On the basis of previous studies, this study intends to explore the efficacy of preoperative oral administration of Lactobacillus reuteri (Lr) combined with preoperative neoadjuvant/conversion therapy in patients with primary resectable hepatocellular carcinoma (HCC). We hypothesize that this combination represents a novel, microbiota-based therapeutic strategy to facilitate perioperative hepatic recovery and improve long-term survival outcomes.
This study is an open-label, randomized, blank-controlled clinical trial. Patients undergoing liver resection were randomly allocated to one of two groups. The intervention group received preoperative oral Lactobacillus reuteri (Lr) supplementation alongside neoadjuvant/conversion immunotherapy. The control group received preoperative neoadjuvant/conversion immunotherapy alone. Fecal and peripheral blood samples will be collected at baseline (pre-medication), 3 days prior to surgery, and at 5 days, 1, 3, 6, 9, 12, 18, and 24 months postoperatively. Intraoperative liver tissue samples will also be obtained. Statistical analyses will be performed to compare intergroup differences in postoperative liver function recovery, overall survival, hepatic and peripheral immune markers, and gut microbiota composition.
This study aims to develop adjuvant strategies to enhance therapeutic outcomes for HCC patients undergoing preoperative neoadjuvant/conversion immunotherapy.
Understanding and voluntarily signing the informed consent form for this study;
Age≥18 years and ≤75 years; gender not restricted;
Histologically (pathologically), cytologically, or radiologically confirmed hepatocellular carcinoma (HCC);
Patients who require preoperative immune checkpoint inhibitor (ICI) combination therapy followed by potentially curative hepatectomy;
Inability to comply with the study protocols or procedures;
Known intrahepatic cholangiocarcinoma, sarcomatoid hepatocellular carcinoma, mixed cell carcinoma (ICC more than 30%) and fibrolaminar cell carcinoma
Hepatic encephalopathy, hepatorenal syndrome, or severe decompensated cirrhosis;
Planned use of probiotics, yogurt, or bacterial-fortified foods during the treatment period;
Parallel
Dietary Supplement: L. reuteri DSM 17938
Dietary supplement1 \* 10\^8 CFU of L. reuteri DSM 17938 two capsules per day for 3 months
Comparison of liver function recovery with ALT and AST
The levels of the alanine aminotransferase (ALT) and aspartate aminotransferase (ALT) after surgery will be compared.
Comparison of liver function recovery with total bilirubin
The levels of the total bilirubin after surgery will be compared.
Comparison of liver function recovery with prothrombin activity
The levels of the prothrombin after surgery will be compared.
Incidence of postoperative complications
The postoperative complication rates including surgical site infection, hemorrhage, and bile leakage.
Analysis of hepatic tissue microbiota
Postoperative liver specimens will be collected to compare or quantitatively detect microbial content (e.g., Lactobacillus reuteri) in liver tissues (tumor and peritumoral regions) through culture-based methods, or to assess microbial community diversity changes via microbiome sequencing.
Alterations in gut microbiota
16S rRNA sequencing will be used to measure fecal sample. The alpha and beta diversity of gut microbiota between two groups will be analyzed, including a series of statistical analysis indexes such as Chao, Shannon, Simpsonace, Simpson and Coverage, in order to reflect the microbial community diversity.
Differences among hepatic immune cell subsets
Single-cell sequencing will be used to analyzed the immune cell subsets in tumor tissues and paired normal tissues. The immune cell clusters comprised: 9 clusters of CD4+ T cells (CD3+CD4+), 8 clusters of CD8+ T cells (CD3+CD8+), 3 clusters of B cells (CD3-CD19+), 2 clusters of monocytes (CD3-CD19-CD14+) and 10 clusters of other subsets, such as dendritic cells (DCs, CD3-CD19-CD14-CD20-HLA-DR+), and NK cells (CD3-CD19-CD14-C-D20-CD56+).
The alterations of peripheral immune cell subsets
Single-cell sequencing will be used to analyze the immune cell subsets in peripheral blood. The peripheral immune cell subsets comprised: 9 clusters of CD4+ T cells (CD3+CD4+), 8 clusters of CD8+ T cells (CD3+CD8+), 3 clusters of B cells (CD3-CD19+), 2 clusters of monocytes (CD3-CD19-CD14+) and 10 clusters of other subsets, such as dendritic cells (DCs, CD3-CD19-CD14-CD20-HLA-DR+), and NK cells (CD3-CD19-CD14-C-D20-CD56+).
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