Effect of Butyrate‐Producing Enterobacteria and Proton Pump Inhibitors on Advanced Hepatocellular Carcinoma Treatment With Durvalumab and Tremelimumab

ABSTRACT Aim The gut microbiome modulates immune responses, and butyrate‐producing bacteria have been linked to improved immune checkpoint inhibitor (ICI) efficacy. Conversely, proton pump inhibitors (PPIs) may negatively impact ICI outcomes by altering gut microbiota. This study aims to elucidate their effects in hepatocellular carcinoma (HCC). Methods This retrospective multicenter cohort study included 208 HCC patients treated with durvalumab plus tremelimumab at 25 hospitals in Japan. Patients were classified into a butyric acid group ( n = 27), who ingested drugs containing butyrate‐producing enterobacteria, and a non‐butyric acid group ( n = 181), as well as a PPI group ( n = 107) and a non‐PPI group ( n = 101). Overall survival (OS) was analyzed using inverse probability of treatment weighting, and risk factors were assessed with Cox proportional hazards modeling. Tumor response was evaluated by RECIST v1.1. Results No significant OS differences were observed between the butyric acid and non‐butyric acid groups ( p = 0.921), or between PPI and non‐PPI groups ( p = 0.917). The objective response rate was 3.7% in the butyric acid group versus 15.5% in the non‐butyric acid group ( p = 0.543) and 15.8% in the PPI group versus 12.1% in the non‐PPI group ( p = 0.222). Disease control rates were comparable. Multivariate analysis identified ECOG performance status ( p = 0.019) and ALBI score ( p < 0.001) as independent prognostic factors, while butyrate‐producing bacteria and PPI use were not associated with survival outcomes. Conclusion Neither butyrate‐producing bacteria nor PPI use significantly influenced the efficacy of durvalumab plus tremelimumab in HCC. The liver's immunotolerant microenvironment may limit the impact of microbiome modulation on ICI efficacy.