Scientists have discovered a surprising way that gut bacteria interact with the human body. Certain microorganisms that live in the digestive system can deliver proteins directly into human cells and actively influence the operation of the immune system. The research, led by Helmholtz München in collaboration with Ludwig-Maximilians-Universität (LMU), Aix-Marseille University, Inserm and other international collaborators, uncovered a previously unknown form of communication between bacteria and human cells. The findings provide new insights into how the gut microbiome influences health and may help explain its role in conditions such as Crohn’s disease.
Researchers have long linked the gut microbiome to immune, metabolic, and inflammatory diseases. However, most of that evidence is based on correlations, and the biological processes behind those associations remain unclear.
“Our goal was to better characterize some of the underlying processes of how gut bacteria influence human biology,” says Veronica Young, lead author of the study along with Bushra Dohaj. “By systematically mapping the direct protein-protein interactions between bacteria and human cells, we are now able to suggest the molecular mechanisms behind these associations.”
A hidden injection system for “friendly” gut bacteria
The research team discovered that many common harmless gut bacteria possess type III secretion systems. These are small syringe-like structures that allow bacteria to inject their proteins directly into human cells. Previously, scientists thought these systems were limited to disease-causing bacteria such as salmonella.
“This fundamentally changes the way we look at commensal bacteria,” says Professor Pascal Falter-Brown, director of the Institute for Network Biology at Helmholtz München and corresponding author of the study. “This shows that these non-pathogenic bacteria are not just passive residents, but can actively manipulate human cells by injecting their proteins into the cells.”
Mapping how gut bacteria affect human cells
To find out what happens after these proteins enter human cells, the researchers mapped more than 1,000 interactions between bacterial effector proteins and human proteins. This large network revealed that bacterial proteins tend to target pathways involved in immune regulation and metabolism.
Follow-up experiments confirmed that these proteins can influence key immune signaling systems such as NF-κB and cytokine responses. Cytokines are signaling molecules that regulate immune activity and prevent excessive reactions that can lead to autoimmune diseases. For example, blocking the cytokine tumor necrosis factor (TNF) is a common treatment for Crohn’s disease, an autoimmune disease that affects the intestines.
Potential association with Crohn’s disease
The researchers also found that the genes responsible for these bacterial effector proteins were more common in the gut microbiome of Crohn’s disease patients. This finding suggests that direct transfer of proteins from bacteria to human cells may contribute to long-term intestinal inflammation. This also provides a possible explanation for earlier observations linking microbiome changes and disease.
Rethinking the interaction between the microbiome and the immune system
By identifying a previously unknown layer of interaction between gut bacteria and the immune system, this study moves the field beyond simple associations to an understanding of cause and effect. It also raises new questions about the origin of these injection systems, including whether they first evolved to support coexistence with the host or were later adapted by harmful bacteria.
Future research will focus on how specific bacterial proteins interact with human cells in different tissues and disease settings. These insights could ultimately lead to more targeted approaches for disease prevention and treatment.
