A rodent that recycles nitrogen to hibernate

Thanks to hibernation, groundhogs, hedgehogs and many other animals slow down their metabolism by up to 99% before winter during the hypothermic phases. However, such periods of fasting lead to a significant protein imbalance, as they deprive sleeping people of essential nutrients. This is the case for nitrogen, a building block of amino acids and therefore proteins, normally supplied with food and involved in particular in the maintenance of muscle mass. In animals, protein breakdown results in the release of ammonia (NH3), a toxic compound that the liver cells convert into urea. Thus, the latter is the final form in which nitrogenous waste products are excreted in mammals. Carried by the blood, it is filtered in the kidneys and then excreted in the urine, but is therefore not reused. Thus obtaining nitrogen is a major problem during hibernation. How do hibernators adapt? Matthew Regan’s team at the University of Wisconsin-Madison in the US studied the role of the gut microbiota in urea nitrogen recycling during hibernation. They found that in striped ground squirrels, certain bacteria play a critical role in nitrogen reincorporation.

For most hibernators, a lack of nitrogen leads to muscle wasting, a post-waking problem not experienced by the striped ground squirrel, a hibernating rodent native to North America. We knew that the urea produced by this animal is metabolized by certain intestinal microorganisms, which extract their own sources of nitrogen from it. However, it was not known whether this urea nitrogen released by the microbiota could be reused in the metabolism of these ground squirrels to compensate for nitrogen deficiency. To answer this question, the scientists injected urea labeled with traceable isotopes of carbon and nitrogen into the blood of ground squirrels at different times of the year: in summer, at the beginning of hibernation, and at the end of winter. They also treated some of the animals with antibiotics to eliminate some of the microorganisms from their gut microbiota. This allowed them to compare the response of rodents with intact or depleted microbiota.

Through isotopic labeling, scientists have followed the process of nitrogen exchange between the host and its microbiota. They showed that incorporation of labeled nitrogen (from the degradation of injected urea) into tissue proteins of striped ground squirrels was higher in late winter, suggesting that nitrogen recovery increases as fasting continues. This is facilitated by an increased ability to transport urea from the blood into the intestinal lumen due to higher expression and hence more urea transporters (UTBs) in winter compared to when the animals are active. On the contrary, in the tissues of animals with a depleted microbiota, there was less labeled nitrogen. Therefore, nitrogen recirculation appears to be dependent on the presence of intestinal microorganisms.

The team then focused on the expression of urease, an enzyme that is not produced by animals but is specifically expressed by certain intestinal microorganisms. This enzyme hydrolyzes urea to ammonia (NH3) and carbon dioxide (CO2). After sequencing the genome of bacteria present in the gut of rodents, the researchers found that the increase in urease gene expression coincided with the incorporation of nitrogen (in its hydrolyzed form of ammonia) by ground squirrels during the winter season. Thus, it would appear that the host and its microbiota co-evolved towards a close symbiotic relationship in which the host benefits from the ureolytic activity of its gut bacteria to re-incorporate nitrogen during periods of hypometabolism.

Researchers do not exclude the existence of similar mechanisms in other mammals, including humans. These findings may open up potential applications for maintaining muscle mass during aging.

A rodent that recycles nitrogen to hibernate

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