Indole-3-acetic acid alleviates intestinal failure associated liver disease via the miR-216a-5p/LRH-1 axis

Long-term total parenteral nutrition can cause intestinal failure-associated liver disease (IFALD). Gut microbiota-derived indole-3-acetic acid (IAA) has been linked to liver disease, but mechanisms remain unclear. This study aimed to verify the protective role of Lactobacillus reuteri and IAA in IFALD and to investigate whether IAA acts through the miR-216a-5p/LRH-1 axis. We used male C57BL/6 mice and established a total parenteral nutrition (TPN) model following dextran sulfate sodium (DSS) administration. Differential bacterial species and metabolites were screened and validated through multi-omics analyses and fecal microbiota transplantation (FMT) experiments. Downstream miRNAs and mRNAs were identified by transcriptome and miRNA sequencing. Gene overexpression and knockdown were performed using an adeno-associated virus (AAV) or plasmid vectors. Histopathological staining and serological indicators were used to assess the pathological changes in each group. We found that the abundance of Lactobacillus reuteri (L. reuteri) in IFALD was significantly reduced, and supplementation with L. reuteri protected against liver injury in IFALD. IAA, a tryptophan metabolite of L. reuteri, can alleviated hepatic steatosis and metabolic disorders in an IFALD mouse model by downregulating miR-216a-5p in hepatocytes, which in turn promotes the expression of liver receptor homologue-1 (LRH-1, Nr5a2). However, the overexpression of miR-216a-5p abolished the hepatoprotective effects of IAA. Overall, our study identified IAA as important mediator for alleviating liver injury via the miR-216a-5p-LRH-1 axis, providing evidence for the diagnosis and treatment of IFALD.