which is a hallmark of antimicrobial proteins (AMPs), and bacteria tend to use AMPs as small weapons against other microbes … But we still do not fully understand the benefits of BefA production. provides within the framework of a complex microbial community, “said Hill.” These are important questions to consider because if we can understand the circumstances that lead to bacteria producing BefA, we may be able to use that knowledge to increase natural BefA production in hosts that are more susceptible to disease. “

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

“We are currently working on experiments to evaluate the effects of BefA later in life, and on mature beta cells,” says Hill. “If BefA can promote the turnover or regeneration of mature adult beta cells, it would be promising as a potential beta cell replacement therapy.”

The hygiene hypothesis that is often discussed today suggests that certain diseases we see more often, such as T1D, are the result of changing societal practices that have reduced microbial exposure and reduced microbiome diversity. Hill and her team suggest in their thesis that enhancing these microbial activities in children carrying risk alleles for T1D may be a strategy for preventing or delaying disease.

Hill was initially drawn to microbiology research through an inspiring professor, Patty Siering, at Humboldt State University in California. “Working in her lab really revealed to me how much potential is hidden in the unexplored space of bacterial genomes.”

After graduating, Hill completed a scholarship to the University of California San Francisco in Didier Stainier’s lab and worked on beta-cell regeneration of zebrafish, creating the unique research pathway that would lead to her award-winning research.

“[W]When I began my dissertation in Karen Guillemin’s lab in Oregon, which was an emerging leader in studying microbiota effects in development, it was a coincidence to marry the only previous research experience I had in microbiology and beta cell development. And to our surprise, it was an idea with real legs! ” in Hill.

Hill reflected on the importance of winning this award in his field of research. “There is a fantastic and fascinating work being done all over the microbiome field,” she said, “and being selected from it is a great honor. I am thrilled to be recognized, especially as a young researcher trying to establish my own niche. My work has been supported by fantastic mentors and colleagues, and it would certainly not be possible without them. I am incredibly grateful. It is a very exciting time to study the microbiota, and this award helps to draw attention to the innovation that this area has to offer. . ”

“Control of the microbiome is expected to help prevent and treat many chronic diseases,” said Kohey Kitao, CEO of Noster Inc. for the benefit of human health and that the children of the world who will be the architects of the future of our earth will be inspired by the wonders of scientific discovery. ”


Apollo Stacy is the finalist for his essay “Host-derived metabolite trains the microbiota to develop colonization resistance”, which focused on analyzing the intestinal microbiota in previously infected mice, discovering that transient infection can increase colonization resistance, and found that microbiota can be “trained” by Sta infection metabolites. received his undergraduate degree from Washington University in St. Louis, PhD from the University of Texas at Austin, and is currently a postdoctoral fellow at the National Institutes of Health and started his laboratory at the Cleveland Clinic Lerner Research Institute in 2022. His research examines how host-derived metabolites shape ecological balance and thus host susceptibility to inflammatory diseases.

Irina Leonardi is a finalist for her essay “Mycobiota modulates immunity and behavior”, which focused on fungal communities as an integral part of the intestinal microbiota and worked to show that mucosal-associated fungi are associated with host-protective immunity. Leonardi received a bachelor’s degree from ETH Zurich and a doctorate from the University of Zurich. She did her postdoctoral work at Weill Cornell Medicine. Her research examined the cellular mechanisms of fungal recognition in the gut and the local and systemic consequences of intestinal fungal colonization. She is currently the Scientific Communications Lead at Immunai in New York.

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