IDDF2024-ABS-0292 Mechanisms of lactobacillus paragallium LPG-9 in ameliorating placental inflammation in cholestasis of pregnancy through BSH regulation of the TGR5-NF-κB axis

Background

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy characterised by elevated maternal serum bile acids, which can induce adverse foetal complications. It has been found that ICP is accompanied by an imbalance in gut microbiota and probiotics have the potential to treat ICP. In this study, the changes in gut microbiome and bile acid in ICP were explored to improve maternal cholestasis and pregnancy outcomes through probiotics.

Methods

Targeted metabolomics, 16S rRNA sequencing, faecal transplantation (FMT), RT-qPCR and western blot were used to explore the relationship between ICP gut microbiome and pregnancy outcome. In vivo and in vitro assays were used to screen a strain of Lactobacillus paragallium LPG-9 that highly expresses the bile salt hydrolase (BSH). Animal interventions were conducted using LPG-9, and the underlying mechanism was investigated through whole-genome assays and targeted metabolomics.

Results

Aberrant expression of the Takeda G protein-coupled receptor 5 (TGR5)-nuclear factor-κB (NF-κB) pathway in ICP placentas and a reduced proportion of secondary bile acids in the blood was found. The intestinal microbiome of ICP was disturbed with a reduced abundance of Lactobacillus and reduced bile acid excretion as predicted by tax4fun. The RT-qPCR results showed a low expression of the BSH gene in ICP faeces. The results of FMT demonstrated that a disturbed gut microbiota (with reduced BSH abundance) can contribute to the development of ICP by impairing bile acid metabolism. We identified a strain of LPG-9 that was shown to be enriched in bile acid transformation-related genes (BSH) by whole genome sequencing. The supplementation of ICP model rats with LPG-9 resulted in the restoration of the intestinal microbiota and BSH genes, as well as an increase in faecal bile acid excretion. Additionally, the proportion of serum secondary bile acids increased, activating the placental TGR5 and negatively regulating the NF-κB signalling pathway.

Conclusions

The gut microbiota, especially BSH, plays a role in the pathogenesis of ICP by influencing bile acid metabolism. Supplementation with LPG-9 inhibited placental inflammation by restoring intestinal bacterial balance and bile acid metabolism through BSH (IDDF2024-ABS-0292 Figure 1).