The effects of probiotics duration and type on immunotherapy efficacy in non-small cell lung cancer with or without antibiotics

BACKGROUND: In non-small cell lung cancer (NSCLC) patients, antibiotics impair immunotherapy efficacy, while probiotics can enhance it. The relationship between the duration of probiotics and the restoration of immunotherapy efficacy compromised by antibiotics, as well as its potential to enhance immunotherapy outcomes in antibiotic-naive patients, remains unclear. Furthermore, more probiotic types and their mechanisms for improving immunotherapy efficacy need to be identified and elucidated. METHODS: This multicenter study enrolled wild-type NSCLC patients. Clinicopathological features were recorded, focusing on antibiotic and probiotic use and duration. Baseline fecal and blood samples were collected. Gut microbiota were analyzed via 16S rRNA sequencing, and serum metabolites were analyzed through untargeted metabolomics. Flow cytometry was used to explore potential mechanisms. RESULTS: 524 wild-type NSCLC patients were enrolled in the study, with fecal samples collected from 22 patients. Patients receiving antibiotics alone exhibited poorer PFS and OS. For those receiving antibiotics, the use of probiotics, regardless of duration, led to improved PFS and OS, which were comparable to those of patients in the No antibiotics + No probiotics group. Among the patients who did not receive antibiotics, those who were treated with probiotics for more than 15 days showed improved PFS. Patients with enriched gut microbiota in un-f-Bifidobacterium and roseburia showed better PFS. The frequency of peripheral Th cells was positively associated with the abundance of un-f-Bifidobacterium. There was also a positive correlation between o-Methoxyphenyl sulfate and the gut microbiota that exhibited better immunotherapy efficacy. CONCLUSIONS: Antibiotics weaken immunotherapy efficacy in wild-type NSCLC patients. Probiotics, regardless of duration, can restore it. For antibiotic-naive patients, taking probiotics over 15 days can improve immunotherapy efficacy. Certain probiotics, including un-f-Bifidobacterium and Roseburia, may be potential candidates for improving the efficacy of immunotherapy.