Hibernating corals and the microbiomes that sustain them

As winter approaches, many species of animals -- from bears and squirrels to parasitic wasps and a few lucky humans -- hunker down for some needed rest. The northern star coral (Astrangia poculata)also enters a hibernating state of dormancy, or quiescence, during this time. But what happens to its microbiome while it's sleeping?

A study led by University of California, Davis, Assistant Professor Anya Brown found that microbial communities shift while this coral enters dormancy, providing it an important seasonal reset. The work may carry implications for coral in warmer waters struggling with climate change and other environmental issues.

"Dormancy, at its most basic, is a response to an environmental stressor -- in this case, cold stress," said Brown, who is part of the UC Davis Bodega Marine Laboratory in the Department of Evolution and Ecology. "If we understand more about this recovery period, it might help us understand what microbes may be responsible for recovering coral in warmer tropical systems."

The study, published in the journal Applied and Environmental Microbiology with scientists from Woods Hole Oceanographic Institution, or WHOI, and Roger Williams University, is the first to demonstrate a persistent microbial community shift with dormancy in a marine animal.

"This study shows that microbes respond to stress and recover in a predictable pattern," said co-author Amy Apprill, an associate scientist at WHOI. "It's foundational knowledge that may help us develop probiotics or other microbial treatments for stressed tropical corals."

While you were sleeping

From October 2020 through March 2021, researchers dove 60 feet down into cold, nearly 40 degrees Fahrenheit water to collect 10 distinct colonies of the coral A. poculata from a dock in Woods Hole, Massachusetts. This coral is found in Atlantic waters extending from the Gulf of Mexico to Massachusetts. As water temperatures cool, the coral retracts its tentacles, stops eating or responding to touch, and goes dormant.

The scientists characterized the microbiomes of the wild coral before, during and after dormancy. They found that while the coral "sleeps," its microbiome sheds nutrient-loving and pathogen-associated microbes, while increasing microbes that may contribute nitrogen while the coral is no longer eating. The scientists found that this restructuring helps the corals maintain their microbial community structure.

"We have long hypothesized that Astrangia's seasonal dormancy allows the coral microbiome to reset and restructure," said co-author Koty Sharp, associate professor at Roger Williams University. "Our research found evidence for a shuffling during that dormant period that may help us identify microbial associates that are key to coral health and recovery from disturbance."

Why does coral wake up?

With this study, a marine species -- the coral A. poculata -- now joins bears, squirrels, crickets and others on the list of animals found to have microbiomes that shift while they are dormant. For example, the ground squirrel's gut microbiome plays an important role in nitrogen recycling while the squirrel fasts during hibernation.

"This work opens a lot of questions," Brown said. "A big one is: Why does the coral 'wake up' in the early spring? This study suggests that key microbial groups may play an important role in triggering the onset of or emergence from this coral's dormancy and the regulation of its microbiome."

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Hibernation slows biological aging in bats

The most common bat in the United States, the big brown bat, boasts an unusually long lifespan of up to 19 years. A new study led by University of Maryland researchers identifies one of the secrets to this bat's exceptional longevity: hibernation.

"Hibernation has allowed bats, and presumably other animals, to stay in northerly or very southerly regions where there's no food in the winter," said the study's senior author, UMD Biology Professor Gerald Wilkinson. "Hibernators tend to live much longer than migrators. We knew that, but we didn't know if we would detect changes in epigenetic age due to hibernation."

The researchers determined that hibernating over one winter extends a big brown bat's epigenetic clock -- a biological marker of aging -- by three-quarters of a year. The study, published in the journal Proceedings of the Royal Society BonAugust 10, 2022, also included scientists from McMaster University and the University of Waterloo, both in Ontario, Canada.

They analyzed small tissue samples taken from the wings of 20 big brown bats (Eptesicus fuscus) during two periods: in the winter when they hibernated and in the summer when they were active. The bats, kept in a research colony at McMaster University, ranged in age from less than 1 year old to a little over 10 years old.

Once the samples were collected, the researchers measured changes in DNA methylation -- a biological process associated with gene regulation -- between samples taken from the same animal during active and hibernating periods. They discovered that changes in DNA methylation occurred at certain sites in the bat's genome, and these sites appeared to be affecting metabolism during hibernation.

"It's pretty clear that the sites that decrease methylation in the winter are the ones that appear to be having an active effect," Wilkinson said. "Many of the genes that are nearest to them are known to be involved in regulating metabolism, so they presumably keep metabolism down."

Some of these genes are the same ones that Wilkinson and fellow researchers identified as "longevity genes" in a previous study. Wilkinson said that there is significant overlap between the hibernation genes and the longevity genes, further highlighting the link between hibernation and longer lifespans.

The earlier study also established the first epigenetic clock for bats, capable of accurately predicting the age of any bat in the wild. That clock was applied to this latest study, enabling the researchers to demonstrate that hibernation reduces a bat's epigenetic age in comparison to a non-hibernating animal of the same age.

