# Discovery of a Human Metabolite That Mimics the Bacterial Quorum-Sensing Autoinducer AI‑2

## TL;DR

Scientists discovered a human metabolite, l-xylosone, that mimics a bacterial signaling molecule called AI-2, which could help explain how human cells communicate with gut bacteria.

## Contribution

The study identifies l-xylosone as a new human metabolite that mimics the bacterial autoinducer AI-2, expanding our understanding of host-microbe communication.

## Key findings

- l-xylosone and l-xylulose were identified as AI-2 mimics using a reactivity-based metabolomics approach.
- The l-configuration of xylosone is required for bacterial receptor recognition, similar to AI-2.
- l-xylosone is a new addition to the human metabolome and suggests the existence of other reactive molecules in host-microbe interactions.

## Abstract

Bacteria use small molecules to orchestrate collective
behaviors
in a process called quorum sensing (QS), which relies on the production,
release, and group-wide detection of extracellular signal molecules
referred to as autoinducers. One QS autoinducer, termed AI-2, is broadly
used for interspecies bacterial communication, including in the mammalian
gut. AI-2 consists of a family of interconverting compounds and adducts
originating from 4,5-dihydroxy-2,3-pentanedione. This complex speciation,
coupled with the inherent instability of AI-2 congeners, have complicated
isolation efforts. It has been known that mammalian epithelial cells
produce an AI-2 mimic to which bacteria respond. However, the identity
of the AI-2 mimic has remained elusive, presumably due to its instability,
similar to that of known AI-2 compounds. Here, we developed a reactivity-based
metabolomics approach to capture and identify a mammalian AI-2 mimic.
Using a chemical strategy targeted at the α-diketone moiety
of known AI-2s, we identify the unusual sugar l-xylosone,
as well as the related metabolite l-xylulose, as AI-2 mimics.
While l-xylulose is a common and naturally occurring sugar
known in human metabolism, l-xylosone is a rare and highly
reactive oxidation product. We established a facile synthetic route
to access pure enantiomers of xylosone and confirmed that, like AI-2,
the l-configuration is required for recognition by the bacterial
AI-2 receptor, LuxP, whereas d-xylosone is inactive. l-xylosone is new to the human metabolome, suggesting that other
chemically reactive small molecules that mediate host–microbe
interactions await discovery. The identification of l-xylosone
expands the AI-2 family of molecules and adds a new word to the lexicon
of host–bacterial interactions.