Modulation of intestinal homeostasis and inflammation by Prevotella intestinalis (nov. sp.)

Intestinal homeostasis is maintained by the dynamic interplay between the gut microbiota and the host immune system. Alterations in the composition and function of the gut microbiota have been associated with increased susceptibility to intestinal inflammation, but whether these candidate microbes actively modulate host phenotypes is frequently not known. The role of members of the Prevotella genus within the intestinal microbiota and their effects on the host is not completely understood and somewhat conflicting interpretations have been reported. Whereas association with plant-rich diet and improved glucose metabolism suggested Prevotella spp. are beneficial for the host, their increased relative abundances in microbial ecosystems at multiple body sites have been associated with diverse diseases. Yet, whether Prevotella spp. actively contribute to the development of these diseases is not known. The detailed investigation of the immunomodulatory properties of Prevotella spp. has been prohibited by the poor characterization of Prevotella species and high strain diversity, as well as the lacking availability of diverse intestinal Prevotella isolates. In the present work, we isolated three novel intestinal Prevotella species from mice prone to intestinal inflammation. Characterization of the impact of Prevotella colonization on the interplay between host and the microbiota during intestinal homeostasis and inflammation was performed using P. intestinalis, which among the three novel species shared the highest similarity to the predominant human gut Prevotella species - P. copri. We identified that colonization by this novel member of the Prevotella genus significantly decreased the production of the bacterial fermentation product SCFAs and the immunomodulatory cytokine IL-18, which was associated with an increase in the severity of intestinal inflammation. Our findings suggested that Prevotella-mediated intestinal injury may be influenced via different pathways, yet the ability to ameliorate Prevotella-induced disease severity by supplementation of IL-18 suggested that remodeling of the microbial metabolome and specifically SCFA production may be the dominating pathomechanism. Finally, the consequences of modulation of SCFA production in the intestine by Prevotella spp. may have far-reaching consequences for the host, as SCFA have immunomodulatory effects in distant sites such as the liver, bones or the brain.