Intratumor microbiome-derived butyrate promotes lung cancer metastasis

Most recurrences of lung cancer (LC) occur within 3 years after surgery, but the underlying mechanism remains unclear. Here, we collect LC tissues with shorter (<3 years, recurrence group) and longer (>3 years, non-recurrence group) recurrence-free survival. By using 16S sequencing, we find that intratumor microbiome diversity is lower in the recurrence group and butyrate-producing bacteria are enriched in the recurrence group. The intratumor microbiome signature and circulating microbiome DNA can accurately predict LC recurrence. We prove that intratumor injection of butyrate-producing bacteria Roseburia can promote subcutaneous tumor growth. Mechanistically, bacteria-derived butyrate promotes LC metastasis by increasing expression of H19 in tumor cells through inhibiting HDAC2 and increasing H3K27 acetylation at the H19 promoter and inducing M2 macrophage polarization. Depletion of macrophages partially abolishes the metastasis-promoting effect of butyrate. Our results provide evidence for the cross-talk between the intratumor microbiome and LC metastasis and suggest the potential prognostic and therapeutic value of the intratumor microbiome.