Plasma lipidomics and fungal peptide-based community analysis identifies distinct signatures of early mortality in acute liver failure.

BACKGROUND AND AIMS

Acute liver failure (ALF) has high mortality predominantly due to compromised immune system and increase vulnerability to bacterial and fungal infections.

METHOD

Plasma lipidome and fungal peptide-based-community (mycobiome) analysis were performed in Discovery cohort (40-ALF, 5-healthy) and validated in a validation cohort of 230-ALF using High-resolution-mass-spectrometry, artificial-neural-network (ANN) and machine-learning (ML).

RESULTS

Untargeted lipidomics identified 2,013 lipids across 8 lipid-groups. 5 lipid-species (Phosphatidylcholine, PC(15:0/17:0), PC(20:1/14:1), PC(26:4/10:0), PC(32:0) and TG(4:0/10:0/23:6)) significantly differentiated ALF-NS (FC>10, p<0.05, FDR<0.01). Mycobiome (alpha/beta diversity) was significantly higher and showed 4 phyla and >20 species significantly dysregulated in ALF-NS linked with lipid-metabolism, fatty-acid-elongation in ER, and others (p<0.05). Lipid and mycobiome diversity in ALF-NS were strongly correlated(r2>0.7, p<0.05). Multi-modular correlation network showed striking associations between lipid, Fungal-peptides modules, and Clinical parameters specific to ALF-NS (p<0.05). Cryptococcus amylolentus CBS6039 and Penicillium oxalicum1142 directly correlated with Phosphatidylcholine, Triglycerides, and severity in ALF-NS(r2>0.85, p<0.05). POD-fungus and POD-lipids showed direct association with infection, necrosis, and hepatic encephalopathy (Beta>1.2, p<0.05). POD-lipid (AUC=0.969) and HR=1.99(1.02-2.04) superseded POD-fungus and severity indices for early-mortality prediction. Finally, significant increase in PC(15:0/17:0) level showed highest normalized importance and predicted early-mortality with >95% accuracy/sensitivity/specificity using ANN and ML. Interestingly, fungal surveillance protein Clec7a was significantly downregulated (>2-fold), leading to a notable rise in fungal infection-mediated choline/phosphatidylcholine and associated enzymes (FC>1.5; Kennedy cycle). This contributed to phosphatidic acid-mediated hyper-inflammation in ALF-non-survivors.

CONCLUSION

In ALF plasma lipidome and mycobiome are dysregulated. Increase circulating phosphatidylcholine could stratify ALF predisposed to early-mortality or require emergency liver transplantation.