Impact of N-Acyl-Homoserine Lactones, Quorum Sensing Molecules, on Gut Immunity

Abstract

Among numerous molecules found in the gut ecosystem, quorum sensing (QS) molecules represent an overlooked part that warrants highlighting. QS relies on the release of small molecules (auto-inducers) by bacteria that accumulate in the environment depending on bacterial cell density. These molecules not only are sensed by the microbial community but also interact with host cells and contribute to gut homeostasis. It therefore appears entirely appropriate to highlight the role of these molecules on the immune system in dysbiosis-associated inflammatory conditions where the bacterial populations are imbalanced. Here, we intent to focus on one of the most studied QS molecule family, namely, the type I auto-inducers represented by N-acyl-homoserine lactones (AHL). First described in pathogens such as Pseudomonas aeruginosa, these molecules have also been found in commensals and have been recently described within the complex microbial communities of the mammalian intestinal tract. In this mini-review, we will expound on this emergent field of research. We will first recall evidence on AHL structure, synthesis, receptors, and functions regarding interbacterial communication. Then, we will discuss their interactions with the host and particularly with agents of the innate and adaptive gut mucosa immunity. This will reveal how this new set of molecules, driven by microbial imbalance, can interact with inflammation pathways and could be a potential target in inflammatory bowel disease (IBD). The discovery of the general impact of these compounds on the detection of the bacterial quorum and on the dynamic and immune responses of eukaryotic cells opens up a new field of pathophysiology.

Keywords: gut inflammation; gut microbiota; inflammatory bowel disease; interkingdom communication; quorum sensing.

Figure 1

Quorum sensing signaling in bacteria. Acyl-homomserine lactones (AHLs) are auto-inducers used by Gram-negative bacteria to communicate. The enzyme LuxI synthesizes the AHL, and the latter can diffuse freely through the membrane. Upon reaching a threshold concentration, AHL can bind to its receptor LuxR. The dimerization of the receptor allows it to act as a transcription factor on the Lux box. This triggers not only the expression of target genes involved in the virulence of the bacteria but also the expression of AHL system LuxI/LuxR.

Figure 2

Proposed model of modulation of gut mucosa inflammation by N-acyl-homoserine lactone (AHL)-driven quorum sensing and associated cellular pathways. Inflammatory bowel disease (IBD) is the result of multiple factors. It involves an imbalance of the microbiota (dysbiosis), an alteration of the epithelial barrier, as well as an uncontrolled inflammation in the gut mucosa, as described on the left panel. As a result of the dysbiosis, the AHL composition is changed compared to a physiological state. During normobiosis (right panel), when the bacterial communities are balanced, the AHL profile is modulated compared to a disease state. Beyond reshaping bacterial composition, AHL can modulate the inflammatory state of gut mucosa as well as restore epithelial barrier integrity. The pathways involved in those effects are listed on the right panel of the figure. We propose a strategy to control gut inflammation by modulating AHL composition using natural or synthetic AHL.