University of Pennsylvania
Metabolite Circuits as Regulators of the Host-microbiome Interface
The intestinal host-microbiome interface is a fascinating ecosystem which provides a range of metabolic functions that support human health. The gastrointestinal tract comprises one of the highest microbial densities on Earth, including more than 1,000 species of bacteria, viruses, fungi and parasites, collectively termed the microbiota. This vast microbial community resides only micrometers away from the sterile inner milieu of the human body. The intestinal microbiome has been recognized as a key component of human physiology, which is pivotal for many aspects of human health, but at the same time needs to be tightly contained within the intestinal lumen. This complex task is performed by a single layer of epithelial cells that line the intestinal surface.
The research in my lab is focused on understanding the biology of intestinal epithelial cells and on harnessing their function to treat multi-factorial human disease. The critical impact that the intestinal microbiota exerts on health and disease makes a detailed knowledge of the nature of host-microbiota interactions essential for the rational design of therapeutic interventions. Typical approaches to modulating the intestinal host-microbiota interface include prebiotic and probiotic microbiome engineering to alter the prokaryotic community in a way that is beneficial for host health. However, this strategy has been hampered by the enormous inter-individual variability of the intestinal microbiome and by the colonization resistance that gut microorganisms provide against foreign microbes. The approach pursued in my lab runs entirely counter to this trend. We harness the vast biochemical repertoire of the intestinal microbiota to focus on the most concrete molecules by which the intestinal microbiome contributes to host physiology: microbial metabolites. A large number of host-commensal interactions are mediated by diverse and specialized metabolites that are secreted, degraded, or modified by the gut microbiome. These metabolites constitute a rich communication network of signaling molecules that impact both the host and the microbiome.
We explore how intestinal epithelial cells sense microbial metabolites and initiate appropriate regulatory responses. We apply this strategy to several intestinal inflammatory, infectious, metabolic, and neoplastic diseases of poorly defined etiology. Using a combination of metabolomics and gnotobiotics in mouse models of human disease, we devise “postbiotic” therapeutics, which aim at restoring healthy levels of intestinal metabolites. A detailed understanding of the host-microbiota metabolite circuitry is the stepping stone for a large number of innovative therapeutic approaches for numerous multi-factorial human diseases.