Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response

Abstract

Background: Experimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD).

Methods: Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement and absence of acute decompensation or infections were included (n = 249). Serum biomarkers of BT (lipopolysaccharide [LPS], lipoteichoic acid [LTA], bacterial DNA [bactDNA]), systemic inflammation and markers of circulatory dysfunction were assessed. T-cell subsets in intestinal biopsies (n = 7 ACLD, n = 4 controls) were analyzed by flow cytometry.

Results: Patients had a median HVPG of 18 (12-21) mmHg and 56% had decompensated ACLD. LPS (0.04 [0.02-0.06] vs. 0.64 [0.30-1.06] EU/mL), LTA (4.53 [3.58-5.97] vs. 43.2 [23.2-109] pg/mL), and detection of bactDNA (≥ 5 pg/mL; 5% vs. 41%) were markedly higher in patients with ACLD than healthy controls (n = 40; p < 0.001) but were similar between different clinical stages of compensated and decompensated ACLD and displayed no meaningful correlation with HVPG and systemic hemodynamics. TNF-α and IL-10 correlated with LPS (Spearman's r_s = 0.523, p < 0.001/r_s = 0.143, p = 0.024) but not with LTA. Presence of bactDNA was associated with higher LPS (0.54 [0.28-0.95] vs. 0.88 [0.32-1.31] EU/mL, p = 0.001) and TNF-α (15.3 [6.31-28.1] vs. 20.9 [13.8-32.9] pg/mL). Patients with ACLD exhibited a decreased CD4:CD8-ratio and increased T_H1-cells in the intestinal mucosa as compared to controls. During a median FU of 14.7 (8.20-26.5) months, bacterial antigens did not predict decompensation or liver-related death (in contrast to HVPG, IL-6, and MAP) as well as infections at 24 months.

Conclusion: BT occurs already in early ACLD stages and triggers a systemic inflammatory response via TNF-α and IL-10. Interestingly, BT markers showed no clear correlation with portal hypertension and circulatory dysfunction in patients with stable ACLD.

Clinical trial number: NCT03267615.

Keywords: Bacterial translocation; Circulatory dysfunction; Cirrhosis; Cytokine; Endotoxin; Gut–liver axis; Immunity; Inflammation; PAMPs; Portal hypertension.