T cell regulation by fed state bacterial metabolites

Project Information

T Cell Feedback

Grant agreement ID: 101117175

DOI

10.3030/101117175

EC signature date 12 September 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 499 548,00

EU contribution

€ 1 499 548,00

Coordinated by

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

Periodic Reporting for period 1 - T Cell Feedback (T cell regulation by fed state bacterial metabolites)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

The human gut is home to trillions of bacteria that help our bodies work properly. These microbes help us digest food, extract energy, and produce important vitamins. Because of how essential they are, scientists often think of the gut microbiome as an “extra organ” that develops after birth.
However, having so many bacteria living inside us creates a big challenge for the immune system. Normally, the immune system attacks bacteria to protect us from infection—so how does it tolerate the helpful bacteria in our gut without causing constant inflammation?
The answer lies in balance. The immune system uses different types of immune cells, some that promote inflammation and others that suppress it. My research showed that when gut bacteria break down bile acids and dietary fiber from our food, they produce substances that encourage the development of immune cells that calm the immune response. This helps the body live peacefully with its gut microbes.
Despite this progress, the gut microbiome is extremely complex, and we still don’t fully understand what other bacterial signals help regulate the immune system or how they work. To tackle this, I propose a new idea: many of the molecules that help control immune tolerance are produced by gut bacteria specifically in response to eating food.
Using this idea, I have chosen two new groups of bacterial molecules to study. I developed a strategy to identify additional immune-regulating molecules by closely analyzing how bacterial metabolism changes after food intake. I will then determine how these molecules work by identifying their targets in the body using chemical screening techniques. Finally, I will test their effects in living organisms by introducing genetically modified bacteria into mice that are raised without any microbes.
This project builds on my expertise in interactions between microbes and the immune system and makes use of advanced laboratory facilities at my institution, as well as collaborations with experts in complementary fields. Together, this approach will provide a detailed understanding of how gut bacteria help maintain immune balance and support intestinal health—from the molecules they produce to their effects on the body.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We found that eating has a rapid and powerful effect on gut bacteria and the immune system. After food intake, gut microbes switch into a growth mode and start producing more communication molecules. These molecules increase when animals eat, suggesting that bacteria actively sense and respond to food. We discovered that gut bacteria make these communication signals using enzymes that were not previously thought to be important in the gut. When we tested one of these enzymes in bacteria, it successfully produced the expected signals, showing that gut microbes can use this pathway. We also began testing how these bacterial signals affect the immune system in living animals, and those analyses are still underway.
We also expanded our work on bile acids, another group of molecules shaped by gut bacteria and food intake. By analyzing large existing datasets, we identified a previously unrecognized group of bile acids linked to gut inflammation. These bile acids disrupt normal regulatory feedback and promote unhealthy microbial communities, helping explain how diet and microbial metabolism can contribute to chronic intestinal disease.
On the immune side, we observed that eating quickly changes immune cell behavior in the gut. Certain immune cells became more active, and others moved from the gut to nearby lymph nodes. This suggests that food intake helps shape how the immune system samples gut bacteria and decides how strongly to respond to them.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project resolves several long-standing open questions in gut microbiome research and introduces new ways of thinking about how food, bacteria, and the immune system interact.
First, it clarifies a major controversy around whether bacteria in the mammalian gut use chemical “communication signals” known as AHLs. For years, scientists struggled to detect these molecules and could not find the genes thought to produce them, leading to uncertainty about whether they existed in the gut at all. By identifying a different, previously overlooked group of bacterial enzymes capable of producing these signals, this work explains why earlier studies came up empty-handed and establishes a new framework for understanding bacterial communication in the gut. This moves the field decisively beyond its previous technical and conceptual limits.
Second, the finding that eating itself triggers immune cells to move from the gut to nearby lymph nodes introduces food intake as a previously unrecognized biological signal that shapes immune decision-making. This suggests that the immune system may be especially tuned to tolerate new antigens during meals, providing a physiological explanation for how the body learns to accept harmless food components. This insight opens new avenues for designing therapies for food allergies and other immune-mediated diseases by leveraging the timing and metabolic context of feeding.
Finally, this work reveals a new role for bile acids in driving unhealthy gut microbial communities. Rather than being a mere consequence of intestinal inflammation, high bile acid levels are shown to actively promote microbial imbalance on their own. This fundamentally changes how bile acids are viewed in inflammatory bowel disease and suggests that correcting bile acid metabolism could be key to restoring a healthy microbiome. These insights have direct implications for improving microbiome-based therapies, including live bacterial treatments and fecal microbiota transplantation, by highlighting bile acid control as a critical factor for long-term success.