Antibiotic pretreatment attenuates liver ischemia–reperfusion injury by Farnesoid X receptor activation

Abstract

Prophylactic antibiotics (Abx) are used before liver surgery, and the influence of antibiotic pretreatment on hepatic ischemia–reperfusion injury (IRI) remains unclear. Hence, we explored the impact of Abx pretreatment on hepatic IRI in the present work. The gut microbiota has an essential role in hepatic bile acid (BA) metabolism, and we assumed that depletion of the gut microbiota could affect the composition of hepatic BAs and affect liver IRI. The IRI model demonstrated that Abx pretreatment attenuated liver IRI by alleviating cell apoptosis, reducing the inflammatory response, and decreasing the recruitment of CCR2+ monocytes. Mechanistically, Abx pretreatment reshaped the gut microbiota, especially decreasing the relative abundance of Firmicutes and increasing the relative abundance of Clostridium, which were related to the transformation of BAs and were consistent with the altered bile acid species (unconjugated BAs, especially UDCA). These altered BAs are known FXR agonists and lead to the activation of the farnesoid X receptor (FXR), which can directly bind to the FXR response element (FXRE) harbored in the TLR4 promoter and further suppress downstream mitogen-activated protein kinase (MAPK) and nuclear kappa B (NF-κB) pathways. Meanwhile, the CCL2–CCR2 axis was also involved in the process of FXR activation, as we confirmed both in vivo and in vitro. Importantly, we proved the importance of FXR in mice and clinical occlusion samples, which were inversely correlated with liver injury. Taken together, our study identified that Abx pretreatment before liver resection was a beneficial event by activating FXR, which might become a potential therapeutic target in treating liver injury.

Gastrodia elata Blume extract improves high-fat diet-induced type 2 diabetes by regulating gut microbiota and bile acid profile

“…We also found that GEBE treatment increases the abundances of Lactobacillus salivarius and Mucispirillum schaedleri by means of LEfSe (Figure 2D). In a recent study, Lactobacillus salivarius influenced glucose metabolism in diabetic mice by increasing the expression of glucose transporter protein 2 in human intestinal epithelial cells (Hsieh et al, 2020;Wang et al, 2022). Furthermore, Mucispirillum schaedleri has a protective effect against Salmonella-induced colitis in mice (Herp et al, 2019).…”

“…thereby reduces inflammation and insulin resistance (Chen et al, 2019;Xing et al, 2020;Liu et al, 2022).…”

G protein subunit alpha i2's pivotal role in angiogenesis

“…Cellular assays. Cellular functional assays, including the assessment of cell proliferation through EdU (5-ethynyl-2'-deoxyuridine) staining of cell nuclei, "Transwell" in vitro cell migration and "Matrigel Transwell" in vitro cell invasion, in vitro capillary tube formation, nuclear TUNEL staining assay, JC-1 staining of mitochondrial depolarization the Caspase-3 and the Caspase-9 activity assays were described early [12,13,[29][30][31]. qRT-PCR (quantitative reverse transcription polymerase chain reaction) and Western blotting assays have been previously detailed in earlier publications [20,32,33].…”