Studies like this help explain why bats have longer lifespans than expected for a small mammal about the size of a mouse. However, they also raise new questions.

"We still don't have a very good understanding of why some bats can live a really long time and other ones don't," Wilkinson said. "We've shown that the ones that live a really long time all share the ability to hibernate, or to go into torpor frequently. That seems to be a corollary, but it's not sufficient because hibernating rodents don't live 20 years."

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What wintering squirrels can teach astronauts

When bears and ground squirrels hibernate in winter, they stop eating, lasting until spring simply on the fat reserves they've stored up in their bodies. Usually, this sort of prolonged fasting and inactivity would significantly reduce the mass and function of muscle, but hibernators don't suffer this fate. How they avoid it, however, has been a mystery.

Now, in research published in Science, an Université de Montréal biologist has figured out why, and his findings could have implications for, of all things, the future of space travel . By studying a variety called the 13-lined ground squirrel that is common in North America, Matthew Regan has confirmed a theory known as "urea nitrogen salvage" dating back to the 1980s.

The theory posits that hibernators harness a metabolic trick of their gut microbes to recycle the nitrogen present in urea, a waste compound that is usually excreted as urine, and use it to build new tissue proteins.

How could this discovery be of use in space? Theoretically, Regan posits, by helping astronauts minimize their own muscle-loss problems caused by microgravity-induced suppression of protein synthesis and which they now try to reduce by intensively exercising.

If a way could be found to augment the astronauts' muscle protein synthesis processes using urea nitrogen salvage, they could be able to achieve better muscle health during long voyages into deep space in spacecraft too small for the usual exercise equipment, the argument goes.

"Because we know which muscle proteins are suppressed during spaceflight, we can compare these proteins with those that are enhanced by urea nitrogen salvage during hibernation," said Regan, who carried out this research while a postdoc at the University of Wisconsin-Madison.

He is now continuing his work through a Canadian Space Agency research grant at UdeM, where he last year took up a position as assistant professor of animal physiology in the Department of Biological Sciences.

"If," Regan continued, "there is an overlap between the proteins in spaceflight and the ones from hibernation, then it suggests this process may have benefits to muscle health during spaceflight."

A model hibernator

In his study, Regandesigned a series of techniques and experiments to investigate the major steps in the urea salvage process and provide evidence for whether or not they occur in the 13-lined ground squirrel when it hibernates.

To do that, in their lab they injected their test squirrels' blood with "double-labeled" urea, meaning the urea's carbon atom was 13C instead of the usual 12C, and its nitrogen atoms were 15N instead of the usual 14N. These labels allowed them to track the urea-sourced carbon and nitrogen through the different steps of the urea nitrogen salvage process.

That process, they found, led from the initial transport of urea from the blood into the gut, to the breakdown of urea into its component parts by gut microbes, to the flow of substances -- called metabolites -- containing urea nitrogen back into the animal, and finally to the eventual appearance of this urea nitrogen in tissue protein.

"Essentially, seeing 13C and/or 15N in metabolites at these various steps indicated that they originated from urea, and thus, that the hibernator was using urea nitrogen salvage," said Regan.

He did his experiments on squirrels with and without gut microbiomes at three times of the year: summer, when they were active and not hibernating; early winter, when they were one month into fasting and hibernation; and late winter, when they were four months into fasting and hibernation.

'Clear evidence of nitrogen salvage'

What they found was definitive: at each step of the process, there was clear evidence of urea nitrogen salvage by the squirrels with intact gut microbiomes.

Importantly, the squirrels with depleted gut microbiomes displayed no evidence of urea nitrogen salvage at any step, confirming this process was wholly dependent on the gut microbes' ability to degrade urea, something the squirrels themselves cannot do.

Regan and his team also made two other important findings:
 

• First, the incorporation of urea nitrogen into the tissue protein of the squirrels was highest during late winter, suggesting that urea nitrogen salvage becomes more active as the hibernation season proceeds. This is unlike most physiological processes during hibernation, when tend to be significantly reduced.
• Second, there was evidence the microbes themselves were using the urea nitrogen to build their own new proteins, which is useful for them because they, like the squirrel, are under conditions of fasting hibernation. Thus, both the squirrel and its microbes benefit from urea nitrogen salvage, which makes this process a true symbiosis.

What this means, Regan said, is that the squirrels emerge from hibernation in the spring in good shape. This is important because the year's only mating season, which is a time of intense physical activity for both males and females, occurs directly after they emerge from hibernation. Tissue function -- particularly muscle tissue function -- is therefore highly important for a successful mating season.

"By facilitating muscle protein synthesis late in the hibernation season, urea nitrogen salvage may help optimize the emerging squirrels' muscle function and contribute to their reproductive success during the mating season," said Regan. "Urea nitrogen salvage may therefore enhance the animals' overall biological fitness."

