For her work showing that restoring lost bacterial cues in the gut can stimulate development of insulin-producing cells, potentially protecting against the autoimmune destruction associated with type 1 diabetes (T1D), Jennifer Hampton Hill, PhD, has won this year’s NOSTER & Science Microbiome Prize.
“When we started this work, virtually nothing was known about the role of the microbiota in type 1 diabetes,” said Hill. While it had been established that individuals with T1D have reduced microbiota diversity—suggesting they’d lost, or were never colonized with, specific bacteria that played important disease protection roles—Hill’s work goes a step farther, showing that a particular bacterial protein BefA, which is found in rodent and human gut microbes, can help restore insulin production. “If we can continue to learn more about the mechanisms driving specific effects of the microbiota,” Hill said, “I think we can … hopefully use that knowledge to treat many autoimmune diseases.” Hill reported on the work in Science, in an essay titled “From bugs to ß cells.”
One hundred years ago, Frederick Banting and Charles Best transformed the prognosis of type 1 diabetes through their discovery of the hormone insulin. Scientists have since made great progress in understanding T1D, which is now known to be an autoimmune disease characterized by the destruction of insulin-producing ß cells of the pancreas.
Treatment approaches for T1D focus on either restoring endogenous insulin or tempering autoimmunity. “However, a cure still evades discovery, and its realization will require a dual approach that tempers autoimmunity while simultaneously restoring endogenous insulin production.” Hill wrote. There have been notable advances related to the former approach— restoring insulin—the field hasn’t yet had much luck stimulating endogenous insulin renewal. One reason for this is the inconsistency in beta-cell physiology between rodents and humans.
“While mice and rats have a great deal of similarity with us, there are also important differences,” Hill said. “These differences often become apparent when researchers test whether an exciting finding from a mouse islet translates to a human islet.”
Hill explained that many in the field have found that human ß cells are repeatedly recalcitrant to signals that robustly stimulated rodent cells. But she and colleagues identified a pathway to restoring insulin that stimulates rodent cells and holds promise for human ß cells.
Hill and colleagues had hypothesized that because animals evolved in a microbial world, it is plausible that they used microbial cues to gather information about the environment, such as local nutrient availability, and set their metabolisms to match. “We investigated whether animals use microbial cues to tune the number of cells producing the conserved metabolic regulator, insulin,” Hill explained. “To optimize energy needed for development of these cells, animals need to match insulin production capacity to environmental nutrient availability. Thus, we hypothesized that hosts incorporate information from their resident microbiomes to accomplish this optimization.”
So Hill’s team set out to investigate whether animals tune the number of cells producing insulin by incorporating information from their resident microbiomes. To test this idea, they used the zebrafish model to study development of pancreatic ß cells with or without the microbiota. “We leveraged a vertebrate zebrafish model to study development of pancreatic ß cells with or without microbiota, by comparing sterile or germ-free (GF) larvae and their conventionally reared (CV), microbe-carrying counterparts,” noted Hill in the published report.” When comparing larvae grown in environments without microbes to their conventionally reared, microbe-carrying counterparts, they found that latter larvae had significantly more ß cells than the microbe-free larvae.
Then, Hill explained, taking a reductionist approach “we systematically added back individual zebrafish gut bacteria and their secreted products until we identified a single protein that was sufficient to restore GF ß cell mass. The protein we identified was previously unknown, and we named it ß cell expansion factor A (BefA).
To test whether BefA elicited similar responses in mammalian species, they analysed ß cell development in microbe-free mouse models. Adding purified BefA was enough to increase developing ß cell mass in these animals, they showed. “Not only did we find that newborn GF mice had the same paucity of ß cells as GF larval fish, but purified BefA was sufficient to increase their developing ß cell mass,” Hill wrote in the paper.
The team’s studies found that Befa might originate from certain microbiome species. “Searches for BefA-related sequences uncovered homologs in a handful of bacteria of the Enterobacteriaceae family commonly found in healthy mammalian microbiomes after birth, when ß cells normally undergo substantial expansion.”
