With only a single layer of epithelial cells standing between what we’ve eaten and our inner tissues, the intestinal lining is constantly facing a unique conundrum: how does it absorb nutrients from food while maintaining a barrier against potentially infectious pathogens? What’s more, how does it maintain this balance in the face of constantly shifting environmental circumstances? A study using mice published in Science last month (March 19) may have unearthed a clue.

The researchers show that poorly understood immune cells called gamma-delta T cells are responsible for altering the relative abundance of various epithelial cell types, effectively specializing the gut to maximize nutrient absorption in the face of a changing diet.

To first author Zuri Sullivan, this finding was really surprising “because not only is it the first description of an immune cell being directly involved in nutrition,” she says, “but it’s a completely new function for these gamma-delta T cells that hadn’t been described before.”

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

In the new paper, Sullivan shifted mice from their normal chow onto one of two new diets. They each contained the same total number of calories, but one was high in protein and the other was high in carbohydrates. Then she analyzed gene expression within the small intestine after five days of being on each special diet. Not surprisingly, she noticed that compared to mice chowing down on the high-protein diet, mice eating a heavy carb load had a higher expression of genes involved in carbohydrate processing and absorption.

But the changes went beyond gene regulation. When Sullivan and her colleagues used single-cell RNA sequencing to get an in-depth look at the epithelial cell populations in the gut, they observed different subsets of cells depending on whether the mice were eating carbs or protein. “The intestine is actually getting remodeled by the diet,” Medzhitov says. The gut can selectively expand populations of specialized cell types in response to various intestinal pathogens, he says, but researchers didn’t know until now that it could also do this with nutrients.

Although the composition and health of the gut microbiome is intimately linked to host nutrition and metabolism, Sullivan documented the same gut adaptations when she repeated the experiments in germ-free mice, indicating that they were occurring independently of the resident microbiota.

To determine whether the epithelial cells were directly sensing and responding to the different diets, Sullivan cultured small intestinal organoids in a dish. These mini guts are grown from intestinal stem cells that differentiate into most of the major 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 elevated concentrations of glucose (to mimic the high-carb diet) and measured gene expression. Although the organoids could express the carbohydrate-processing genes, the activity levels of these genes didn’t increase with increasing glucose, suggesting that another, nonepithelial cell type was orchestrating the remodeling.

Because gut lymphocytes are important for the gut remodeling that occurs during infections, the researchers looked to see if they were also at play in responding to diet. When mice with no lymphocytes ate the high carb chow, their intestinal epithelium no longer changed to accommodate the dietary shift. By repeating the experiment in mice lacking specific types of lymphocytes, Sullivan pinned down a class of lymphocytes called gamma-delta T cells, which are abundant in the gut but poorly understood, as the cells responsible.

Unconventional immune cells

Gamma-delta T cells have been shown to increase airway mucus during influenza infection. They also control anxiety behaviors in mice, and help regulate body temperature. Medzhitov says the discovery that gamma-delta T cells are required for gut adaptation to different nutrients supports the idea that instead of being primarily responsible for host defense, they may be more important for regulating tissue homeostasis. “That’s very exciting,” he says, and consistent with growing indications that gamma-delta T cells might be involved in nontraditional roles for immune cells.

“The thing that I love about these types of papers is that it shows the immune system is so much more than just protecting us against pathogens,” says Lydia Lynch, an immunologist at Harvard Medical School who was not involved in the work.

“A large fraction of the immune system’s energy is devoted to [allowing] the host to adapt to different challenges” beyond infections, including tissue damage, inflammation, and even malnutrition, says National Institute of Allergy and Infectious Diseases immunologist Yasmine Belkaid, who was not involved in the study.

Medzhitov’s group is interested in studying how the gut handles more-complicated nutritional adaptation, such as regulating the transport of essential versus nonessential amino acids, as well as studying whether there is a tradeoff when the gut has to adapt to new nutrients at the same time it encounters an infection.  

“The way that this tissue operates 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’re going to die. If you don’t protect yourself against pathogens, you’re also going to die. But you need to do those two things at the right time, depending on what’s going on outside.”

Z.A. Sullivan et al. γδ T cells regulate the intestinal response to nutrient sensing. Science. doi:10.1126/science.aba8310, 2021.