Abstract
BACKGROUND Liver cirrhosis is characterized by chronic inflammation and fibrosis, with Th17 cells playing a crucial role in its progression. Recent evidence suggests that dietary salt influences immune diseases by modulating Th17 differentiation. This study assessed the impact of dietary salt on Th17-driven inflammation in patients with compensated cirrhosis and explored its effects on liver injury in mouse models.METHODS A nondrug, open-label, nonrandomized study involved 37 patients with compensated cirrhosis, who were given personalized guidelines to reduce salt intake over 3 months. Changes in Th17-driven inflammation and liver function markers were assessed at baseline and after salt restriction. In parallel, the impact of a high-salt diet on hepatic CD4+ T cells was analyzed in mouse models of acute liver injury and fibrosis.RESULTS High salt intake was associated with Th17-mediated inflammation and correlated with markers of impaired liver function in these patients. Importantly, moderating salt intake through a personalized nutritional intervention was sufficient to reduce CD4+ T cell–mediated inflammation. Furthermore, analysis of RNA-seq data revealed enrichment of salt-induced Th17 gene signatures in both liver tissue and peripheral cells from patients with liver disease. Similarly, mice fed a high salt diet showed hepatic enrichment of Th17 cells and exacerbated liver fibrosis upon injury. Mechanistic studies revealed that high sodium conditions activated NF-κB and induced IL-6 production in hepatocytes, which may promote Th17 responses.CONCLUSION Dietary salt exacerbates Th17-driven inflammation and contributes to cirrhosis progression. Salt reduction may represent a viable therapeutic approach to manage inflammation in compensated cirrhosis.FUNDING Grants PI19/01554 and PI22/01907 from Instituto de Salud Carlos III (Madrid, Spain), CDEI-03/20-A and CIPROM/2023/4 from Generalitat Valenciana (Valencia, Spain), CNS2023-145676 from the National Research Agency (AEI) (Madrid, Spain), and LCF/BQ/D121/11860047 from La Caixa Foundation (Barcelona, Spain).
Authors
Amalia Tzoumpa, Beatriz Lozano-Ruiz, Yin Huang, Joanna Picó, Alba Moratalla, María Teresa Pomares, Iván Herrera, Juanjo Lozano, María Rodríguez, Cayetano Miralles, Pablo Bellot, Paula Piñero, Fabián Tarín, Pedro Zapater, Sonia Pascual, José Manuel González-Navajas
Figure 8
NaCl-induced hepatocyte IL-6 production promotes Th17 cell differentiation via NF-κB activation.
