Triggering receptor expressed on myeloid cells‑1 (TREM1) is a cell‑surface protein expressed on tumor‑associated macrophages (TAMs), the predominant inflammatory cells in the tumor microenvironment; however, the mechanisms for the influence of TREM1 on TAM polarization during liver cancer progression have not been investigated. In the present study, 20 patients diagnosed with hepatocellular carcinoma (HCC) who underwent surgery were enrolled, and TREM1 expression on M1/M2 macrophages and on M2 macrophages was assessed by immunohistochemical staining. Human leukemia monocytic cells (THP‑1) were differentiated into M2 macrophages using phorbol 12‑myristate 13‑acetate, IL‑4 and IL‑13. A specific short hairpin RNA was used to knockdown TREM1 expression. To investigate the effects of TREM1 downregulation in macrophages on the migration and invasion of liver cancer cells, HepG2 and MHCC97H cell lines were co‑cultured with specific conditioned media. Reverse transcription‑quantitative PCR and western blot analyses were used to detect M1 and M2 macrophage marker expression. The expression levels of proteins of the PI3K/AKT/mTOR signaling pathway were analyzed by western blotting, revealing that TREM1 expression in HCC tissues was significantly elevated compared with that in adjacent normal tissues, and TREM1 was highly expressed on the cell membranes of M2 macrophages in tumor tissues compared with in adjacent normal tissues. The present results demonstrated that TREM1 downregulation in macrophages shifted M2 macrophages towards an M1 phenotype, as defined by higher expression levels of M1‑associated markers and decreased expression levels of M2‑associated markers. In addition, TREM1 downregulation in macrophages suppressed migration and invasion of HepG2 and MHCC97H cells. Furthermore, TREM1‑knockdown in macrophages inhibited PI3K/AKT/mTOR activation in the polarization of M2 macrophages. In conclusion, downregulation of TREM1 expression in macrophages shifted M2 macrophages towards a M1 phenotype via inhibiting PI3K/AKT signaling. In addition, migration and invasion of HepG2 and MHCC97H cells were inhibited when this signaling pathway was blocked. The present findings suggest TREM1 as a novel potential therapeutic target for liver cancer management.

Primary biliary cholangitis (PBC) may progress to clinically significant portal hypertension (CSPH) before the development of cirrhosis. This study aimed to investigate CSPH incidence as well as the clinicopathological characteristics and predictive value of these features for the prognosis of patients with PBC, especially at early histologic stage. Patients diagnosed with PBC between January 2013 and April 2022 were retrospectively enrolled. The prognostic value of baseline clinicopathological characteristics for long-term outcomes in PBC patients with CSPH was assessed using Kaplan-Meier survival analysis and COX regression analysis. Among 280 patients with PBC, 104 underwent liver biopsy and 68 were at early histologic stage. CSPH was present in 47.2 % of participants with 20.6 % at early histologic stage. CSPH was a risk factor for predicting the liver transplant-free survival in PBC patients (hazard ratio [HR], 6.78; 95 % CI, 2.94-15.63), especially those at early stage. Perisinusoidal fibrosis and nodular regenerative hyperplasia (NRH) were common histopathological features in PBC patients with CSPH at the early stages. Fibrous septa formation in the hepatic lobules (HR, 4.85; 95 % CI, 1.51-15.52) and cholestasis (HR, 7.70; 95 % CI, 2.56-23.18) were independent predictors of adverse outcomes. CSPH indicates an increased risk of adverse outcomes in PBC patients, especially those in early histologic stage. Perisinusoidal fibrosis and NRH are valuable histological features of CSPH in patients with early-stage PBC. Identification of clinicopathological features and assessment of portal hypertension (especially at early stage), contribute to the development of personalized strategies.

Targeting the gut-liver axis is a promising strategy for treating liver diseases. We aimed to assess the therapeutic efficacy of targeting the gut microbiota-bile acid (BA) axis using ursodeoxycholic acid (UDCA) combined with the probiotic Bifidobacterium to treat chronic hepatitis B (CHB). BA profiles were characterized by mass spectrometry, and gut microbiota composition was analyzed using 16S rRNA sequencing in patients with CHB and healthy controls (HCs). The effects of UDCA and Bifidobacterium were assessed both in a preclinical model and in a 2-month clinical trial involving 22 patients with CHB who received either UDCA (250 mg twice daily; n = 6), Bifidobacterium (2 g twice daily; n = 6), or a combination of UDCA and Bifidobacterium (n = 10). UDCA was the most significantly decreased serum BA in patients with CHB compared to HCs (p <0.001), and had the strongest anti-HBV effect in vitro and in vivo. In the gut, the Bifidobacterium abundance was the most dramatically decreased fecal genus in patients with CHB (p = 0.018), and had the anti-HBV effect in vivo. Finally, combined treatment with UDCA and Bifidobacterium significantly reduced serum alanine aminotransferase (p = 0.008), HBV DNA (77% reduction; p <0.001), pregenomic RNA (59% reduction; p <0.001), and hepatitis B surface antigen (15% reduction; p = 0.002) levels. It also decreased NKG2A expression on natural killer (NK) cells and PD-1 expression on CD8⁺ T cells by approximately 50% (p <0.01), while enhancing secretion of granzyme B, perforin, and interferon-γ by CD8⁺ T and NK cells (p <0.05). These effects were superior to those achieved with either monotherapy. Combined treatment with UDCA and Bifidobacterium promotes CD8⁺ T/NK cell function and viral control in patients withCHB and may represent a promising adjunct therapy warranting further investigation. Targeting the gut microbiota-bile acid axis has the potential to treat chronic hepatitis B. Results from preclinical models and a clinical trial show that combination treatment with ursodeoxycholic acid plus the probiotic Bifidobacterium exerts antiviral effects in patients with chronic hepatitis B by promoting CD8⁺ T cell and natural killer cell function. These findings may advance the understanding of HBV immunology and treatment options for chronic hepatitis B. ChiCTR2200062861.

The rate of functional cure (HBsAg loss) remains unsatisfactory following pegylated interferon (PEG-IFN) treatment in chronic hepatitis B. To optimize PEG-IFN administration, this study aimed to evaluate virological markers to predict functional cure and/or hepatitis B e antigen (HBeAg) loss.