Lycium barbarum Polysaccharides as Prebiotics Prevent Colorectal Cancer Liver Metastasis in Non-Alcoholic Fatty Liver Disease by Modulating Gut Microbiota–FGF21-PI3K-AKT Axis

Shuai ZhaoZhenyao TanJiaxin SuoYang Bu^*

• Ningxia Medical University, Yinchuan, China

Introduction: Colorectal cancer liver metastasis (CRLM) is the leading cause of death in colorectal cancer, and nonalcoholic fatty liver disease (NAFLD) promotes CRLM. Lycium barbarum polysaccharides (LBPs), bioactive metabolites of the traditional medicinal plant Lycium barbarum L, inhibit the progression of colorectal cancer and NAFLD by regulating gut microbiota composition. However, their roles in preventing CRLM under NAFLD conditions remain unclear. This study aimed to investigate the preventive effect of LBPs on liver metastasis of colorectal cancer in the context of NAFLD and explore its potential mechanisms Methods: An NAFLD mouse model was established, followed by prophylactic oral administration of LBPs by gavage for 28 days before splenic injection of MC38 colorectal cancer cells to establish liver metastasis. Pseudo-germ-free mice combined with fecal microbiota transplantation were constructed to explore the role of the gut microbiota in LBPs prevention in CRLM. Gut microbiota and fecal short-chain fatty acids were analyzed by16S rRNA sequencing and liquid chromatography–mass spectrometry. Spearman's correlation analysis was used to explore the correlation between bacterial genera and liver lipid metabolism indicators. Serum non-targeted metabolomic profiling and transcriptomic analysis of CRLM cells were performed to elucidate metabolic and molecular mechanisms. Results: Under NAFLD conditions, LBPs markedly reduced hepatic metastatic burden, liver weight, and liver-to-This is a provisional file, not the final typeset article body weight ratio. LBPs ameliorated hepatic lipid metabolism and restored colonic barrier integrity in NAFLD mice. The gut microbiota was identified as a critical mediator of LBPs-induced protection against CRLM, and depletion of the microbiota completely abrogated the anti-metastatic effects of LBPs. LBPs enhanced microbial diversity and richness, enriched butyrate-producing genera, such as Cryptobacteroides, Evtepia, and Bacteroides-H, and elevated colonic butyrate levels. Metabolomic profiling revealed reduced serum acylcarnitines and increased organic acids. Transcriptomic profiling showed upregulation of fibroblast growth factor 21, activation of the PI3K-AKT signaling pathway, and promotion of epithelial–mesenchymal transition in colorectal cancer cells, while LBPs reverse these changes. Discussion: LBPs prevent CRLM associated with NAFLD by modulating the gut microbiota, enhancing butyrate production, improving hepatic metabolic homeostasis, and suppressing prometastatic signaling pathways.