The human large intestine is host to a complex microbial community dominated by obligate anaerobic bacteria belonging to the phyla Bacteroidetes and Furmicutes. On the phylum level, this microbiota composition is highly conserved, not just between individuals but also between different mammalian species. However, conditions of intestinal inflammation lead to dysbiosis, which is characterized by a marked decrease in the representation of the prominent obligate anaerobic Bacteroidetes and Furmicutes and an increased relative abundance of facultative anaerobic Enterobacteriaceae. Our central hypothesis is that terminal respiratory electron acceptors generated as a byproduct of the host inflammatory response drive a bloom of Enterobacteriaceae and enable them to consume short-chain fatty acids (SCFAs) anaerobically, which can further exacerbate intestinal inflammation. We will test key aspects of our hypothesis by investigating whether inhibition of anaerobic respiration restores a normal microbial community structure (Aim 1) and determining whether inhibition of anaerobic respiration reduces intestinal inflammation by preventing a bloom of Enterobacteriaceae (Aim 2). The proposed work is innovative because it is among the first to propose a specific treatment for dysbiosis. It is our expectation that successful completion of the proposed experiments will drive knowledge about causes and consequences of dysbiosis during intestinal inflammation to a higher level by providing insights into one of the underlying mechanisms.
Over 90% of the cells in the human body are microbes, the majority of which reside in the large intestine, where they provide benefit to the host by educating the immune system and by providing nutrients as well as niche protection. The vast majority of microbes in the large intestine are obligate anaerobic bacteria and this bacterial community structure is conserved between humans and mice. However, conditions of inflammation in the large bowel are accompanied by a microbial imbalance, which is characterized by a marked increased relative abundance of facultative anaerobic bacteria, such as Escherichia coli. Here we will develop a potential treatment strategy for this microbial imbalance and study whether this approach reduces inflammation. By developing the first treatment strategy solely aimed at restoring a normal microbial community structure, the proposed experiments will usher in important conceptual advances that have a strong potential to exert a high impact on this field of science.
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