The gut-brain axis is a bidirectional communication network linking the central nervous system with the enteric nervous system (the "second brain" in the gut) via neural, hormonal, and immune pathways.
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Scientific Frontline: "At a Glance" Summary
- Main Discovery: Commensal gut bacteria utilize type III secretion systems, previously thought exclusive to pathogens, to inject effector proteins directly into human cells and actively manipulate host immune responses.
- Methodology: The research consortium constructed a large-scale interactome map identifying over 1,000 protein-protein interactions between bacterial effectors and human host proteins, validated by functional assays of immune signaling pathways.
- Key Data: Analysis revealed that genes encoding these secretion systems are significantly enriched in the microbiomes of patients with Crohn’s disease, with specific proteins targeting the NF-κB signaling pathway and cytokine responses.
- Significance: These findings fundamentally shift the understanding of the microbiome from correlation to causation, demonstrating that non-pathogenic bacteria are active agents capable of directly modulating human physiology and inflammation.
- Future Application: This mechanistic insight facilitates the development of targeted therapeutic strategies that modulate specific bacterial-host interactions to treat inflammatory bowel diseases and potentially other autoimmune disorders.
- Branch of Science: Microbiology, Immunology, and Network Biology
- Additional Detail: The study specifically highlights the modulation of Tumor Necrosis Factor (TNF) activity, a key cytokine in inflammation, providing a molecular basis for the efficacy of anti-TNF therapies in Crohn's disease.
Researchers from Helmholtz Munich, LMU, Aix Marseille University, Inserm, and international partners have discovered a previously unknown mechanism of communication between gut bacteria and human cells. The findings reveal a new way in which the gut microbiome can influence the human body and may help explain how changes in gut bacteria contribute to inflammatory diseases such as Crohn’s disease.
Although the human gut microbiome has long been linked to immune, metabolic, and inflammatory disorders, most evidence is correlative, and the molecular mechanisms behind these connections remain largely unexplored.
“Our goal was to better characterize some of the underlying processes of how gut bacteria affect human biology,” says Veronika Young, first author of the study together with Bushra Dohai. “By systematically mapping direct protein–protein interactions between bacterial and human cells, we can now suggest molecular mechanisms behind these associations.”
Protein Injection Systems in Bacteria of the Healthy Gut
The study shows that many harmless, everyday gut bacteria possess type III secretion systems – microscopic, syringe-like structures that can inject bacterial proteins directly into human cells. Until now, these systems were thought to exist only in pathogenic bacteria such as Salmonella.
“This fundamentally changes our view of commensal bacteria,” says Professor Pascal Falter-Braun, head of the chair of Microbe-Host Interactions at the LMU Faculty of Biology, Director of the Institute for Network Biology at Helmholtz Munich and corresponding author of the study. “It shows that these non-pathogenic bacteria are not just passive residents but can actively manipulate human cells by injecting their proteins into our cells.”
Mapping How Bacteria Talk to Human Cells
To understand what these bacterial proteins do in human cells, the researchers mapped over a thousand interactions between bacterial effector proteins and human proteins, creating a large-scale interaction network. Their analyses showed that bacterial proteins preferentially target human pathways involved in immune regulation and metabolism.
Further laboratory experiments confirmed that these proteins can modulate key immune signaling pathways, including NF-κB and cytokine responses. Cytokines are signaling molecules that help coordinate the immune system and prevent excessive reactions that can lead to autoimmune diseases. For example, inhibiting the activity of the cytokine Tumor Necrosis Factor (TNF) is a widely used treatment for Crohn’s disease, an autoimmune disease of the gut.
Links to Inflammatory Bowel Disease
The researchers also found that genes encoding these bacterial effector proteins are enriched in the gut microbiomes of patients with Crohn’s disease. This suggests that direct protein delivery from gut bacteria to human cells may contribute to chronic intestinal inflammation, providing a potential mechanistic explanation for previously observed microbiome–disease links.
By identifying a previously unrecognized molecular layer between gut bacteria and the human immune system, the study advances our understanding of how the microbiome affects human cells, shifting research from correlation toward causation. It also raises intriguing questions, such as whether these injection systems evolved primarily for pathogenic purposes, or if they originally supported commensal coexistence and were later co-opted by pathogens.
Future research will aim to determine how individual bacterial effector–host interactions function in specific tissues and disease contexts, with the goal of translating these insights into more precise strategies for disease prevention and treatment.
Published in journal: Nature Microbiology
Authors: Veronika Young, Bushra Dohai, Hridi Halder, Jaime Fernandez-Macgregor, Niels S. van Heusden, Thomas C. A. Hitch, Benjamin Weller, Patrick Hyden, Deeya Saha, Daan K. J. Pieren, Sonja Rittchen, Luke Lambourne, Sibusiso B. Maseko, Chung-Wen Lin, Ye Min Tun, Jonas Bibus, Luisa Pletschacher, Mégane Boujeant, Sébastien A. Choteau, Lou Bergogne, Jérémie Perrin, Franziska Ober, Patrick Schwehn, Simin T. Rothballer, Melina Altmann, Stefan Altmann, Alexandra Strobel, Michael Rothballer, Marie Tofaute, Daniel Kotlarz, Matthias Heinig, Thomas Clavel, Michael A. Calderwood, Marc Vidal, Jean-Claude Twizere, Renaud Vincentelli, Daniel Krappmann, Marianne Boes, Claudia Falter, Thomas Rattei, Christine Brun, Andreas Zanzoni, and Pascal Falter-Braun
Source/Credit: Ludwig-Maximilians-Universität München
Reference Number: mcb012626_01
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