Oral administration of Manuka honey induces IFNγ-dependent resistance to tumor growth that correlates with beneficial modulation of gut microbiota composition

Front Immunol. 2024 Feb 20:15:1354297. doi: 10.3389/fimmu.2024.1354297. eCollection 2024.

Abstract

Background: To investigate the potential of Manuka honey (MH) as an immunomodulatory agent in colorectal cancer (CRC) and dissect the underlying molecular and cellular mechanisms.

Methods: MH was administered orally over a 4 week-period. The effect of MH treatment on microbiota composition was studied using 16S rRNA sequencing of fecal pellets collected before and after treatment. Pretreated mice were implanted with CRC cells and followed for tumor growth. Tumors and lymphoid organs were analyzed by flow cytometry (FACS), immunohistochemistry and qRT-PCR. Efficacy of MH was also assessed in a therapeutic setting, with oral treatment initiated after tumor implantation. We utilized IFNγ-deficient mice to determine the importance of interferon signaling in MH-induced immunomodulation.

Results: Pretreatment with MH enhanced anti-tumor responses leading to suppression of tumor growth. Evidence for enhanced tumor immunogenicity included upregulated MHC class-II on intratumoral macrophages, enhanced MHC class-I expression on tumor cells and increased infiltration of effector T cells into the tumor microenvironment. Importantly, oral MH was also effective in retarding tumor growth when given therapeutically. Transcriptomic analysis of tumor tissue highlighted changes in the expression of various chemokines and inflammatory cytokines that drive the observed changes in tumor immunogenicity. The immunomodulatory capacity of MH was abrogated in IFNγ-deficient mice. Finally, bacterial 16S rRNA sequencing demonstrated that oral MH treatment induced unique changes in gut microbiota that may well underlie the IFN-dependent enhancement in tumor immunogenicity.

Conclusion: Our findings highlight the immunostimulatory properties of MH and demonstrate its potential utilization in cancer prevention and treatment.

Keywords: Manuka honey; colorectal cancer; immunomodulation; tumor immunogenicity; type I/II IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Gastrointestinal Microbiome*
  • Honey*
  • Mice
  • Neoplasms*
  • RNA, Ribosomal, 16S / genetics
  • Tumor Microenvironment

Substances

  • RNA, Ribosomal, 16S

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. RM was supported through a scholarship from the College of Graduate Studies, United Arab Emirates University. This work was supported by grants from Zayed Center for Health Sciences (#31R025) and UAEU Program for Advanced Research (#G00002993), Office of Research and Sponsored Projects, United Arab Emirates University, to BA. Additional support was provided to BA’s lab by ASPIRE, the technology program management pillar of Abu Dhabi’s Advanced Technology Research Council, via the ASPIRE Precision Medicine Research Institute Abu Dhabi (ASPIREPMRIAD) award grant #VRI-20-10 (21R098).