Macrophage migration inhibitory factor as a microbial modulator of colitis-associated colorectal cancer 2256450

Abstract

Abstract Introduction The gut microbiome is altered in inflammation and colorectal cancer (CRC), yet how proinflammatory factors induce dysbiosis, which promotes CRC development, remains unclear. Macrophage migration inhibitory factor (MIF) is a proinflammatory molecule produced by various cell types that protects against multiple pathogens but is also linked to inflammatory diseases and cancer progression. The present study examined the role of MIF in shaping the microbiota configuration and its effect on the development of colitis associated with CRC (CAC). Methods We identified the microbiota through 16S rRNA sequencing of fecal samples from BALB/c MIF-knockout (MIF-KO) and wild-type (WT) mice with azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CAC and compared them with healthy MIF-KO and WT mice (CTL). Additionally, WT mice were purchased from Harlan vivarium and received fecal transplants from MIF-KO and WT mice and subsequently subjected to AOM/DSS-induced CAC (WT-Harlan/MIF-KOv CAC and WT-Harlan/WTv CAC, respectively). Microbial dysbiosis was analyzed via linear discriminant analysis effect size (LEfSe). Results The MIF-KO CAC mice developed a greater number of tumors and exhibited pronounced dysbiosis, with an increased abundance of inflammation- and CRC-associated bacteria such as Muribaculaceae, compared to WT CAC mice. Fecal transplantation from MIF-KO donors to WT-Harlan increased the tumor number and size, and an increase in Muribaculaceae levels relative to those in WT-Harlan/WTv CAC mice was also observed. Conclusion The absence of MIF promotes a dysbiotic microbial environment that enhances tumor development, with Muribaculaceae, an inflammation- and CRC- associated bacteria, emerging as a potential microbial signature of MIF deficiency, even in fecal transplant conditions. This is the first demonstration of the role of MIF in the development of gut microbiota in the pathogenesis of CRC. Funding Source State Council of Science and Technology of the State of Mexico (COMECyT), CIKAS-FICDTEM25-019 and the Support Program for Research Projects and Technological Innovation (PAPIIT)-UNAM, IV200425 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)