Gut microbiota-derived propionate reduces cancer cell proliferation in the liver

Abstract

Background:Metabolites released by the gut microbiota may influence host metabolism and immunity. We have tested the hypothesis that inulin-type fructans (ITF), by promoting microbial production of short-chain fatty acids (SCFA), influence cancer cell proliferation outside the gut.Methods:Mice transplanted with Bcr-Abl-transfected BaF3 cells, received ITF in their drinking water. Gut microbiota was analysed by 16S rDNA polymerase chain reaction (PCR)–denaturing gradient gel electrophoresis (DGGE) and qPCR. Serum Short-chain fatty acids were quantified by UHPLC-MS. Cell proliferation was evaluated in vivo, by molecular biology and histology, and in vitro.Results:Inulin-type fructans treatment reduces hepatic BaF3 cell infiltration, lessens inflammation and increases portal propionate concentration. In vitro, propionate reduces BaF3 cell growth through a cAMP level-dependent pathway. Furthermore, the activation of free fatty acid receptor 2 (FFA2), a Gi/Gq-protein-coupled receptor also known as GPR43 and that binds propionate, lessens the proliferation of BaF3 and other human cancer cell lines.Conclusion:We show for the first time that the fermentation of nutrients such as ITF into propionate can counteract malignant cell proliferation in the liver tissue. Our results support the interest of FFA2 activation as a new strategy for cancer therapeutics. This study highlights the importance of research focusing on gut microbes–host interactions for managing systemic and severe diseases such as leukaemia.

Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling

“…PA2 (also termed (S)-2-(4-chlorophenyl)-N-(5-fluorothiazol-2-yl)-3-methylbutanamide (CFMB)) was found to elevate intracellular Ca 2C in intestinal L cells (Tolhurst et al 2012). Another derivative of phenylacetamide, 4-chloro-a-(1-methyl ethyl)-N-2-thiazolyl-benzeneacetamide (CMTB), was shown to reduce the proliferation of leukemia cells (Bindels et al 2012). The application of these synthetic agonists based on phenylacetamide facilitates studies of biological and pathological functions of FFAR2 in various processes, as they have significantly greater potency and specificity than any SCFAs (Lee et al 2008).…”

Microbiote intestinal et réponses aux thérapies anti-tumorales

“…Le microbiote intestinal et le TLR4, récepteur impliqué dans la reconnaissance des produits bactériens, participent ainsi au développement d'HCC [18]. Un métabolite produit par les bactéries, le propionate, possède en revanche la capacité de réduire la prolifération cellulaire dans le cancer du foie [19]. Par ailleurs, la gentamicine, possèdent des taux d'IgA, de plasmocytes et de lymphocytes intraépithéliaux diminués, des plaques de Peyer de plus petite taille ainsi qu'une altération de la sécrétion de peptides antimicrobiens [5].…”

From microbe to man: the role of microbial short chain fatty acid metabolites in host cell biology

“…SCFAs, especially butyrate, exhibit strong antitumorigenic properties, inhibit cell proliferation, and induce differentiation and apoptosis in a variety of cell lines, including human colorectal cancer cell lines HCT-116 and HT-29 (1,3,18,24,44,48,55,72,74,86). In fact, SCFAs have been shown to confer protection from the development of colorectal cancer (3,18,23,55,72,79).…”

“…In fact, SCFAs have been shown to confer protection from the development of colorectal cancer (3,18,23,55,72,79). Propionate and butyrate have been shown to significantly inhibit cell proliferation, whereas acetate does not significantly affect cell proliferation (3,44,66).…”