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The Synergistic Effects of Next-Generation Probiotics Supplementation and Anti-PD-1 Therapy Against Colorectal Cancer Through 16S rRNA Sequencing of Gut Microbiota and Serum Untargeted Metabolomics
46 Pages Posted: 21 Feb 2024
More...Abstract
Objective: Despite significant breakthroughs of therapeutic antibodies targeting PD-1 in cancer treatment, most colorectal cancer (CRC) patients still have a poor response to anti-PD-1 immunotherapy. The combination therapy strategies are used to overcome the aforementioned limitations. Alistipes (A.) onderdonkii has anti-cancer effects. The aim of this study was to investigate the effect of A. onderdonkii and the related mechanisms in the anti-PD-1 treatment for CRC.
Methods: With the establishment of CT26 tumor-bearing mouse model, the anti-tumor effect of anti-PD-1 therapy combined with or without probiotics was evaluated. The anti-tumor effects of each treatment were examined using HE staining and IHC staining. The immune microenvironment of tumors following treatment was investigated using flow cytometry, IHC, and ELISA. Mouse feces were harvested for 16S rRNA gene sequencing of gut microbiota. Mouse serum was isolated for untargeted metabolomics analysis. Additionally, AB-PAS staining and immunofluorescence staining were carried out to assess the expression levels of intestinal barrier-related tight junction proteins and thus to evaluate the intestinal barrier integrity in mice.
Results: Anti-PD-1 therapy notably affected the gut microbiota community composition in mice, particularly upregulating A. onderdonkii abundance. A. onderdonkii supplementation markedly promoted the effectiveness of anti-PD-1 therapy on CRC treatment, as manifested by the elevated CD8+ T cell infiltration, promoted intestinal barrier integrity, and affected serum metabolomics. A. onderdonkii showed similar effects to the identified next-generation probiotics (NGP) A. muciniphila. Additionally, the combination therapy of anti-PD-1 and probiotics supplementation decreased PD-1 level and elevated IL-2 level, indicating that the combination therapy effectively restored the function of T cells via inhibiting suppressive checkpoints.
Conclusion: The combination therapy of anti-PD-1 plus A. onderdonkii supplementation might be a promising strategy for CRC treatment. These results provide strong evidence for A. onderdonkii as a potential NGP.
Funding: This study was supported by Hunan Provincial Key Areas R&D Plan-Key R&D
Projects (2021SK2001).
Declaration of Interest: The authors confirm that there are no conflicts of interest.
Ethical Approval: The guidelines for the care and use of animals were approved by the Medicine
Animal Welfare Committee of Third Xiangya Hospital, Central South University.
Keywords: Alistipes onderdonkii, Colorectal cancer, anti-PD-1 therapy, untargeted metabolomics, 16s rRNA gene sequencing
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