Gut microbes–spinal connection is required for itch sensation

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 <i>Bacteroides fragilis</i> (<i>B. fragilis</i>), a prominent species of the genus <i>Bacteroides</i> with most differential change, corrected the ABX-induced itch dysfunction through its driven metabolite acetyl-l-carnitine (ALC). Mechanistically, gut microbiota or <i>B. fragilis</i> 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 (<i>MrgprF</i>) 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 <i>Fto</i> 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 <i>B. fragilis</i> and itch dysfunction.