Clostridium butyricum inhibits epithelial–mesenchymal transition of intestinal carcinogenesis through downregulating METTL3

Abstract

Colorectal cancer (CRC) is related to gut microbiota dysbiosis, especially butyrateproducing bacteria reduction. Our previous study suggested that administration of Clostridium butyricum, a butyrate-producing bacterium, exerts a crucial effect against CRC, however the potential mechanism is not clear. We first found that methyltransferase-like 3 (METTL3) showed a positive correlation with proliferation, epithelial-mesenchymal transition (EMT), DNA repair, metastasis, and invasion in a database analysis. The expression of METTL3 gradually increased from human normal colon tissue, to adenoma, and carcinoma, and was positively correlated with Ecadherin and CD34 levels. Overexpression of METTL3 promoted the proliferation, migration, and invasion of CRC cells and induced vasculogenic mimicry (VM) formation. Clostridium butyricum could downregulate METTL3 expression in CRC cells and decrease the expression of vimentin and vascular endothelial growth factor receptor 2 to reduce EMT and VM formation. Clostridium butyricum alleviated the pro-oncogenic effect of METTL3 overexpressing plasmid in CRC cells. The anti-EMT effect on METTL3 reduction of C. butyricum could be blunted by knocking down Gprotein coupled receptor 43. Moreover, C. butyricum prevented EMT and VM and inhibited tumor metastasis in nude mice. Accordingly, C. butyricum could inhibit EMT and VM formation of intestinal carcinogenesis through downregulating METTL3.These findings broaden our understanding of probiotics supplement in CRC prevention and treatment.

Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators

“…It is worth noting that the role of butyrate and butyrate-producing bacteria, such as C. butyricum and F. prausnitzii , has also been examined concerning their contribution to EMT in oncogenesis. Indeed, studies have reported that butyrate could potentially mitigate the development of colorectal cancer, a formidable complication of UC, by modulating the Wnt/β-catenin pathway [ 130 ].…”

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

“…Much of the data regarding the role of the gut microbiome/permeability in cancer has focussed on gastrointestinal cancer, where butyrate suppresses EMT [ 154 ] and cancer pathogenesis, as well as chemotherapy side-effects [ 155 ]. However, butyrate and the gut microbiome/permeability have relevant effects in a wide array of cancers, including breast cancer [ 156 ], glioblastoma [ 157 , 158 ] and ovarian cancer [ 159 ].…”

“…However, butyrate and the gut microbiome/permeability have relevant effects in a wide array of cancers, including breast cancer [ 156 ], glioblastoma [ 157 , 158 ] and ovarian cancer [ 159 ]. The mode of butyrate efficacy is variably defined across studies, including via its capacity as an HDACi [ 160 ], especially as HDACi is a general target in cancer treatment [ 161 ], as well as via epigenetic regulation by GPR43 activation suppressing methyltransferase-like 3 (METTL3) [ 154 ] and cancer regulating miRNAs subsequent to HDACi [ 160 ]. However, butyrate also has direct effects on immune cells, indicating that its relevance in cancer pathogenesis, course and treatment may be significantly determined by its regulation of immune responses.…”

“…Although it is clear that much has still to be investigated regarding how the gut microbiome interacts with host pathophysiological processes, the suppression of the gut microbiome short-chain fatty acid, butyrate, seems invariably evident and relevant [151]. Butyrate can regulate a number of physiological processes, including: (1) as an epigenetic regulator via pan histone deacetylase inhibition (HDACi); (2) via G-protein coupled receptor 41 (GPR41), GPR43, and GPR109; (3) the capacity of butyrate to upregulate sirtuin-3, acetyl-CoA and the mitochondrial melatonergic pathway, thereby allowing gut microbiome-derived butyrate to optimize mitochondrial function across body cells [152,153].…”

Role of the epithelial barrier in intestinal fibrosis associated with inflammatory bowel disease: relevance of the epithelial-to mesenchymal transition

“…Some enteric pathogens have been shown to be able to modulate EMT in IECs ( Table 5 ), such us Helicobacter pylori ( Yin et al, 2010 ; Ouyang et al, 2021 ), Citrobacter rodentium ( Chandrakesan et al, 2014 ), Escherichia coli ( Cane et al, 2010 ) or Clostridium butyricum ( Zhang et al, 2023 ), however these infections are not related with intestinal fibrosis.…”