Red meat can be a raw deal, medically speaking, because it is enriched with Neu5Gc, an acidic sugar that has been associated with chronic inflammation and related diseases such as colon cancer and atherosclerosis. Neu5Gc causes health problems because it becomes a part of cell surface glycans, which can enter the circulation and run afoul of anti-Neu5Gc antibodies. If only we could strip red meat of Neu5Gc, we might keep it in our diet without provoking our immune system.
Although we can’t trim away Neu5Gc by ourselves, we might do so with the help of bacteria. Bacteria, it has been established, can use free sialic acids as a nutrient source—and Neu5Gc is a sialic acid. But what about sialic acids that aren’t free, but are, instead, attached to the foods we eat? To answer that question, scientists based at the University of California, San Diego, decided to study the gut microbiome. Perhaps, the scientists reasoned, the gut microbiomes of meat eaters contain high levels of bacteria with an appetite for Neu5Gc.
By experimenting with humanized mice and sequencing metagenomes, the scientists detailed microbiome changes that corresponded to dietary changes. These findings, which highlighted bacteria that produced a Neu5Gc-cleaving enzyme, were confirmed by publicly available genomic data that had been gathered in studies of the Hazda, an indigenous hunter-gatherer group that lives in a remote region of Tanzania. In Tanzania’s dry season, the Hadza hunt and eat meat. In the wet season, they can’t hunt and rely instead on a diet primarily of berries and honey.
Having identified the Neu5Gc-cleaving enzyme, the scientists, led by Karsten Zengler, PhD, a professor in the departments of pediatrics and bioengineering, synthesized it in the lab. Subsequent experiments with the enzyme suggest that it could be used to release Neu5Gc from red meat before it is consumed.
“It’s our hope that this approach could be used as a sort of probiotic or prebiotic to help reduce inflammation and the risk of inflammatory diseases—without giving up steak,” said Zengler, who is the senior author of an article (“Gut bacteria responding to dietary change encode sialidases that exhibit preference for red meat-associated carbohydrates”) that appeared September 23 in Nature Microbiology.
“We found that a Neu5Gc-rich diet induces changes in the gut microbiota, with Bacteroidales and Clostridiales responding the most,” the article’s authors wrote. “Genome assembling of mouse and human shotgun metagenomic sequencing identified bacterial sialidases with previously unobserved substrate preference for Neu5Gc-containing glycans. X-ray crystallography revealed key amino acids potentially contributing to substrate preference.”
The article notes that mice were fed either a red meat diet rich in Neu5Gc or one of two control diets that lacked the carbohydrate. Overall, the red meat–like diet was associated with less bacterial diversity in the mouse gut microbiomes. Yet there were several bacteria types that were more abundant in the guts of the Neu5Gc-fed mice than the mice that didn’t consume the meat-related carbohydrate. One of these was Bacteroides, a type of bacteria known for surviving on carbohydrates.
Moreover, the Neu5Gc-fed mice, Bacteroides produced large amounts of an unfamiliar enzyme notable for its ability to cleave Neu5Gc off of cells. In the laboratory, the synthesized version of this enzyme was active and preferred nonhuman Neu5Gc over similar human carbohydrates.
Zengler then took the study a step further: to the grocery store. His team bought steak and pork sausage from a local store and brought it back to the lab. They rubbed their lab-made sialidase on the meat, and sure enough, most of the Neu5Gc came right off.
“The approach isn’t perfect yet—the sialidase enzyme prefers to cleave Neu5Gc, but it still cleaves a bit of a similar human carbohydrate,” said Zengler. Nonetheless, Zengler and colleagues concluded that “the release of Neu5Gc from red meat using bacterial sialidases could reduce the risk of inflammatory diseases associated with red meat consumption, including colorectal cancer and atherosclerosis.”
Zengler and his team are now working to optimize the enzyme to increase its specificity. The team also wants to explore methods to mass produce the enzyme and further explore its potential for preventing inflammation and inflammatory diseases.
