Anti-proliferative effects of gut microbial metabolites on human gastric adenocarcinoma cells and their potential synergy with dexamethasone

Background: The relevance of gut microbiota in the development, treatment and clinical outcome of cancers is an emerging area of translational research that can pave new avenues in cancer therapeutics. Our recently published reviews have underlined the immunomodulatory and anti-tumoural effects of gut microbiota in cancers through the production of different metabolites [1, 2]. Studies have also reported the anticancer activity of gut microbial metabolites such as short-chain fatty acids (SCFAs; including butyrate, propionate, and acetate) against different cancers. However, the detailed molecular mechanisms of action of these SCFAs and their potential synergistic interactions with standard chemotherapy and immunotherapy have not been investigated thoroughly, especially against gastric cancer. Materials and Methods: This study was designed to evaluate the anti-proliferative effects of three SCFAs against the AGS gastric adenocarcinoma cells using the Alamar Blue assay and to decipher the molecular mechanisms of action of the most active metabolite using label-free quantification proteomics and flow cytometric (apoptotic and cell cycle assays) analyses as per our previously validated methods [3]. The potential synergy between the most active gut metabolite and the anti-inflammatory drug dexamethasone against the AGS cells was also quantified using the combination index (CI) model [4]. Results: All three gut metabolites sodium butyrate (NaB), sodium propionate and magnesium acetate exhibited strong anti-proliferative activity with NaB displaying the greatest inhibitory effect (p < 0.05) against the AGS cells. In addition, NaB induced cell cycle arrest and apoptosis in the AGS cells as evident in the flow cytometric and proteomics analyses and potentially synergised the activity of dexamethasone (CI value < 1) against the AGS cells. Conclusions: The findings of this study demonstrated the potential implementation of gut microbial metabolites against gastric adenocarcinoma as a combination therapy with dexamethasone. However, further in vivo studies are warranted to validate these findings.