Background: Gastric cancer (GC) remains a common cause of cancer death in East Asia. Current treatment strategies for GC, including medical and surgical interventions, are suboptimal. Butyrate, a short-chain fatty acid produced by the intestinal flora, has been reported to be able to inhibit gastric carcinogenesis. This study aimed to investigate the effects of butyrate on human GC and its underlying mechanisms. Materials and methods: Human GC cell lines BGC-823 and SGC-7901, human GC tissues and adjacent normal tissues were used for this study. Cell proliferation was assessed using CCK-8 and EdU staining. TUNEL fluorescence and Annexin V/PI staining were adopted for qualitative and quantitative evaluation of cell apoptosis respectively. Reactive oxygen species (ROS) assay was performed to analyse mitochondrial function. Real-time q-PCR and western blot were carried out to examine the expression of apoptosis-related genes and synthesis of apoptosis-related proteins. The association between G protein-coupled receptor 109a (GPR109a) and GC prognosis was analyzed using data from The Cancer Genome Atlas (TCGA). Results: CCK-8 and EdU staining confirmed inhibitory activities of butyrate against human GC cells. Annexin V/PI staining and TUNEL fluorescence microscopy showed that butyrate promoted GC cell apoptosis. No difference in the expression of GPR109a was found between GC tissues and adjacent normal tissues, and no direct association between GPR109a and GC prognosis was discovered, suggesting that GPR109a may not be a key factor mediating the apoptosis of GC cells. Butyrate increased the synthesis of caspase 9 and decreased BCL-2, the well-known effector and regulator of mitochondria-mediated apoptosis, and significantly induced mitochondrial ROS. Conclusions: Collectively, our results suggest that butyrate is able to inhibit the proliferation of GC cells and induce GC apoptosis possibly via a mitochondrial pathway.

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Nowadays, nonalcoholic fatty liver disease (NAFLD) becomes the most common cause of liver disease worldwide. Mounting evidence indicates that dysbiosis contributes to the pathogenesis of NAFLD. Bile acids (BAs), the molecules that are first synthesized in hepatocytes and further metabolized by gut microbes, can either circulate in enterohepatic system or be found in circulations to exert various effects. Dysbiosis brings about the dysregulated BA composition, which is also observed in the pathology of NAFLD. As important signaling molecules, BAs bind to broadly expressed bile acid receptors (BARs) and play diverse roles in biological activity. Energy metabolism, immune system, and intestinal barrier function are affected by changes in BAs and their signaling pathways, which may explain the mechanisms of how altered BA pool affect NAFLD. Several novel NAFLD treatments targeting BA signaling are under development and their challenges and limitations are also discussed in this review.

Background Ethanol-induced gastric mucosal lesions (EGML) is one of the most common digestive disorders for which current therapies have limited outcomes in clinical practice. Prevotella histicola (P. histicola) has shown probiotic efficacy against arthritis, multiple sclerosis and oestrogen deficiency-induced depression in mice; however, its role in EGML remains unclear in spite of its extensive colonisation of the stomach. Ferroptosis, which is characterised by lipid peroxidation, may be involved in EGML. Herein, we aimed to investigate the effects and underlying mechanism of action of P. histicola on EGML in the ferroptosis-dependent pathway. Methods P. histicola was intragastrically administered for a week, and deferoxamine (DFO), a ferroptosis inhibitor, was intraperitoneally injected prior to oral ethanol administration. The gastric mucosal lesions and ferroptosis were assessed via histopathological examinations, quantitative real-time PCR, Western blot, immunohistochemistry and immunofluorescence. Results P. histicola was originally found to attenuate EGML by reducing histopathological changes and lipid reactive oxygen species (ROS) accumulation. The pro-ferroptotic genes of Transferrin Receptor (TFR1), Solute Carrier Family 39 Member 14 (SLC39A14), Haem Oxygenase-1 (HMOX-1), Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4), Cyclooxygenase 2 (COX-2) and mitochondrial Voltage-dependent Anion Channels (VDACs) were up-regulated; the anti-ferroptotic System Xc-/Glutathione Peroxidase 4 (GPX4) axis was inhibited after ethanol administration. However, the changes of histopathology and ferroptosis-related parameters induced by ethanol were reversed by DFO. Furthermore, P. histicola treatment significantly downregulated the expression of ACSL4, HMOX-1 and COX-2, as well as TFR1 and SLC39A14, on mRNA or the protein level, while activating the System Xc-/GPX4 axis. Conclusions We found that P. histicola reduces ferroptosis to attenuate EGML by inhibiting the ACSL4- and VDAC-dependent pro-ferroptotic pathways and activating the anti-ferroptotic System Xc-/GPX4 axis.

Background: Ethanol-inducedgastric mucosal lesion (EGML) is one of the most common digestivedisorderswith the limited outcomes of current therapies in clinic. P. histicola was shown probiotic efficacy against arthritis, multiple sclerosis and estrogen deficiency-induced depression in mice, but the role of P. histicola in ethanol-induced gastric mucosal lesion remains unclear despite of its high colonization in stomach. Ferroptosis characterized by lipids peroxidation may be involved in EGML. Herein, we aimed to investigate the effects and underlying mechanism of P. histicola on EGML in the ferroptosis dependent pathway. Methods:P. histicolawas intragastrically treated for a week and deferoxamine (DFO), a ferroptosis inhibitor, was intraperitoneally injected prior to oral ethanol administration, respectively. The gastric mucosal lesion and ferroptosis were assessed by pathological examination, quantitative real-time PCR, Western blot and immunofluorescence. Results: P. histicola was originally found to attenuate EGML by the reduced pathological changes and ROS accumulation. The proferroptotic genes of Transferrin Receptor (TFR1), Solute Carrier Family 39 Member 14 (SLC39A14), Heme Oxygenase-1 (HMOX-1), Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4), Cyclooxygenase 2 (COX-2) and mitochondrial Voltage-dependent Anion Channels (VDACs) were upregulated, but the anti-ferroptotic System Xc-/ Glutathione Peroxidase 4 (GPX4)axis was reduced after ethanol administration, which was reversed by DFO. Furthermore, P. histicola treatment significantly downregulated the expression of ACSL4, HMOX-1 and COX-2, as well as TFR1 and SLC39A14 on mRNA or protein level, while activating System Xc-/GPX4 axis. Conclusions: Our study found that P. histicola reduces ferroptosis to attenuate EGML by inhibiting the ACSL4- and VDAC- dependent pro-ferroptotic pathways, and activating anti-ferroptotic System Xc-/GPX4 axis.