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 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 α /β integrin, a receptor frequently overexpressed in human CRC tumours and cell lines. Interaction between PCWBR2 and integrin α /β 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-κB) activation. NF-κB in turn triggers a pro-inflammatory response as indicated by increased levels of cytokines, such as interleukin-10 and interferon-γ in the tumours of P. anaerobius-treated Apc mice. Analyses of tumour-infiltrating immune cell populations in P. anaerobius-treated Apc mice revealed significant expansion of myeloid-derived suppressor cells, tumour-associated macrophages and granulocytic tumour-associated neutrophils, which are associated with chronic inflammation and tumour progression. Blockade of integrin α /β 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 α /β -PI3K-Akt-NF-κB signalling axis and identify the PCWBR2-integrin α /β axis as a potential therapeutic target for CRC.