Chemotherapy-induced microbiota exacerbates the toxicity of chemotherapy through the suppression of interleukin-10 from macrophages

ABSTRACT

The gut microbiota has been shown to influence the efficacy and toxicity of chemotherapy, thereby affecting treatment outcomes. Understanding the mechanism by which microbiota affects chemotherapeutic toxicity would have a profound impact on cancer management. In this study, we report that fecal microbiota transplantation from oxaliplatin-exposed mice promotes toxicity in recipient mice. Splenic RNA sequencing and macrophage depletion experiment showed that the microbiota-induced toxicity of oxaliplatin in mice was dependent on macrophages. Furthermore, oxaliplatin-mediated toxicity was exacerbated in Il10^-/- mice, but not attenuated in Rag1^-/- mice. Adoptive transfer of macrophage into Il10^-/- mice confirmed the role of macrophage-derived IL-10 in the improvement of oxaliplatin-induced toxicity. Depletion of fecal Lactobacillus and Bifidobacterium was associated with the exacerbation of oxaliplatin-mediated toxicity, whereas supplementation with these probiotics alleviated chemotherapy-induced toxicity. Importantly, IL-10 administration and probiotics supplementation did not attenuate the antitumor efficacy of chemotherapy. Clinically, patients with colorectal cancer exposed to oxaliplatin exhibited downregulation of peripheral CD45⁺IL-10⁺ cells. Collectively, our findings indicate that microbiota-mediated IL-10 production influences tolerance to chemotherapy, and thus represents a potential clinical target.

KEYWORDS:

• Chemotherapy-induced toxicity
• microbiota
• interleukin-10
• macrophage

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

Z.H., C.J., S. J., and P.L. supervised the study and designed experiments. Z.H., H.XIE, H.XU, J.W.,W.Z., and Q.H. performed experiments. Z.H., H.XIE, H.XU. And J.W. prepared the manuscript. Z.H., H.XIE, and J.W. assisted with the data analysis. All authors have edited the manuscript.

Data availability statement

The sequencing data used in our manuscript has been uploaded. The 16S rRNA gene sequence data are available at the NCBI by accession number PRJNA902737. The RNA-seq data files have been deposited in NCBI’s BioProject under accession number PRJNA903109. Public datasets are available at the NCBI by accession number PRJEB35526.

Ethical approval

All human samples were collected at the Sixth Affiliated Hospital of Sun Yat-sen University with approval from the Human Medical Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University. Animals were handled in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) at the Sixth Affiliated Hospital of Sun Yat-Sen University and Guangzhou Ruige Biological Technology Co., Ltd.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2319511

Additional information

Funding

This study was supported by the National Key R&D Program of China (P.L., 2022YFA1304000), the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (P.L., 2020B1111170004), National Key Clinical Discipline; National Natural Science Foundation of China (P.L., 81970452; P.L., U21A20344; Z.H., 82273346); Science and Technology Program of Shenzhen, China (P.L., JCYJ20190807161807867); Natural Science Foundation of Guangdong Province, China (J.W., 2021A1515111202); Science and Technology Program of Guangdong Province, China (Z.H., 2021B1212040017); Guang Dong Cheung Kong Philanthropy Foundation.