Researchers led by Sa Kan Yoo at the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan have discovered that the natural turnover of gut cells in the fruit fly depends on how much food the flies get, rather than any specific nutrient. They found that gut cells were replaced more when nutrient levels were low and the insides of gut cells were fluid and watery. Published in Proceedings of the National Academy of Sciences, this finding goes against traditional ideas in nutrient biology, which hold that nutrient sensing relies on biological signaling pathways activated by specific nutrients.

When we eat nutrients, like sugar or protein, the molecules eventually enter our cells and trigger biological reactions. For example, blood sugar is detected by cells in the pancreas, which then make insulin. Amino acids from proteins, particularly leucine, trigger cell growth in most cells, while its lack leads to cell death by self-digestion. In both cases, the biological signaling depends on the type of nutrient.

The cells that line the gut have direct contact with nutrients and are known to be replaced frequently. Yoo and his group at RIKEN BDR have been studying these cells and recently discovered that the rapid turnover is due to a new type of cell death, which they termed erebosis. Scientists do not really understand this process yet, and in the new study the team set out to characterize how erebosis is affected by nutrients.

Strange results

At first the team got expected results. They found that erebosis cell death increased with a low yeast, high-sugar diet. While changing the sugar concentration in the food did not have any effect, reducing amino acid concentration by 90% triggered erebosis.

This is when the results became strange and unexpected. The team expected that cells were detecting amino acids in the usual way. But when they blocked those biological pathways, it did not block erebosis.

They tested each individual amino acid at the concentration found in the high-amino acid diet that suppressed erebosis. In every case, it failed to suppress erebosis. But when they greatly increased the concentration, it suppressed erebosis in every case. This meant that the effect was not due to any specific amino acid.

So, they tried looking at the individual parts that all amino acids have in common. But erebosis was suppressed even when amino acid metabolism was blocked. The team concluded that metabolism might not be required.

The unexpected results were frustrating. "Originally, we thought amino acids affect specific biochemical pathways, or that their byproducts such as ammonia, urate, uric acid were involved," explains Yoo. "However, no matter what we manipulated, we got the same results. The project got stuck for a year."

The mystery is solved

If it wasn't a specific amino acid or metabolite, what could it be? The breakthrough came when they considered nutrient quantity. Specifically, the researchers reasoned that when cells are full of amino acids, they make the fluid inside cells thick and viscous.

"Our struggles ended when we used a non-metabolizable amino acid analog, which surprisingly affected erebosis," says Yoo. "Based on this, the idea that amino acids affect a cytoplasmic biophysical property was born. After that, everything went very smoothly."

The researchers searched for and found two biochemically different molecules that can enter fly cells and make the cytoplasm viscous but are metabolically inactive. Feeding these molecules to the flies had the same results.

"With these findings, we introduce the concept of "viscosatiety", in which gut cells sense their satiety or hunger based on the viscosity of the cytoplasm and adjust their status accordingly."

Yoo and his laboratory are currently investigating whether erebosis occurs in the gut cells of mice and humans.

Source:

Journal reference:

Nakamura, Y., et al. (2026). Cytoplasmic fluidity couples nutrient availability and enterocyte fate in vivo. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2602724123. https://www.pnas.org/doi/10.1073/pnas.2602724123