Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity

Emerging evidence implicates a role of the gut microbiota in colorectal cancer (CRC). Peptostreptococcus anaerobius (P. anaerobius) is an anaerobic bacterium selectively enriched in the faecal and mucosal microbiota from patients with CRC, but its causative role and molecular mechanism in promoting tumorigenesis remain unestablished. We demonstrate that P. anaerobius adheres to the CRC mucosa and accelerates CRC development in Apc(Min/+) mice. In vitro assays and transmission electron microscopy revealed that P. anaerobius selectively adheres to CRC cell lines (HT-29 and Caco-2) compared to normal colonic epithelial cells (NCM460). We identified a P. anaerobius surface protein, putative cell wall binding repeat 2 (PCWBR2), which directly interacts with colonic cell lines via alpha(2)/beta(1) integrin, a receptor frequently overexpressed in human CRC tumours and cell lines. Interaction between PCWBR2 and integrin alpha(2)/beta(1) induces the activation of the PI3K-Akt pathway in CRC cells via phospho-focal adhesion kinase, leading to increased cell proliferation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) activation. NF-kappa B in turn triggers a pro-inflammatory response as indicated by increased levels of cytokines, such as interleukin-10 and interferon-gamma in the tumours of P. anaerobius-treated Apc(Min/+) mice. Analyses of tumour-infiltrating immune cell populations in P. anaerobius-treated Apc(Min/+) mice revealed significant expansion of myeloid-derived suppressor cells, tumourassociated macrophages and granulocytic tumour-associated neutrophils, which are associated with chronic inflammation and tumour progression. Blockade of integrin alpha(2)/beta(1) by RGDS peptide, small interfering RNA or antibodies all impair P. anaerobius attachment and abolish P. anaerobius-mediated oncogenic response in vitro and in vivo. Collectively, we show that P. anaerobius drives CRC via a PCWBR2-integrin alpha(2)/beta(1)-P13K-Akt-NF-kappa B signalling axis and identify the PCWBR2-integrin alpha(2)/beta(1) axis as a potential therapeutic target for CRC.