Current projects of our research group
The gut forms a complex immunological barrier that plays a crucial role in maintaining health. This barrier consists of multiple layers and mechanisms that work synergistically to protect the body from pathogenic microorganisms while supporting a healthy gut flora.
The gut's immunological barrier is also essential for differentiating between pathogenic and non-pathogenic microorganisms and for tolerance to harmless bacterial communities and food components. Disruptions to this fine-tuned balance can lead to a variety of diseases, including allergic reactions, autoimmune diseases and inflammatory bowel disease. Overall, the complexity and importance of the immunological barrier in the gut demonstrates how critical it is to overall health and well-being.
Our research projects focus on the function and regulation of the immunological intestinal barrier. In numerous projects, we investigate the interactions between the microbiome and the immune system, with a particular focus on the role that the intestinal epithelium plays in mediating these interactions.
Regulation of intestinal epithelial cells by signals from the immune system and the intestinal flora
Intestinal epithelial cells are stimulated by bacterial molecules in a complex way, which is essential for maintaining intestinal health. Bacterial components such as lipopolysaccharide (LPS), ADP-heptose, bacterial DNA and peptidoglycans bind to specific receptors on the epithelial cells, such as Toll-like receptors (TLRs), which activate the cells and lead to a cascade of signal transmissions that can trigger immunological and inflammatory responses. These responses include the activation of NF-kB and other transcription factors that lead to the production of cytokines and chemokines, which in turn attract immune cells and modulate the immune response.
In addition, bacterial short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate, by binding to receptors on the epithelial cells, can influence their metabolic pathways and contribute to strengthening the barrier function. These SCFAs also promote the production of mucus and antimicrobial peptides that help protect the intestinal surface from pathogenic invaders. These interactions between bacterial molecules and intestinal epithelial cells are central to understanding the mechanisms that control health and disease in the gut. They therefore play a crucial role in research into preventive and therapeutic approaches for numerous intestinal diseases.
Intestinal epithelial cells are also stimulated by immune cells in the gut in a variety of ways, which is crucial for maintaining immunological homeostasis and response to infection. Immune cells such as T lymphocytes and macrophages release cytokines, such as interleukin-22 (IL-22) and interferon-gamma (IFN-γ), which act directly on epithelial cells to modulate their barrier function and induce the production of antimicrobial peptides. These immune-mediated signal transduction pathways are critical to ensure the integrity and function of the intestinal barrier and to coordinate adaptive immune responses. Such interactions are fundamental to protect gut health and combat pathological conditions such as inflammatory bowel disease and infection.
Our projects are based on the assumption that the intestinal epithelium with its specialized cells not only forms a physical barrier that separates bacteria of the intestinal flora from the immune system, but also constantly mediates between these two parties as a communication interface to prevent destructive inflammatory responses.
Immunological regulation of programmed necrosis (necroptosis) in the intestinal epithelium
Until recent years, the term programmed cell death and apoptosis were used interchangeably, since only in this form of cell death, the cell itself determines the procedures and performs a kind of suicide program. Necrosis in contrast was referred to as an uncoordinated (passive) form of cell death induced by irreversible cell damage, such as following mechanical injury and cytotoxins, due to thermal influences or pathogens. Both apoptosis and necrosis can be differentiated microscopically based on morphological characteristics.
Through research findings in recent years, however, a novel form of cell death, denoted necroptosis, was identified and subsequently characterized. Interestingly, necroptosis combines both apoptotic and necrotic features. Morphologically necroptosis cannot be distinguished from necrosis. On the other hand, it is clearly distinguishable from that, because it is not a passive process, such as necrosis, but can be triggered by regulated cellular pathways. The underlying molecular mechanisms correspond strongly to those of apoptosis, since both processes are regulated by similar intracellular protein complexes.
The first indication of this new form of cell death was obtained by studies, in which the physiological relevance of apoptosis was to be explored in vivo. These studies led to the finding that the molecules FADD and caspase-8, in addition to their classical function as initiators of apoptosis had additional apoptosis-independent functions in fact promoting cell survival under certain circumstances. Around the same time, again under certain experimental conditions following apoptosis induction, researchers were able to observe cells that morphologically strongly differed from apoptotic cells. What they observed were cells with swollen cytoplasm and cell organelles, yet with intact nuclei, typical features of necrotic cells. Thus, these researchers were able to show that a controlled activation of the extrinsic apoptosis pathway can cause cell death morphologically corresponding to necrosis. This form of cell death is now known as necroptosis. Through complementary in vitro experiments researchers were finally able to identify the underlying necroptosis inducing molecules. These belong to the family of kinases and include the "receptor-interacting-protein 1 (RIPK1), RIPK3, and the protein MLKL (mixed lineage kinase domain-like protein). Under physiological conditions, the activation of these proteins is blocked by caspase-8. When caspase-8 activity itself is blocked through genetic deletion of the enzyme, pharmacological methods or cellular inhibitors (e.g. cFLIPs), inactivation of RIPK1 by caspase-8 cannot be maintained. If RIPK3 Is expressed in the same cell, it can then interact with RIPK1, a process that initiates autophosphorylation of both kinases. This in turn leads to the phosphorylation and activation of MLKL and ultimately to necroptosis.
Important goals in the study of necroptosis are not only the elucidation of cellular signaling pathways and research into the significance of necroptosis in various diseases, but also the development of specific and simple detection methods for necroptosis and for the differentiation of necroptosis from other forms of cell death. According to the current state of knowledge, interdisciplinary approaches such as the combination of optical/physical and immunological detection methods appear promising here. Our data show that both the activated and the inhibited form of caspase-8 mediate activation of programmed cell death (see figure). Thus, tight control of caspase-8 expression and activity is required to ensure cell survival. Since the discovery of necroptosis, this form of cell death has been shown to be involved in various pathophysiological processes. Our own work has contributed significantly to the understanding of the importance and regulation of necroptosis. Our current projects are investigating the pathophysiological relevance of necroptosis in intestinal diseases and the role of mitochondria and their metabolic pathways in these processes.
Influence of the enteric nervous system on the immunological barrier and inflammatory reactions in the intestine
The enteric nervous system (ENS) and the immunological barrier of the gut interact in a close and complex way that is crucial for maintaining gut health and overall homeostasis. The ENS, often referred to as the "second brain", consists of millions of neurons distributed along the entire digestive tract. These neurons not only control the motor functions of the gut, but also influence immunological responses.
The ENS plays a key role in modulating gut flora and immune responses through the release of neurotransmitters and neuropeptides that can act directly on immune cells, which in turn influences their release of cytokines and other inflammatory mediators. In addition, the bidirectional communication between the ENS and the immune system enables a rapid response to infectious pathogens and other pathological changes in the gut. When the immune system recognizes a threat, it can send signals to the ENS, which then adjusts intestinal motility and secretion to accelerate elimination of the pathogen.
Disturbances in this interaction favor a variety of diseases, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Research into the complex interactions between the enteric nervous system and the immunological barrier therefore offers important insights into the mechanisms underlying these diseases and could lead to new therapeutic approaches. .