<i>Lactobacillus acidophilus</i> KLDS1.0901 ameliorates non-alcoholic fatty liver disease by modulating the tryptophan metabolite indole-3-aldehyde and acting on its receptor AhR

Our previous study demonstrated that <i>Lactobacillus acidophilus</i> KLDS1.0901 significantly alleviated symptoms of high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and showed a strong association with the gut microbiota; however, the underlying mechanisms remained unclear. In this study, we focused on changes in intestinal metabolic pathways in mice following intervention with <i>Lactobacillus acidophilus</i> KLDS1.0901, using non-targeted metabolomics. Tryptophan metabolism was found to be closely associated with NAFLD alleviation, and indole-3-aldehyde (IAld) was identified as a key target. Animal experiments showed no significant differences in the levels of liver triglycerides, fasting blood glucose, alanine aminotransferase, aspartate aminotransferase, IL-6, IL-1β, TNF-α, and IL-10 between the direct-feeding IAld group and the <i>Lactobacillus acidophilus</i> KLDS1.0901 group. This suggests that the IAId, produced by <i>Lactobacillus acidophilus</i> KLDS1.0901, is the key intermediate mediator responsible for its improvement of NAFLD. The alleviating effect of <i>Lactobacillus acidophilus</i> KLDS1.0901 on NAFLD symptoms was suppressed after the inhibition of the IAld receptor aromatic hydrocarbon receptor (AhR), suggesting that the bacterium relies on the AhR signaling pathway to mediate its effect on NAFLD. Cellular experiments showed that IAld significantly reduced triglyceride content, decreased lipid accumulation, and increased glycogen levels in oleic acid-induced cells. The effects of IAld on gene transcription levels in oleic acid-induced HepG2 cells were further analyzed using high-throughput sequencing. Transcriptomic analysis revealed that IAld regulates key pathways, including the NF-κB, chemokine and AGE-RAGE signaling pathways. Our study identified the ameliorative effects of tryptophan metabolites, particularly IAld, on NAFLD, along with the underlying mechanisms, offering new insights into potential treatment strategies for NAFLD.