Mysterious immune cells alter the lining of the intestine to accommodate nutrition

After five days on a high-carbohydrate diet, a mouse’s small intestine produces proteins that help it process carbohydrates better, including sucrase isomaltase (an enzyme that breaks down sucrose, shown in magenta around the edge of the cells next to the black background). and Slc2a2 (a glucose transporter, marked in green). Cyan reflects the overlap of the magenta and green labels. Cores are marked in blue.

Rachel Zwick

W.With just a single layer of epithelial cells between what we have eaten and our internal tissues, the intestinal lining is constantly exposed to a unique puzzle: how does it absorb nutrients from food while maintaining a barrier against potentially infectious pathogens? What’s more, how does it maintain that balance in the face of ever-changing environmental conditions? A study with mice published in science The last month (March 19th) may have found a clue.

The researchers show that poorly understood immune cells called gamma-delta T cells are responsible for changing the relative abundance of different epithelial cell types and effectively specialize the gut to maximize nutrient uptake in the face of changing diets.

For the first author Zuri Sullivan, this result was really surprising, “because it is not only the first description of an immune cell that is directly involved in nutrition,” she says, “but it is a completely new function for this gamma-delta-T – Cells that did not exist have never been described. “

When Sullivan, who is now a postdoctoral fellow at Harvard University, was a graduate student in Ruslan Medzhitov’s lab at Yale School of Medicine, the two were interested in how the intestines adapt to different foods. Animals on highly specialized diets like koalas, pandas, and certain carnivores have genetically and morphologically adapted their intestines to efficiently digest the nutrients they eat, Sullivan says. “But for animals like us, who eat a lot of different foods that change from season to season and throughout our lives, we thought the gut should be able to adapt to that in order to be more efficient.”

What I love about these types of paper is that it shows that the immune system is so much more than just protecting us from pathogens.

– Lydia Lynch, Harvard Medical School

In the new paper, Sullivan switched mice from their normal diet to one of two new diets. They each had the same total number of calories, but one was high in protein and the other high in carbohydrates. She then analyzed gene expression in the small intestine five days after each specific diet. Unsurprisingly, mice that ate a heavy load of carbohydrates had higher levels of expression of genes involved in carbohydrate processing and absorption compared to mice that ate the high protein diet.

However, the changes went beyond gene regulation. When Sullivan and her colleagues used single-cell RNA sequencing to get a detailed look at epithelial cell populations in the gut, they observed different subsets of cells based on whether the mice ate carbohydrates or protein. “The gut is actually reshaped by diet,” says Medzhitov. The gut can selectively expand populations of specialized cell types in response to various gut pathogens, he says, but until now researchers didn’t know that nutrients could do the same.

Although the composition and health of the gut microbiome is closely related to the host’s diet and metabolism, Sullivan documented the same gut adaptations when she repeated the experiments on aseptic mice, suggesting that they occurred regardless of the resident microbiota.

To determine whether the epithelial cells were directly aware of and responded to the various diets, Sullivan cultivated organoids of the small intestine in a dish. These mini-guts are grown from intestinal stem cells, which differentiate into most large intestinal epithelial cell populations, and allow researchers to study epithelial cells without interference from other cells in the gut such as neurons, immune cells, or microbes. She grew the organoids in increased concentrations of glucose (to mimic the high-carbohydrate diet) and measured gene expression. Although the organoids were able to express the carbohydrate processing genes, the levels of activity of these genes did not increase with increasing glucose, suggesting that a different, nonepithelial cell type coordinated remodeling.

Because gut lymphocytes are important for the remodeling of the gut that occurs during infections, the researchers investigated whether they also play a role in the response to diet. When mice without lymphocytes ate the carbohydrate-rich food, their intestinal epithelium no longer changed to accommodate the change in diet. By repeating the experiment on mice lacking certain types of lymphocytes, Sullivan pinned a class of lymphocytes called gamma-delta T cells that are abundant in the gut but poorly understood as responsible cells.

Unconventional immune cells

Gamma-delta T cells have been shown to increase airway mucus during influenza infection. They also control fear behavior in mice and help regulate body temperature. Medzhitov says the discovery that gamma-delta T cells are required for the gut to adapt to various nutrients supports the idea that they are not primarily responsible for host defense, but may be more important in regulating tissue homeostasis. “This is very exciting,” he says, and is consistent with growing evidence that gamma-delta T cells may be involved in nontraditional roles for immune cells.

“What I love about these types of paper is that it shows that the immune system is so much more than just protecting us from pathogens,” says Lydia Lynch, an immunologist at Harvard Medical School who isn’t at work was involved.

“A large part of the immune system’s energy is used for this [allowing] The host has to adapt to different challenges, ”says Yasmine Belkaid, immunologist at the National Institute for Allergies and Infectious Diseases, who was not involved in the study.

Medzhitov’s group is interested in studying how the intestine deals with more complicated nutritional adjustments, such as regulating the transport of essential and non-essential amino acids, as well as the question of whether there is a compromise when the intestine has to adapt to new nutrients at the same time encounters an infection.

“The way this tissue works is to use the same machinery for its two main functions,” says Sullivan, “both of which are essential for survival. If you don’t get nutrients, you will die. If you don’t protect yourself from pathogens “You will die too. But you have to do these two things at the right time, depending on what is going on outside.”

ZA Sullivan et al.γδ T cells regulate the intestinal response to nutrient measurement. ” science, doi: 10.1126 / science.aba8310, 2021.

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