Why BefA evolved as a microbial product remains a question. The team resolved the crystal structure of BefA, and identified a previously unknown protein fold for a putative lipid-binding domain that was sufficient for the protein’s activities. The team also determined that BefA was capable of binding to, and perturbing lipid bilayers, which is something the team noted is common to antimicrobial proteins, “like the Reg proteins,” that are secreted in the gut to prevent infection by microbes.
“We know BefA can bind to and disrupt cell membranes, which is a hallmark of an antimicrobial proteins (AMP), and bacteria tend to utilize AMPs as tiny weapons against other microbes,” Hill noted. “But we still don’t fully understand the advantages that BefA production provides in the context of a complex microbial community. These are important questions to think about because if we can understand the circumstances that lead bacteria to produce BefA, we might be able to use that knowledge to boost natural BefA production in hosts more susceptible to disease.”
Knowing BefA’s mechanism for impacting ß cells could pave the way to researchers restoring or increasing ß cell production, said Hill, though she noted her own work has been focused on developing cells—and there are important differences between ß cells from infants versus mature adults.
“We are currently working on experiments to evaluate the effects of BefA later in life, and on mature ß cells,” said Hill. “Because our discovery of BefA is highly conserved [across vertebrates] … we’re optimistic about the potential of our discovery to overcome [existing] translational hurdles … If BefA can promote the turnover or regeneration of mature adult ß cells, it would be promising as a potential ß cell replacement therapy.” As she concluded in her essay, “Understanding current declining microbiome diversity as a loss of ancient developmental cues allows us to imagine future strategies to correct the environmental information conveyed during human pancreas development to ward off T1D.”
The hygiene hypothesis that is often discussed today posits that certain diseases we are seeing more frequently, such as T1D, are the result of changing societal practices that have reduced microbial exposures and decreased microbiome diversity. “In the case of T1D, decreased gut microbiome diversity is characteristic of and can be predictive of disease onset, suggesting that at-risk children may be missing specific microbes with disease-mitigating functions,” Hill wrote. The team further suggested in their essay that fortification of these microbial activities in children who carry risk alleles for T1D could be a strategy to prevent or delay disease.
Hill was initially drawn to microbiology research through an inspiring undergraduate 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.”
Post-undergraduate, Hill completed a fellowship at the University of California San Francisco in Didier Stainier’s lab working on zebrafish beta-cell regeneration, creating the unique path of research that would lead to her prize-winning research.
“When I started my dissertation in Karen Guillemin’s lab at Oregon, who was an emergent leader in studying microbiota effects during development, it was sort of fortuitous to marry the only previous research experiences I’d had in microbiology and ß cell development. And to our surprise, it was an idea with real legs!” Hill said.
The NOSTER & Science Microbiome Prize awarded to Hill for her diabetes-focused work aims to reward innovative research from young investigators working on the functional attributes of the microbiota of any organism that has potential to contribute to our understanding of human or veterinary health and disease, or to guide therapeutic interventions.
Hill reflected on the significance of winning this prize in her research area. “There is amazing and fascinating work being done all across the microbiome field,” she said, “and to be selected from it is a huge honor. I’m elated to be recognized, especially as a young scientist trying to establish my own niche. My work has been supported by remarkable mentors and colleagues, and it certainly wouldn’t be possible without them. I’m incredibly grateful. It’s a very exciting time to be studying the microbiota, and this award helps to draw attention to the innovation that 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 truly hope that the prize will motivate young scientists to passionately pursue their research to develop microbiome-based therapeutic drugs for the benefit of human health and that world’s children who will be the architects of the future of our Earth will be inspired by the wonders of scientific discovery.”
“Submissions for the 2022 NOSTER/Science Prize have been outstanding,” added Caroline Ash, senior editor at Science. “It is a great privilege to be given a glimpse of the fascinating, sophisticated and important research that today’s generation of scientists is contributing to understanding the interactions of the microbiota with their hosts.”