Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma

Abstract

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium-containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs). mRCC patients initiating VEGF-TKIs, regardless of the line of therapy, were randomized to probiotic-supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic-restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole-metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic-supplemented arm versus two patients in the probiotic-restricted arm. Clinical benefit rate was similar in probiotic-supplemented versus probiotic-restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10-6 and p = 5.6 × 10-3 , respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617.

Keywords: VEGF-TKI; dietary supplement; microbiome; probiotics; renal cell carcinoma; targeted therapies.

Conflict of interest statement

SKP reports consulting roles in Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, BMS, and Astellas. ND has consulting roles in Vivreon. JDG, MF, LR, SH, and JT are employees of Translational Genomics Research Institute, Flagstaff, AZ. JH and PB declare no conflict of interest.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Hierarchical cluster of top 20 taxa identified in all metagenomic samples identified by MetaPhlAn2. 14 , 15 Bray–Curtis clustering and heatmap generation were performed using hclust2. Clinical benefit by patient is indicated at the top by color boxes. Barnesiella intestinihominis and Akkermansia muciniphila are indicated with red arrows. Patient number and sample number are shown on the x‐axis

FIGURE 2

LEfSe plot of bacterial taxa with linear discriminant analysis (LDA) scores greater than three significant associated with no clinical benefit (NCB, red) and clinical benefit (CB, green). LDA score (log 10) is shown on the x‐axis

FIGURE 3

Relative abundances of Akkermansia muciniphila, Bacteroides caccae, Faecalibacterum prausnitzii, and Barnesiella intestinihominis in patients who has clinical benefit and no clinical benefit with VEGF‐TKIs. Boxplots were generated using the Kruskal–Wallis H test