Cytokine and microbiota function in gut development: spatiotemporal analysis in the zebrafish

Project Information

Cytok-Gut

Grant agreement ID: 101041422

DOI

10.3030/101041422

EC signature date 31 March 2022

Start date 1 January 2023

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - Cytok-Gut (Cytokine and microbiota function in gut development: spatiotemporal analysis in the zebrafish)

Reporting period: 2023-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

How Our Microbiota Shapes Gut Development: Unlocking the Role of Cytokines

From the moment we are born, our body interacts with trillions of microbes that live in and on us. These bacteria are not just passive passengers—they actively shape how our organs develop and function. Among the most critical organs influenced by these microbes is the gut, where they help digest food, train the immune system, and maintain health. However, the precise mechanisms by which these bacteria influence gut development remain largely unknown.

Our project explores how cytokines—small signaling proteins that cells use to communicate—regulate gut development and interact with microbiota. Cytokines are well known for their role in immunity, but our findings suggest they also control early gut formation, long before the immune system is fully developed. Surprisingly, we found that certain cytokines are first produced by gut epithelial cells (which form the intestinal lining) and later by immune cells, particularly innate lymphoid cells (ILCs). Understanding this transition could reveal fundamental principles of how organs develop and adapt to their environment.

Why Is This Important?
• A New Understanding of Gut Development: By studying zebrafish—a powerful model organism for live imaging and genetic manipulation—we will uncover how cytokine signaling integrates microbial cues to guide gut formation.
• Implications for Human Health: The same cytokine pathways exist in humans, and disruptions in these signals are linked to diseases like inflammatory bowel disease (IBD). Understanding how these signals work during development could provide new therapeutic targets.
• Interdisciplinary Impact: Our research will connect developmental biology, immunology, and microbiome science, providing insights that extend beyond gut health into areas like cancer biology and regenerative medicine.

How Will We Achieve This?

We will combine advanced imaging, genetic tools, and microbiota manipulation in zebrafish to:
1. Investigate how cytokines shape gut development at the cellular and molecular level.
2. Unravel how microbiota and cytokines communicate to influence gut formation.
3. Understand how immune cells take over cytokine production as the gut matures.

This research will transform our understanding of how genes and microbes work together to build organs, opening new avenues for treating gut-related diseases and potentially guiding the development of future therapies.

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

How Microbes and Immune Signals Shape Gut Development

From the moment we are born, trillions of microbes colonize our intestines, influencing digestion, immune function, and overall health. But how do these microbes communicate with our bodies to guide the development of such a complex organ? Our project explores this question by studying cytokines, small signaling proteins that help cells communicate and that we found play a crucial role in shaping the gut during early life.

We discovered that certain cytokines are essential for gut development, controlling cell growth, gut movement, and interactions with microbes. Interestingly, these cytokines are first produced by non-immune cells and later by the immune system, revealing a dynamic shift as the gut matures. Our research also shows that gut microbes regulate cytokine production, ensuring proper intestinal function. When these signals are disrupted, gut development is altered, leading to changes in microbiota composition and gut physiology. Additionally, we found that specific bacterial species help restore normal gut function, suggesting a potential link between microbiota and gut health.

To explore these interactions, we developed new tools to track gut development in real-time, including advanced imaging and genetic approaches. We also established a new gut regeneration model, allowing us to study how the intestine repairs itself after injury. Through collaborations with experts in imaging, microbiology, and regenerative biology, we are expanding our understanding of how the gut develops and adapts to its environment.

Why Is This Important?

Our research sheds light on how microbes and immune signals work together to shape organ development, providing key insights into gut health. Understanding these fundamental processes could help develop new therapeutic strategies for conditions like inflammatory bowel disease (IBD) and other gut disorders. By uncovering the rules that govern gut development and repair, this work paves the way for future discoveries in medicine, microbiology, and regenerative therapies.

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)

Advancing Knowledge on Gut Development and Microbe-Immune Communication

Our project has made significant advances in understanding how the gut develops before the immune system is fully mature. While it is well known that immune cells and their signaling molecules, called cytokines, regulate intestinal function in adults, much less was understood about how these signals contribute to gut development in early life. Our research has helped fill this gap by uncovering new roles for cytokines in shaping the gut before immune cells fully populate the organ.

One of our key findings is that non-immune cells in the developing gut produce cytokines that influence intestinal function, challenging the previous assumption that these molecules are exclusively made by immune cells. We also discovered that gut microbes play a crucial role in regulating these signals, revealing a new way in which the microbiota influences organ development. These findings represent a major step forward in understanding how intestinal function is established early in life, before the immune system is fully active.

Potential Impact and Future Applications

Our discoveries could open new avenues for research on gut health and disease. Understanding how microbes and cytokines shape intestinal function may lead to new strategies for improving gut health, particularly in early life and in diseases such as inflammatory bowel disease (IBD). The insights gained from this work may also help guide the development of therapies that use beneficial microbes or cytokine-based treatments to restore intestinal balance.

To fully realize the potential of these findings, further research will be needed to explore how these early signals contribute to long-term gut health. Additionally, the tools and models we developed in this project could be used by other researchers to study gut regeneration, microbiota interactions, and immune system development. By expanding our understanding of gut development, this work lays the foundation for future biomedical applications in gastroenterology, immunology, and regenerative medicine