Elaidic acid suppresses hepatocellular carcinoma growth through modulating the production of intestinal Ligilactobacillus murinus-derived spermidine.

Among 44 types of fatty acids measured by targeted fatty acid metabolomics, elaidic acid concentration decreased most significantly in plasma from HCC patients compared to healthy individuals.

• Targeted fatty acid metabolomics was used to compare plasma samples from HCC patients with plasma from healthy people.
• 44 types of fatty acids were analyzed in this comparison.
• Elaidic acid (EA) showed the most significant decrease among all fatty acids measured.
• EA accounts for 80-90% of total trans fatty acids in foods.

Dietary elaidic acid attenuates HCC growth in vivo in both orthotopic and xenograft mouse models.

• In vivo assays were conducted using HCC orthotopic and xenograft mouse models.
• Dietary EA administration was sufficient to reduce tumor growth in both model types.
• These results established an anti-tumor effect of EA in hepatocellular carcinoma.

The anti-tumor effect of elaidic acid is dependent on gut microbiota, as depletion of gut microbiota with antibiotics abolished the anti-tumor effect.

• A cocktail of antibiotics was used to deplete gut microbiota in mouse models.
• When gut microbiota was depleted, the anti-tumor effect of dietary EA was diminished.
• This finding confirmed that EA suppresses HCC tumor growth by modulating gut microbiota.

Dietary elaidic acid markedly increases the abundance of intestinal Ligilactobacillus murinus as revealed by 16S ribosomal RNA sequencing.

• 16S ribosomal RNA sequencing was performed to analyze gut microbiota composition.
• Dietary EA markedly increased the abundance of intestinal Ligilactobacillus murinus (L. murinus).
• This increase in L. murinus was identified as a key mechanistic link in EA's anti-tumor activity.

Dietary elaidic acid drives the production of L. murinus-derived spermidine, which attenuates HCC growth both in vitro and in vivo.

• Untargeted metabolomic sequencing analysis was used to identify metabolites produced by L. murinus.
• Dietary EA was found to drive the production of L. murinus-derived spermidine (SPD).
• SPD attenuated HCC growth in vitro as well as in vivo.
• The anti-tumor effect of SPD correlated with phosphorylation of p38 MAPK and upregulation of tumor protein 53, bcl-2-associated X protein (BAX), and cysteine-requiring aspartate protease 3 (caspase-3).

Spermidine-mediated HCC suppression is associated with activation of apoptotic signaling pathways including p38 MAPK phosphorylation and upregulation of apoptosis and proliferation biomarkers.

• The observed anti-tumor impact correlated with phosphorylation of p38 MAPK.
• Upregulation of tumor protein 53 (p53) was observed.
• Bcl-2-associated X protein (BAX) was upregulated.
• Cysteine-requiring aspartate protease 3 (caspase-3) was upregulated.
• These biomarkers are pertinent to apoptosis and proliferation.