Anserine restores antibacterial immunity in cirrhosis via a protective CCL5-mediated hepatocyte-CD44⁺pDC crosstalk

Patients with liver cirrhosis exhibit increased susceptibility to bacterial infections; however, the specific immune defects facilitating this vulnerability remain incompletely understood. We aimed to characterize the dysregulated intercellular crosstalk within the cirrhotic liver that compromises antibacterial defense.

We performed single-cell RNA sequencing (scRNA-seq) on livers from control and cirrhotic mice with or without bacterial infection. Inferred cellular interactions were validated using flow cytometry, targeted metabolomics, and functional assays, including ex vivo co-culture, in vivo adoptive transfer, antibody blockade, and transgenic mouse models. Clinical relevance and mechanistic conservation were established utilizing human bulk and single-cell transcriptomic datasets from GEO, alongside validation in a nationwide multicenter prospective clinical cohort (CATCH-LIFE).

scRNA-seq and functional assays revealed a significantly depleted CD44⁺ plasmacytoid dendritic cells (pDCs) subpopulation responsible for impaired antibacterial immunity in cirrhosis. Mechanistically, CD44⁺pDCs do not kill bacteria directly; rather, they sense pathogens via TLR7/9 to secrete type I IFN-α, which subsequently stimulates macrophage chemotaxis, reactive oxygen species (ROS) production, and bacterial phagocytosis. The hepatic recruitment of CD44⁺pDCs is governed by the CCL5-CCR5 axis, orchestrated by a specific subset of CCL5-associated hepatocytes (marked by Mup11 in mice). Targeted metabolomics identified that anserine, a histidine metabolite depleted in cirrhosis, intrinsically upregulates hepatocyte CCL5 expression. Anserine supplementation successfully restored the hepatocyte-pDC protective axis, significantly reducing bacterial burden and mortality in cirrhotic mice. Finally, multi-omics human data and the CATCH-LIFE cohort demonstrated that levels of CCL5, anserine, and CD44⁺ pDCs were significantly correlated with infection incidence and clinical outcomes in patients with cirrhosis.

We uncover a novel anserine-CCL5-pDC-macrophage metabolic-immune axis that is critically impaired in cirrhosis. Restoring this network offers a promising predictive and therapeutic strategy for cirrhosis-associated infections.

Patients with cirrhosis face a critically high risk of bacterial infections, yet the specific immune defects driving this susceptibility have remained elusive. This study uncovers a novel metabolic-immune mechanism wherein the histamine metabolite anserine potentiates a protective crosstalk between hepatocytes and CD44⁺ plasmacytoid dendritic cells (pDCs). We demonstrate that this axis relies on conserved CCL5-CCR5 signaling to recruit pDCs, which subsequently orchestrate bacterial clearance via TLR7/9-mediated IFN-α secretion and macrophage activation. Importantly, these findings were validated in a multi-center prospective human cohort, showing that anserine, CCL5 and CD44⁺ pDCs levels significantly correlate with infection incidence and clinical outcome. This uncovers a previously unrecognized metabolic-immune vulnerability in cirrhosis and suggests that anserine supplementation or targeting the CCL5-pDC axis could serve as a precision therapy to decrease infection-related mortality in cirrhosis.