Secretory IgA Is a Key Marker Among Gut Barrier Dysfunction-Related Immunoglobulins Predicting Outcomes in ACLF

In cirrhosis, impaired gut mucosal immunity facilitates bacterial translocation (BT) instigating the proinflammatory cascade that exacerbates hepatic damage. The role of antibody-mediated immunity in this process remains unclear. We assessed serum immunoglobulins (Ig) linked to gut barrier function as prognostic markers in a prospective MICROB-PREDICT cohort of patients with acutely decompensated (AD) cirrhosis.

Serum samples of 128 patients were assayed for IgA and IgG antibodies against various targets (filamentous-actin; Saccharomyces cerevisiae [ASCA]; glycoprotein-2 [GP2]; gliadin; endotoxin-core [EndoCab]), secretory (s)IgA, total-IgA, IgG, IgM and free Ig kappa/lambda light chains. Mortality was assessed during a 3-month follow-up period. An independent ACLF patient cohort (n = 50) was used to validate sIgA-related findings.

IgA-type target-specific antibodies were more prevalent than IgG types. Target-specific antibody diversity and concentrations, total-IgA levels and Child-Pugh severity exhibited concordant elevations. Total-IgG levels were inversely associated with CLIF-C AD score and presence of ACLF. sIgA levels increased in parallel with ACLF grades. Elevated sIgA levels were associated with 90-day mortality in ACLF patients (n = 37; AUROC: 0.859; at the cut-off of > 20.9 μg/mL: 11.1% vs. 78.9% Mortality p < 0.001). These findings were confirmed in the validation cohort. In the merged ACLF cohort (n = 87), high sIgA levels predicted 90-day mortality independent of CLIF-C ACLF score (HR: 3.367; CI: 1.563-7.225; p = 0.002).

Enhanced BT-triggered immune activation is indicated by increased total-IgA levels in association with the occurrence of target-specific IgA antibodies. Serum sIgA is a promising marker of gut barrier failure and 90-day mortality in ACLF.