A FUNCTIONAL METAGENOMIC APPROACH OF HUMAN MICROBIOTA IDENTIFIES A BACTERIAL STRAIN THAT CONFERS PROTECTION DURING INTESTINAL INFLAMMATION VIA IL-22

Abstract

Abstract The gastrointestinal microbiota has been shown to play an important role in resistance to pathogen invasion and in the regulation of the host metabolism. Further, it is widely recognized that the microbiota also influences the development and homeostasis of the immune system. Alteration in the microbial flora, so called dysbiosis, has been linked to many human diseases, including autoimmune and/or autoinflammatory disorders and allergies. Despite the advances in the DNA sequencing technology, a deeper understanding of the gut microbiota is still hindered by the inability to culture most of the bacterial species. In this study, we used a high throughput cell-based functional metagenomic approach to identify several bioactive bacterial clones in the human fecal microbiota. In subsequent co-culture experiments we selected one clone, related to the phylum of Firmicutes, which indirectly activated dendritic cells through the stimulation of intestinal epithelial cells and subsequently modulated T cell functions. This effect was associated to an ABC transporter. In ex-vivo human organ culture experiments we found that this clone prevented Salmonella-induced destruction of the intestinal mucosa by stimulating the production of IL-22 in the CD4+ T cells. These results were confirmed in vivo by using a mouse model of DSS-induced colitis. Here pre-treatment of the mice with the identified clone was able to significantly reduce intestinal inflammation. This protective effect was abrogated by the administration of anti-IL22 antibody or the use of AHR antagonist. Altogether, our functional metagenomic approach allowed the identification of bacteria and bacteria-induced genes modulating the immune system.