# Gut microbes–spinal connection is required for itch sensation

## TL;DR

Gut microbes influence itch sensation in the spinal cord through an epigenetic mechanism involving RNA modifications and a specific metabolite.

## Contribution

The study reveals a gut-microbe to spinal connection in itch sensation via RNA m6A modification and the role of Bacteroides fragilis metabolite ALC.

## Key findings

- Gut microbiota depletion increases itch tolerance in mice.
- B. fragilis and its metabolite ALC restore normal itch sensation in antibiotic-treated mice.
- Microbial changes affect RNA m6A levels and MRGPRF protein expression via FTO and ETS1.

## Abstract

The gut microbiota has been linked to a number of neurological disorders. However, it is unclear whether the gut microbiota is involved in the genesis of chronic itch, a refractory condition that afflicts patients both physically and mentally. Here, we report that depletion of gut microbiota enhances tolerance to itch in mice orally administered with antibiotics (ABX) and mice free of germ. Of note, oral gavage with Bacteroides fragilis (B. fragilis), a prominent species of the genus Bacteroides with most differential change, corrected the ABX-induced itch dysfunction through its driven metabolite acetyl-l-carnitine (ALC). Mechanistically, gut microbiota or B. fragilis depletion caused a decrease in RNA N6-methyladenosine (m6A) demethylase FTO expression in the dorsal horn and a consequent increase in RNA m6A sites in Mas-related G protein-coupled receptor F (MrgprF) mRNA, leading to decreased MRGPRF protein. The downregulation of FTO was triggered by inactivation of ETS proto-oncogene 1 (ETS1), a transcription factor that binds to the Fto promoter. These findings support a gut microbe – spinal connection in modulation of itch sensation in RNA m6A epigenetic-dependent manner and highlight a critical role of ALC in linking the altered B. fragilis and itch dysfunction.