Study: The Amount of Nutrients Matters More Than Their Type for Intestinal Cell Turnover

Researchers led by Sa Kan Yu of the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan have found that the natural turnover of intestinal cells in fruit flies depends on how much food the insects receive rather than on any particular nutrient. The scientists discovered that more intestinal cells were replaced when nutrient levels were low and the cells’ cytoplasm was more fluid and watery.

The findings, published in Proceedings of the National Academy of Sciences, challenge the traditional understanding of nutrient biology, which holds that nutrient sensing is largely controlled by biological signaling pathways activated by specific substances.

When we consume nutrients such as carbohydrates or proteins, their molecules eventually enter our cells and trigger biological responses. For example, pancreatic cells respond to blood glucose levels by producing insulin. Amino acids found in proteins, particularly leucine, stimulate the growth of most cells, while their absence can lead to cell death through self-digestion. In both cases, biological signaling depends on the type of nutrient involved.

The cells lining the intestine are in direct contact with nutrients and are known to be replaced frequently. Yu and his team previously discovered that the rapid turnover of these cells is driven by a new type of cell death, which they named erebosis. Scientists do not yet fully understand this process, so in the new study the team set out to determine how nutrients influence erebosis.

At first, the researchers obtained results they expected. They found that erebosis increased on a low-carbohydrate, high-sugar diet. Changing the concentration of sugar in the food had no effect, whereas reducing the concentration of amino acids by 90% triggered erebosis.

This was where the results became strange and unexpected. The team initially assumed that the cells were sensing amino acids through conventional biological pathways. However, when the researchers blocked these signaling pathways, erebosis continued.

The scientists then tested each individual amino acid at the concentration found in a high-amino-acid diet that suppresses erebosis. None of the amino acids suppressed the process on its own. But when their concentrations were increased substantially, erebosis was suppressed in every case. This indicated that the effect was not linked to any particular amino acid.

The researchers then examined individual components common to all amino acids. Yet erebosis was still suppressed even when amino acid metabolism was blocked. The team concluded that metabolism itself might not be required.

“The unexpected results were disappointing. Initially, we thought amino acids affected specific biochemical processes or that their byproducts, such as ammonia, urates and uric acid, were involved,” Yu explained. “However, no matter what we changed, the results were the same. The project stalled for a year.”

If the effect was not caused by a specific amino acid or metabolite, what was responsible? The breakthrough came when the researchers focused on the amount of nutrients. They hypothesized that when cells are saturated with amino acids, the fluid inside them becomes thicker and more viscous.

“Our struggle ended when we used a non-metabolizable amino acid analog that, surprisingly, affected erebosis,” Yu said. “From this, we concluded that amino acids affect the biophysical properties of the cytoplasm. After that, everything fell into place.”

The researchers identified two biochemically different molecules that can enter fruit fly cells and make their cytoplasm more viscous while remaining metabolically inactive. Introducing these molecules into the flies produced the same result.

“Based on these findings, we introduce the concept of ‘viscosity sensing’, in which intestinal cells determine their state of nutrient abundance or starvation based on the viscosity of their cytoplasm and adjust their condition accordingly,” Yu concluded.

Yu is now investigating whether erebosis also occurs in intestinal cells of mice and humans.

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