Immune maturation in early life

The most pronounced colonization of the newborn infant occurs in the intestine. The mucosal epithelium of the gastrointestinal tract is the largest surface of the human body where an important cross talk between microbial antigens, epithelial cells and the immune system takes place. These interactions seem to be of major importance for intestinal and epithelial homeostasis as well as for immune maturation, as demonstrated in several different murine models, but there is still a large knowledge gap regarding how this works in humans. 

We have studied immune maturation in early life for many years, often in cohorts where longitudinal analyses have been possible (1-6). In this work, we have described different aspects of immune maturation during the first years of life (1-4) and that the early-life gut microbiome, in particular colonization with certain lactobacilli-species, correlates with the developing immune phenotype (1-2). In material from a cohort of extremely premature neonates participating in a randomized placebo-controlled clinical trial on probiotic supplementation, we were able to show that these neonates have aberrant conventional - as well as unconventional T cell compartments, in particular during their first weeks of life (5-6). Here we have also reported that probiotic supplementation of these neonates was associated with a more diverse microbiota, but also to clinical parameters like better head growth, time to full enteral feeding (7-8).

Gut microbiota, immune characteristics and function, and allergic disorders

The intestinal microbiota has been connected different types of allergies. It is believed that a dysbiotic gut microbiota can influence immune processes in the gut but also at distal sights like the lung, with possible consequences for e.g. asthma. Further, the prevalence of food allergies is increasing world-wide and one of the most severe is allergy to peanut. Today, there is no curative treatment for any food allergy, but oral immunotherapy (OIT) is performed in clinical research studies. During OIT, the allergic individual initially ingests very low doses and then gradually increases the amounts of the food allergen until the person can tolerize a maintenance dose. Although food allergic individuals are reported to show signs of dysbiosis, we still do not know how the gut-immune axis is involved in the disorder or how it is influenced by oral immunotherapy. 

In prospective longitudinal cohorts we have demonstrated that the presence of lactobacilli in the very early neonatal gut seems to protect against allergy development, also in children with a high allergy-risk (two allergic parents) (9-10), and that there is a strong association between the presence of certain lactobacilli species in the neonatal gut microbiota and immune functions during infancy (1-2; 11-12). These findings are also supported by more recent work in experimental in vivo models (13). In previous work we have further shown that adolescents undergoing OIT with peanut, had positive effects of simultaneous anti-IgE treatment (14-15), but how gut-immune interactions contribute is not clear. 

Mechanisms in gut microbe-immune interactions

Immunological dogmas are continuously challenged. Newer concepts, e.g. T-cell plasticity and “trained” recall responses of antigen presenting cells, open up for revised interpretations and new studies of immune development and the role of different cells in disease. As yet, most of our current knowledge on immune development, its instruction by microbes in the gut environment and how this relates to disease, originate from murine studies. The human situation is more of a “black box”, particularly regarding mechanisms. Our proposed project is translational and will provide a better understanding of how the human immune system develops over time, how it deviates in allergic conditions, how it is modulated by immunotherapy, but also how it is influenced by the gut environment and mechanisms behind this. This information can be used to better identify children at risk for allergy development, and to develop effective non-invasive prevention- and treatment strategies in the future. 

To address mechanism behind microbe-mediated immune modulation we have performed several studies in the past. In our work, we have particularly focused on different lactobacilli, but also Staphylococcus (S.) aureus. Lactobacilli species are among the first gut colonizers. In the neonatal gut, they seem to have different types of positive health effects and they produce several molecules with immune modulatory effects. S. aureus is a bacterium frequently found in the neonatal intestine, and can be considered both a commensal and a pathogen. S. aureus can produce several enterotoxins which are known as superantigens for their ability to cause a strong immune activation. 

We have investigated by which mechanisms mucosa- and bacteria-derived factors modulate immune function in several in vitro studies (16-19). Here we have demonstrated that lactobacilli-derived factors significantly impact both myeloid and T cell immune functions (16-17) and further identified that these effects are mediated by different lactobacilli-derived factors, including extracellular membrane vesicles (18). We have shown that the effects on T cells are indirect and mediated through monocytes and dendritic cells, by introducing significant changes in their epigenome (18-19). In other studies, we focus on how dietary metabolites commonly found in mucosal tracts, like retinoic acid, regulate immune function and T helper cell polarization (20). In addition, we have shown how enterotoxins can induce atypical regulatory responses in regulatory T cells (21) and also how these toxins activate unconventional T cells and Natural Killer cells, that lack the receptors for being activated by the toxins (4, 17). 

Ongoing and future work

In ongoing and future work, we continue to investigate bacteria-derived molecules, enterotoxins and extracellular membrane vesicles and their ability to influence functional properties in human immune cells in vitro. Further we develop in vitro models to explore the gut-lung axis and its role in asthma, and continue to study epigenetic alterations in different types of immune cells in individuals that develop allergic disorders. We will also have the unique possibility to study the gut-immune axis during a deliberate immune skewing (oral immunotherapy) in very young children.