Research project THE GUT ENVIRONMENT AS AN INSTRUCTOR OF IMMUNITY, TOLERANCE AND ALLERGIC DISEASE

Immune maturation in early life

Our group has a long-standing interest in immune maturation during early life and has contributed substantially to the understanding of how microbial colonization shapes the developing immune system. Through longitudinal human cohorts, we have demonstrated that specific early-life microbial signatures, including lactobacilli colonization, are associated with immune development and protection from allergic disease as exemplified in (1-3). We have further investigated the very early immune development and how this relates to gut microbiota signatures in extremely preterm infants. They display profound alterations in both conventional and unconventional T-cell populations, have a substantially altered monocyte population, which relates to their microbiota composition. Further, probiotic-induced modulation of the gut microbiota is associated with both immunological and clinical benefits (4-9). These studies provide a unique foundation for our current efforts to identify the cellular and molecular mechanisms linking microbial exposures to immune development, allergy, asthma, and immune tolerance.

Host-microbe communication and immune-cell programming

A major focus of our work is understanding how microbial signals influence myeloid cells, including monocytes, macrophages, and dendritic cells, but also T cells. Myeloid cells are among the first immune cells to encounter microbial and epithelial signals and play a central role in directing adaptive immune responses. We study how interactions between microbes and myeloid cells and/or different T cells shape immune development and contribute to either immune tolerance or inflammation (10-16). To identify causal mechanisms, we use primary human immune cells together with epithelial barrier models, intestinal and airway organoids, and experimental animal models. A particular focus is on microbial metabolites and extracellular membrane vesicles, which represent important mediators of communication between the microbiota and the host. These factors influence immune-cell activation, epithelial integrity, gene expression, and cellular metabolism, but many of the underlying pathways remain poorly understood (17-19).

Current projects investigate how beneficial gut bacteria and their secreted products reprogram myeloid cells through transcriptional, epigenetic, and metabolic mechanisms. A particular emphasis is placed on macrophage differentiation and the concept that microbial exposure can induce long-lasting functional states in innate immune cells. We combine functional analyses with RNA sequencing, chromatin accessibility studies, and cellular metabolism measurements to identify pathways through which microbial signals regulate immune-cell fate and function. We also investigate how microbial vesicles and metabolites interact with epithelial barriers, how they are sensed by immune cells, and how they influence immune-cell differentiation and tissue-specific immune responses. By integrating mechanistic studies with observations from human cohorts, we aim to define the biological pathways linking the gut microbiota to immune development, allergy, asthma, and immune tolerance.

Immune tolerance, allergy and immune programming

A central question in our research is how immune tolerance develops and why it fails in allergic disease. Food allergy, particularly peanut allergy, provides a unique opportunity to study these processes in humans. We investigate immune-, microbial- and metabolomic trajectories in young children undergoing oral immunotherapy and compare them with those of children who remain allergic (20-21). Through longitudinal analyses of immune-cell populations, microbial communities, and metabolic signatures, we seek to identify the mechanisms that distinguish successful induction of tolerance from persistent allergic disease.

Our studies integrate traditional immunological analyses with transcriptional, epigenetic, and metabolic profiling. We focus on how microbial signals influence the balance between inflammatory and regulatory immune responses and how these interactions shape long-term immune outcomes. Understanding these pathways may provide new opportunities for prevention and treatment of allergic disease.

Immune development, the microbiota and the gut-lung axis

The intestinal epithelium represents the body's largest interface with the external environment and is continuously exposed to a diverse microbial community. Interactions between microbes, epithelial cells, and immune cells contribute to tissue homeostasis and immune maturation.

Using long-term prospective cohorts followed from infancy into adulthood, we investigate how early-life microbiota composition and respiratory tract infections relates to asthma and allergy development, lung function, and airway inflammation but also to immune functionality, also in experimental models (1, 22-24). By integrating microbiota analyses with immune profiling, clinical phenotyping, and molecular studies, we aim to understand why some individuals develop allergic disease and asthma whereas others remain healthy despite similar environmental exposures.