Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy

The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that—in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours—oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC. Dextran nanoparticles loaded with a chemotherapeutic agent and bound to phages that eliminate a pro-tumoural gut bacterium and promote the growth of anticancer-compound-producing bacteria boost chemotherapy responses in mouse models of colorectal cancer.