More Than Just Roommates: How Gut Bacteria Regulate Immune Responses

Researchers from Helmholtz Munich, LMU, Aix-Marseille University, Inserm, and other international partners have discovered a previously unknown communication mechanism between gut bacteria and human cells. The findings highlight the influence of the gut microbiome on the human body and may explain the extent to which changes in the gut flora contribute to inflammatory diseases, including Crohn’s disease.

Although the human gut microbiome has long been associated with immunological, metabolic, and inflammatory diseases, most of the evidence to date is correlational, and the molecular mechanisms underlying these associations remain largely unexplored.

“Our goal was to better characterize some of the underlying processes through which gut bacteria influence human biology,” says Veronika Young, co-first author of the study with Bushra Dohai. “By systematically mapping direct protein-protein interactions between bacterial and human cells, we can now propose molecular mechanisms underlying these relationships.”

Protein delivery 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 be used to inject bacterial proteins directly into human cells. Until now, it was assumed that such systems were found exclusively in pathogenic bacteria such as Salmonella.

“This fundamentally changes our understanding of commensal bacteria,” says Professor Pascal Falter-Braun, head of the Chair of Microbe-Host Interactions at LMU’s 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 merely passive inhabitants, but can actively influence human cells by introducing their proteins into them.”

How bacteria communicate with human cells

To understand the functions these bacterial proteins perform in human cells, the researchers mapped over a thousand interactions between bacterial effector proteins and human proteins, thereby creating a large-scale interaction network. The analyses showed that bacterial proteins preferentially target human signaling pathways involved in immune regulation and metabolism.

Further laboratory studies confirmed that these proteins can modulate key signaling pathways of the immune system, including NF-κB and cytokine responses. Cytokines are signaling molecules that coordinate the immune system and prevent excessive reactions that can lead to autoimmune diseases. For example, inhibition of the cytokine tumor necrosis factor (TNF) is a widely used treatment for Crohn’s disease, an autoimmune disease of the intestine.

Link 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 the direct transfer of proteins from gut bacteria to human cells may contribute to chronic intestinal inflammation and provides a possible mechanistic explanation for previously observed links between the microbiome and disease.

By identifying a previously unrecognized molecular level of interaction between gut bacteria and the human immune system, the study deepens our understanding of how the microbiome influences human cells and shifts research from mere correlations to causal relationships. At the same time, it raises intriguing questions, such as whether these injection systems originally evolved for pathogenic purposes or whether they initially supported coexistence with the host and were only later appropriated by pathogens.

Future research will aim to clarify how individual bacterial effector-host interactions function in specific tissues and disease contexts, with the goal of translating these findings into more precise strategies for disease prevention and treatment.

Veronika Young & Bushra Dohai et al., 2026: Effector–host interactome map links type III secretion systems in healthy gut microbiomes to immune modulation. Nature Microbiology 2026