Intestinal GPR128 deficiency protects against acetaminophen-induced liver injury through the gut-liver axis.
TL;DR
Intestinal GPR128 deficiency protects against AILI through a gut-liver axis involving goblet cell-associated A. muciniphila, microbial β-galactosidase, dietary GA, and the HSP90α-CBFβ/RUNX1-UPP1 pathway, identifying this cascade as a potential therapeutic target for APAP-induced liver injury.
Abstract
Background
&
Aims
Acetaminophen (APAP)-induced liver injury (AILI) is the leading cause of acute liver failure, but the intestinal host gene-microbe interactions that regulate AILI through the gut-liver axis remain poorly defined. We investigated whether intestinal GPR128 regulates susceptibility to AILI and sought to elucidate the underlying microbiota-dependent molecular mechanisms.
Methods
We used intestinal GPR128-deficient mice challenged with APAP to assess liver injury, goblet cell and mucus-layer integrity, gut microbiota composition, and microbial β-galactosidase activity. The roles of Akkermansia muciniphila, dietary gentisic acid (GA), and the HSP90α-CBFβ/RUNX1-UPP1 pathway were evaluated using mouse, cellular, biochemical, and metabolic assays.
Results
Intestinal GPR128 deficiency protected mice from AILI and was associated with preservation of goblet cell mucus-layer homeostasis and enrichment of mucus-associated A. muciniphila. A. muciniphila-associated β-galactosidase activity promoted dietary GA liberation and increased systemic GA levels. GA appeared to act through HSP90α and concomitantly reduced its interaction with CBFβ, thereby inhibiting CBFβ nuclear translocation and suppressing RUNX1-dependent UPP1 transcription. Inhibition of UPP1 reduced uridine-derived lactate production and ameliorated AILI.
Conclusions
Intestinal GPR128 deficiency protects against AILI through a gut-liver axis involving goblet cell-associated A. muciniphila, microbial β-galactosidase, dietary GA, and the HSP90α-CBFβ/RUNX1-UPP1 pathway. These findings identify this cascade as a potential therapeutic target for APAP-induced liver injury.