Oral administration of Bifidobacterium longum and Bifidobacterium infantis ameliorates cefcapene pivoxil-induced attenuation of anti-programmed cell death protein-1 antibody action in mice

Abstract

Gut bacteria play pivotal roles in the antitumor effects of immune checkpoint inhibitors (ICIs). However, antimicrobial therapy, often necessary for infections in cancer patients, can reduce the efficacy of ICIs. The potential of probiotics to restore ICI efficacy remains uncertain. This study evaluated the effects of Bifidobacterium longum and Bifidobacterium infantis (BLBI) in a CT-26 subcutaneous tumor mouse model treated with anti-programmed cell death protein 1 antibody (αPD-1) and cefcapene pivoxil (CFPN-PI). BALB/c mice received daily oral gavage of CFPN-PI for 5 days before tumor inoculation, followed by weekly αPD-1 administration and tumor growth monitoring. BLBI was administered via ad libitum feeding, mixed in powdered feed. Gut microbiota composition and fecal short-chain fatty acid concentrations were assessed, along with gene expression and immune cell populations in the tumor microenvironment, using quantitative RT-PCR and flow cytometry, respectively. CFPN-PI alone increased tumor growth and attenuated the antitumor effect of αPD-1. In contrast, BLBI inhibited CFPN-PI-induced tumor growth and improved the efficacy of αPD-1. Probiotic treatment increased the stool propionic acid concentration and the number of tumor-infiltrating conventional type 1 dendritic cells. Relative decreases in Bacteroides and Lachnospiraceae _NK4A136_group species and relative increases in Muribaculaceae and Unclassified_f_Oscillospiraceae species correlated with an improved αPD-1 response. These results suggest that probiotic administration may be a new therapeutic strategy to rescue the attenuated efficacy of ICIs in patients with cancer who require antimicrobial therapy.

Keywords: Antimicrobial; Dendritic cell; Gut microbiota; Immune checkpoint inhibitors; Probiotics; Propionic acid.