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

Abstract

ObjectiveGut microbiota have been linked to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Akkermansia muciniphila (A. muciniphila) 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 A. muciniphila engages the immune response in CAC.DesignMice were given dextran sulfate sodium to induce colitis, followed by azoxymethane to establish CAC with or without pasteurised A. muciniphila 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 A. muciniphila or Amuc_1100 on the immune response in acute colitis and CAC were investigated.ResultsA. muciniphila was significantly reduced in patients with IBD and mice with colitis or CAC. A. muciniphila 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, A. muciniphila 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.ConclusionsThese data indicate that pasteurised A. muciniphila or Amuc_1100 can blunt colitis and CAC through the modulation of CTLs.

Diversity in the Extracellular Vesicle-Derived Microbiome of Tissues According to Tumor Progression in Pancreatic Cancer

“…In another study, it significantly reduced the number of tumors in the gastrointestinal tract in a mouse model [ 38 ]. A membrane protein purified from A. muciniphila reduced colitis-associated tumorigenesis through CD8+ T cell modulation in a mouse model [ 39 ] and had beneficial effects on the gut barrier and metabolism through interaction with toll-like receptor 2 [ 40 ]. Furthermore, we obtained interesting results in the analysis of Streptococcus by comparing pairs of normal and tumor tissues ( Figure 3 F,G).…”

Linking Obesity with Colorectal Cancer: Epidemiology and Mechanistic Insights

“…Treatment with Akkermansia inhibited DSS-induced colitis in mice [ 146 ]. Amuc_1100 and pasteurized Akkermansia blunted colitis and associated CRC tumorigenesis through regulation of macrophages and CD8 + cytotoxic T lymphocytes in mouse colon [ 147 ]. Lactobacillus casei is a genus of Lactobacillus .…”

Bidirectional interaction between intestinal microbiome and cancer: opportunities for therapeutic interventions

“…Treatment of obese and diabetic mice with recombinant AMUC_1100 lowered plasma high-density lipoprotein (HDL), enhanced glucose tolerance, and improved gut permeability, and increased gut tight-junction markers claudin 3 and occludin [ 126 ]. In a mouse model of colitis-associated CRC, AMUC_1100 delayed tumor formation and reduced tumor number and size [ 134 ]. AMUC_1100 increased CD8 + T cells and TNF-α secretion in colon.…”