Lactobacillus acidophilus potentiates oncolytic virotherapy through modulating gut microbiota homeostasis in hepatocellular carcinoma

Jiayu Zhang, Jinneng Yang, Jinyan Luo, Weili Wu, Haidan Luo, Wenxia Wei, Haimei Lyu, Yuzhi Wang, Hairong Yi, Yijing Zhang, Zongmin Fan, Haiwen Lyu, Vishnu Priya Kanakaveti, Baifu Qin, Ping Yuan, Runxiang Yang, Haipeng Zhang, Tao Zuo, Dean W. Felsher, Mong-Hong Lee () and Kai Li ()
Additional contact information
Jiayu Zhang: Sun Yat-sen University
Jinneng Yang: Sun Yat-sen University
Jinyan Luo: The First Affiliated Hospital of Nanjing Medical University
Weili Wu: Sun Yat-sen University
Haidan Luo: Sun Yat-sen University
Wenxia Wei: Sun Yat-sen University
Haimei Lyu: Sun Yat-sen University
Yuzhi Wang: Sun Yat-sen University
Hairong Yi: Sun Yat-sen University
Yijing Zhang: Sun Yat-sen University
Zongmin Fan: Sun Yat-sen University
Haiwen Lyu: Sun Yat-sen University
Vishnu Priya Kanakaveti: Stanford University
Baifu Qin: Sun Yat-sen University
Ping Yuan: Sun Yat-sen University
Runxiang Yang: The Third Affiliated Hospital of Kunming Medical University
Haipeng Zhang: Jinan University
Tao Zuo: Sun Yat-sen University
Dean W. Felsher: Stanford University
Mong-Hong Lee: Sun Yat-sen University
Kai Li: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Oncolytic viruses (OVs) hold promise for cancer treatment. However, the antitumor efficacy is limited. Microbiota plays a pivotal role in cancer treatment and its impact on oncolytic virotherapy is unknown. Here, we show that VSVΔ51 has higher antitumor efficacy for hepatocellular carcinoma in the absence of microbiota in female mouse models. VSVΔ51 infection causes microbiota dysbiosis, increasing most of the gut bacteria abundance, while decreasing the commensal Lactobacillus. VSVΔ51 reduced intestinal expression of SLC20A1 that binds to Lactobacillus acidophilus (L. acidophilus) CdpA cell wall protein through IL6-JAK-STAT3 signaling, thereby attenuating attachment and colonization of L. acidophilus. L. acidophilus supplementation confers sensitivity to VSVΔ51 through restoring gut barrier integrity and microbiota homeostasis destroyed by VSVΔ51. In this work, we show that targeting microbiota homostasis holds substantial potential in improving therapeutic outcomes of oncolytic virotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-58407-z

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