Obesity-induced gut microbiota transplantation promotes the occurrence and development of hepatocellular carcinoma (Dec 2025, mice) FMT

[Michael Harrop]

https://www.tandfonline.com/doi/full/10.1080/20565623.2025.2599729

Abstract​

Objective​

Obesity is a recognized risk factor for hepatocellular carcinoma (HCC), yet the causal role of obesity-remodeled gut microbiota remains poorly defined. This study aims to investigate the direct impact of obesity-related gut microbiota on the development of hepatocellular carcinoma.

Methods​

C57BL/6J mice were fed a high-fat diet (HFD) to establish obesity. Fecal microbiota from HFD or normal-chow diet (NCD) mice was transplanted into DEN-initiated recipients. Tumor burden was assessed by incidence, multiplicity, and size. Histomorphology and biochemical methods were employed to assess liver injury, inflammation, fibrosis, lipid metabolism, and the potential signaling pathways involved in these events.

Results​

The gut microbiota of obese mice significantly promoted the incidence of HCC, and increased tumor number, and size spectrum. Specifically, obesity-related gut microbiota significantly aggravated hepatocarcinogenesis (increasing GPC3, GP73, AFP, and N-cadherin, and decreasing E-cadherin), pro-inflammatory cytokine surge (increasing IL-6, IL-1β, IL-17, and TNF-α), and fibrotic activation (increasing α-SMA, TGF-β, and Col1a1) were observed. Mechanistically, obesity-FMT dysregulated lipid metabolism (increasing free fatty acids, total cholesterol, and triglycerides) and activated TLR4-NF-κB and mTOR pathways.

Conclusion​

Our findings suggest that gut microbiota from obese donors directly promotes HCC progression via TLR4-NF-κB/mTOR-driven inflammation, fibrosis, and metabolic dysregulation, offering novel targets for microbiota-based interventions in obesity-associated liver cancer.

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PLAIN LANGUAGE SUMMARY​

Obesity increases the risk of liver cancer, but it was not clear if the specific mix of gut bacteria in obese individuals directly causes cancer beyond the effect of a fatty diet. To investigate this, we conducted a study in mice. We first fed a group of mice a high-fat diet to make them obese. We then collected their gut bacteria and transferred them into another group of mice using a procedure called fecal microbiota transplantation. The recipient mice had already received a low dose of a cancer-causing chemical. We compared these mice to others that received gut bacteria from lean mice. We found that mice receiving bacteria from obese donors developed more severe liver cancer. They had more tumors, and the tumors were larger and more frequent. We discovered that these harmful bacteria caused increased liver inflammation, more scar tissue, and disrupted fat processing in the blood. We linked this effect to the activation of two key signals inside liver cells that control inflammation and cell growth. These results mean that the altered gut bacteria community in obesity is an active driver of liver cancer progression. This understanding highlights the gut-liver connection as a promising new target for developing prevention and treatment strategies for liver cancer in people with obesity.

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Highlights​

1. Obesity-remodeled gut microbiota directly promotes hepatocellular carcinoma progression.
2. Fecal microbiota transplantation from obese donors increases tumor incidence, multiplicity, and size in mice.
3. Obesity-associated gut microbiota exacerbates hepatic inflammation, fibrosis, and epithelial-mesenchymal transition.
4. Altered gut microbiota leads to host lipid metabolism dysregulation and serum lipid accumulation.
5. The activation of TLR4-NF-κB and mTOR signaling pathways is a key mechanism by which the obese microbiota drives the occurrence of liver cancer.

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