Escherichia coli expressing the kpsM gene exacerbates drug-induced liver injury through up-regulating α1,2-fucosyltransferase and disturbing the host taurine metabolism-from animal models and clinical studies.

BACKGROUND AND AIMS: Drug-induced liver injury (DILI) is a leading cause of acute liver failure. Patients with DILI have disorders of the gut microbiota, yet little is known about the influence of gut microbes on this disease. Herein, we investigated the alterations of gut microbiota in DILI patients, and elucidated the mechanism by which Escherichia coli expressing kpsM gene (kpsM+E. coli) exacerbates DILI, in order to provide targets for intervention of related signaling pathways to improve DILI.

METHODS

Full-length 16S sequencing was performed on fecal samples from a prospective cohort of patients with DILI (n = 42). Quantitative PCR was employed for analysis of E. coli and its kpsM gene in human feces. The DILI model was established by intraperitoneal injection of acetaminophen (300 mg/kg) into mice (n = 5-12). Two hours later, kpsM+ or kpsM knockout E. coli strains were gavaged to determine their roles during DILI. Intestinal epithelial Fut2 gene knockout mice (Fut2ΔIEC) and hepatic metabolome were used to assess the pathogenic mechanisms of the kpsM+E. coli. Plasma metabolome of DILI patients was further validated the discoveries in mice.

RESULTS

The percentage of subjects carrying kpsM were 14.7 %, 40.0 %, 76.5 % in healthy controls, patients with mild DILI, and patients with moderate-to-severe DILI, respectively. Mice transplanted with kpsM+E. coli exhibited more severe DILI, primarily achieved through impaired gut barrier function and enhanced expression of intestinal Fut2. Fut2ΔIEC mice alleviated the aggravation of DILI caused by E. coli via up-regulating the hepatic levels of taurine and tauroursodeoxycholic acid. In addition, the level of plasma taurine was lower in patients with moderate-to-severe DILI than in those with mild DILI.

CONCLUSIONS

The kpsM+ E. coli was associated with the severity of DILI in human. This strain can exacerbate DILI in mice through up-regulating intestinal Fut2 expression and disrupting taurine metabolism.