Therapeutic potential of Clostridium butyricum anticancer effects in colorectal cancer

Abstract

Probiotic roles of Clostridium butyricum (C.B) are involved in regulating disease and cancers, yet the mechanistic basis for these regulatory roles remains largely unknown. Here, we demonstrate that C.B reprograms the proliferation, migration, stemness, and tumor growth in CRC by regulating pivotal signal molecules including MYC. Destabilization of MYC by C.B supplementation suppresses cancer cell proliferation/metastasis, sensitizes 5-FU treatment, and boosts responsiveness of anti-PD1 therapy. MYC is a transcriptional regulator of Thymidylate synthase (TYMS), a key target of the 5-FU. Also MYC is known to impact on PD-1 expression. Mechanistically, C.B treatment of CRC cells results in MYC degradation by enhancing proteasome-mediated ubiquitination, thereby mitigating MYC-mediated 5-FU resistance and boosting anti-PD1 immunotherapeutic efficacy. Together, our findings uncover previously unappreciated links between C.B and CRC cell signaling, providing insight into the tumorigenesis modulating mechanisms of C.B in boosting chemo/immune therapies.

Keywords: 5-FU; Anti-PD1; Clostridium butyricum; MYC; TYMS; immunotherapy; ubiquitination.

Figure 1.

Clostridium butyricum regulates cell proliferation, migration and invasion, patient derived organoid (PDO) growth, and metastasis in CRC.

Figure 2.

C.B instigates MYC ubiquitination and destabilization in regulating CRC progression.

Figure 3.

C.B attenuates MYC-mediated expression of TYMS to enhances the chemo sensitivity of CRC to 5-FU.

Figure 4.

C.B boosts 5-FU treatment efficacy in mouse xenograft CRC model.

Figure 5.

Therapeutic benefits of C.B by downregulating MYC expression and enhancing the immune response through increased CD8+ cell infiltration.

Figure 6.

C.B or C.B conditioned medium significantly boost the efficacy of anti-PD1.

Figure 7.

Schematic summary of C.B’s role in modulating 5-FU drug resistance and boosting anti-PD1 immunotherapy.