Impact of genetic and environmental factors in intestinal inflammation

Abstract

The gastrointestinal tract, is continuously exposed to a wide variety of stimuli, including dietary-derived metabolites, environmental compounds and the microbiota. Since these antigens can be beneficial or detrimental for the organism, proper sensing of the luminal content is essential for orchestrating both pro-inflammatory and tolerogenic immune responses on demand and therefore, ensure the establishment of intestinal homeostasis. Disruption of these mechanisms might result in inflammation, a characteristic of intestinal disorders, such as inflammatory bowel disease (IBD). How environmental triggers modulate intestinal inflammation in genetically susceptible host leading to IBD is largely unclear. The gap in knowledge around this topic is likely due to the lack of versatile in vivo models allowing the testing of a wide variety of compounds in a cost-effective manner. The aim of my doctoral thesis was to understand how intestinal inflammation is impacted by genetic factors and environmental exposures.

In study I and II we analyzed how the sensing of dietary-derived metabolites modulate immune homeostasis. In study I, we found that retinoic acid receptor a (RARa) signaling in intestinal epithelial cells modulated lineage specification of secretory cells and the development of the intestinal immune system. Epithelial RARa signaling was essential for mounting protective responses against pathogen infection and maintaining intestinal homeostasis. In study II, we explored how combinatorial activation of ligand-activated transcription factors that sense dietary metabolites in vivo modulate cytokine signaling. We found that co-exposure with more than one ligand resulted in activation of the corresponding receptors, and in induction of specific cytokine profiles as a result of their interaction.

In study III, we investigated how GPR35, an IBD-risk gene, modulated intestinal immune homeostasis. We found that Gpr35 deficiency in macrophages resulted in exacerbated colitis, due to low expression of genes involved in corticosterone synthesis and tumor necrosis factor (Tnf). We also identified lysophosphatidic acid as a potential GPR35 ligand that induces Tnf expression in macrophages in a GPR35-dependent manner.

In study IV, we further examined how environmental factors modulate intestinal inflammation and found that perfluorooctane sulfonic acid (PFOS), an environmental pollutant, exacerbates intestinal inflammation. This was associated with impaired epithelial barrier function and systemic T cell responses. Taken together, this doctoral thesis provides insight into how environmental and genetic factors modulate immune responses contributing to the maintenance of intestinal homeostasis.