Acyl caprolactam-mediated quorum sensing in human microbiome Bacteroidetes

Abstract

Quorum sensing (QS) is a mechanism of chemical signaling that enables bacteria to regulate gene expression and coordinate cell density-dependent behaviors. Quorum sensing bacteria produce chemical signaling molecules known as autoinducers and secrete these molecules into the extracellular environment. At high concentrations, autoinducers can alter the expression of genes involved in processes such as virulence factor production, bio-film formation, and luminescence. In the human microbiome, host-microbe and microbe-microbe interactions are crucial to regulating biological processes and influencing diseases and immunity. However, current knowledge of QS systems in many microbiome genera has remained limited. Here, I characterize a novel quorum sensing system discovered in association with biosynthetic gene clusters in Bacteroidetes, one of the major phyla of the human microbiome. The circuit consists of three genes and synthesizes a novel autoinducer, N-acyl-caprolactams (ACLs). We heterologously expressed the Prevotella copri ACL circuit with a GFP reporter in Flavobacterium johnsoniae and show that environmental ACLs induce upregulation of fluorescent reporter expression. Analysis of circuit constructs in F. johnsoniae revealed the presence of positive and negative feedback mechanisms potentially regulating the expression of circuit genes. We demonstrate that the ACL circuit exhibits increased sensitivity for certain ACL side chain lengths. Furthermore, my analysis of the circuit in metagenomes revealed that the circuit is present in the gut and oral microbiomes and is highly prevalent in the oral microbiomes within the U.S. population. This work uncovers a chemical signaling system that sheds new light on microbial interactions and may offer insights into new drugs, therapies, and behaviors to protect microbiome health.