Starving masses and the elderly

Beyond the implications for space travel and the health of astronauts, Regan's discovery could have more immediate impacts now right here on Earth -- in the starving masses of the underdeveloped world, and in the elderly.

Hundreds of millions of people globally experience muscle wasting as a consequence of various conditions -- undernourishment, for instance, affects over 805 million people globally. More prevalent in Canada is sarcopenia, an age-related decline in muscle mass stemming from anabolic insensitivity that affects all humans, leading to a 30- to 50-per-cent decline in skeletal muscle mass between the ages 40 and 80.

"The mechanisms that mammals like the 13-lined ground squirrel have naturally evolved to maintain protein balance in their own nitrogen-limited situations may inform strategies for maximizing the health of other nitrogen-limited animals, including humans," said Regan. One solution might be to develop a pre- or probiotic pill that people could take to promote a gut microbiome of the kind that hibernators like squirrels have.

"To be clear, these applications, though theoretically possible, are a long way from delivery, and a lot of additional work is needed to translate this naturally evolved mechanism safely and effectively to humans," Regan said.

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An unusual creature is coming out of winter's slumber: Here's why scientists are excited

 If you binged on high-calorie snacks and then spent the winter crashed on the couch in a months-long food coma, you'd likely wake up worse for wear. Unless you happen to be a fat-tailed dwarf lemur.

This squirrel-sized primate lives in the forests of Madagascar, where it spends up to seven months each year mostly motionless and chilling, using the minimum energy necessary to withstand the winter. While zonked, it lives off of fat stored in its tail.

Animals that hibernate in the wild rarely do so in zoos and sanctuaries, with their climate controls and year-round access to food. But now our closest hibernating relative has gone into true, deep hibernation in captivity for the first time at the Duke Lemur Center.

"They did not disappoint," said research scientist Marina Blanco, who led the project. "Indeed, our dwarf lemurs hibernated just like their wild kin do in western Madagascar."

The researchers say recreating some of the seasonal fluctuations of the lemurs' native habitat might be good for the well-being of a species hardwired for hibernation, and also may yield insights into metabolic disorders in humans.

"Hibernation is literally in their DNA," Blanco said.

Blanco has studied dwarf lemurs for 15 years in Madagascar, fitting them with tracking collars to locate them when they are hibernating in their tree holes or underground burrows. But what she and others observed in the wild didn't square with how the animals behaved when cared for in captivity.

Captive dwarf lemurs are fed extra during the summer so they can bulk up like they do in the wild, and then they'll hunker down and let their heart rate and temperature drop for short bouts -- a physiological condition known as torpor. But they rarely stay in this suspended state for longer than 24 hours. Which got Blanco to wondering: After years in captivity, do dwarf lemurs still have what it takes to survive seasonal swings like their wild counterparts do? And what can these animals teach us about how to safely put the human body on pause too, slowing the body's processes long enough for, say, life-saving surgery or even space travel?

To find out, Duke Lemur Center staff teamed up to build fake tree hollows out of wooden boxes and placed them in the dwarf lemurs' indoor enclosures, as a haven for them to wait out the winter. To mimic the seasonal changes the lemurs experience over the course of the year in Madagascar, the team also gradually adjusted the lights from 12 hours a day to a more "winter-like" 9.5 hours, and lowered the thermostat from 77 degrees Fahrenheit to the low 50s.

The animals were offered food if they were awake and active, and weighed every two weeks, but otherwise they were left to lie.

It worked. In the March 11 issue of the journal Scientific Reports, the researchers show for the first time that fat-tailed dwarf lemurs can hibernate quite well in captivity.

For four months, the eight lemurs in the study spent some 70% of their time in metabolic slow-motion: curled up, cool to the touch, barely moving or breathing for up to 11 days at a stretch, showing little interest in food -- akin to their wild counterparts.

Now that spring is afoot in North Carolina and the temperatures are warming, the lemurs are waking up. Their first physical exams after they emerged showed them to be 22% to 35% lighter than they were at the start but otherwise healthy. Their heart rates are back up from just eight beats per minute to about 200, and their appetites have returned.

"We've been able to replicate their wild conditions well enough to get them to replicate their natural patterns," said Erin Ehmke, who directs research at the center.

Females were the hibernation champs, out-stuporing the males and maintaining more of their winter weight. They need what's left of their fat stores for the months of pregnancy and lactation that typically follow after they wake up, Blanco said.

Study co-author Lydia Greene says the next step is to use non-invasive research techniques such as metabolite analysis and sensors in their enclosures to better understand what dwarf lemurs do to prepare their bodies and eventually bounce back from months of standby mode -- work that could lead to new treatments for heart attacks, strokes, and other life-threatening conditions in humans.

Blanco suspects the impressive energy-saving capabilities of these lemurs may also relate to another trait they possess: longevity. The oldest dwarf lemur on record, Jonas, died at the Duke Lemur Center at the age of 29. The fact that dwarf lemurs live longer than non-hibernating species their size suggests that something intrinsic to their biological machinery may protect against aging.

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