Patients with acutely decompensated cirrhosis frequently present a paradoxical immune state characterized by persistent systemic inflammation together with severe immunosuppression. This dysfunctional immune response increases their susceptibility to bacterial infections, one of the main precipitants of ACLF, a syndrome characterized by multi-organ systems failure and high short-term mortality.

To better understand the molecular mechanisms underlying immune dysfunction in these patients, researchers at EF CLIF from Hospital Clínic de Barcelona and Institut d’Investigacions Biomèdiques Pi i Sunyer (IDIBAPS) performed a comprehensive lipidomics analysis of 308 plasma samples longitudinally collected from 93 patients with acutely decompensated cirrhosis with and without ACLF, as well as from healthy subjects. Using liquid chromatography coupled to tandem mass spectrometry, researchers profiled 98 immunomodulatory lipid mediators and integrated these findings with gene expression, flow cytometry, and functional immune cell analyses.

The study identified the linoleic acid-derived leukotoxin 9,10-DiHOME as the only lipid mediator specifically elevated in patients who developed infections and ACLF. Levels of 9,10-DiHOME closely tracked disease severity and peaked during episodes of infection and organ failure.

“Previous results from our group showed that patients with acutely decompensated cirrhosis presented an altered lipidomic profile. This condition would disrupt the lipid mediator composition, which is a well-known modulator of the immune response. Therefore, functional characterization of the immune system under this altered environment was needed to better understand the impaired immune response”, said first author in the paper Bryan J. Contreras, predoctoral researcher at IDIBAPS.

Functional studies revealed that 9,10-DiHOME critically impaired the defensive capacity of circulating immune cells. In polymorphonuclear leukocytes—rapid-response components of the innate immune system—the lipid mediator reduced phagocytosis, degranulation, and respiratory burst activity, all essential mechanisms required for pathogen clearance. In mononuclear leukocytes—specialized immune cells responsible for targeted, long-term defense—9,10-DiHOME induced the expression of MerTK, a marker strongly associated with immunosuppressive phenotypes, while simultaneously reducing inflammatory cytokine responses and disrupting mitochondrial and autophagic functions.

“These findings provide a mechanistic explanation for the immune paralysis observed in patients with advanced cirrhosis”, said Contreras. “Our data indicate that 9,10-DiHOME not only accumulates in the most severe stages of the disease, but actively suppresses immune cell defensive responses against pathogens”, he added.