A purified membrane protein from <i>Akkermansia muciniphila</i> or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8⁺ T cells in mice.

Abstract

Gut microbiota have been linked to inflammatory bowel disease (IBD) and colorectal cancer (CRC). <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>) is a gram-negative anaerobic bacterium that is selectively decreased in the faecal microbiota of patients with IBD, but its causative role and molecular mechanism in blunting colitis-associated colorectal cancer (CAC) remain inconclusive. This study investigates how <i>A. muciniphila</i> engages the immune response in CAC. Mice were given dextran sulfate sodium to induce colitis, followed by azoxymethane to establish CAC with or without pasteurised <i>A. muciniphila</i> or a specific outer membrane protein (Amuc_1100) treatment. Faeces from mice and patients with IBD or CRC were collected for 16S rRNA sequencing. The effects of <i>A. muciniphila</i> or Amuc_1100 on the immune response in acute colitis and CAC were investigated. <i>A. muciniphila</i> was significantly reduced in patients with IBD and mice with colitis or CAC. <i>A. muciniphila</i> or Amuc_1100 could improve colitis, with a reduction in infiltrating macrophages and CD8⁺ cytotoxic T lymphocytes (CTLs) in the colon. Their treatment also decreased CD16/32⁺ macrophages in the spleen and mesenteric lymph nodes (MLN) of colitis mice. Amuc_1100 elevated PD-1⁺ CTLs in the spleen. Moreover, <i>A. muciniphila</i> and Amuc_1100 blunted tumourigenesis by expanding CTLs in the colon and MLN. Remarkably, they activated CTLs in the MLN, as indicated by TNF-α induction and PD-1downregulation. Amuc_1100 could stimulate and activate CTLs from splenocytes in CT26 cell conditioned medium. These data indicate that pasteurised <i>A. muciniphila</i> or Amuc_1100 can blunt colitis and CAC through the modulation of CTLs.