Background Pre-administration of probiotic Lactobacilli attenuates ethanol-induced gastric mucosal injury (GMI). The underpinning mechanisms remain to be elucidated. We speculated that lactate, the main metabolite of Lactobacillus that can be safely used as a common food additive, mediated the gastroprotective effect. This study aimed to gain experimental evidence to support our hypothesis and to shed lights on its underlying mechanisms. Methods Lactate was orally administrated to mice at different doses 30 min prior to the induction of GMI. Gastric tissue samples were collected and underwent histopathological and immunohistochemical assessments, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (qPCR) and western blot analyses. Results Pretreatment with lactate at 1–3 g/kg significantly curtailed the severity of ethanol-induced GMI, as shown by morphological and histopathological examinations of gastric tissue samples. Significantly lower level of cytokines indicative of local inflammation were found in mice receiving lactate treatment prior to ethanol administration. Western-blot, immunohistochemical analysis and qPCR suggested that gastroprotective properties of lactate were mediated by its modulatory effects on the expression of the apoptosis regulator gene Bax, the apoptotic executive protein gene Casp3, and genes critical for gastric mucosal integrity, including those encoding tight junction proteins Occludin, Claudin-1, Claudin-5, and that for lactate receptor GPR81. Conclusion Lactate mitigates ethanol-induced GMI by curtailing local gastric inflammatory response, down-regulating the expression of the apoptosis regulator and executor genes Bax and Casp3, and up-regulating the expression of genes encoding tight junction proteins Occludin, Claudin-1, and Claudin-5 and the lactate receptor GPR81.
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.
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.
Butyrate is one of the most abundant short-chain fatty acids produced by intestinal bacteria. In the present study, the action of butyrate on chronic gastric mucosa lesions was investigated, as well as its underlying mechanism in mice. Male mice from the Institute of Cancer Research were randomly divided into three groups: Sham, model and butyrate groups. Butyrate was administered intragastrically for 7 days to butyrate group mice following the establishment of a gastric ulcer model. Hematoxylin and eosin staining, immunohistochemical analysis, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine the therapeutic effects and molecular mechanism of butyrate treatment. The findings demonstrated that butyrate induced a marked shift in superoxide dismutase and catalase activities, along with a decrease in malondialdehyde levels, thereby attenuating oxidative stress. Furthermore, butyrate decreased the levels of pro-inflammatory cytokines interleukin-1β, tumour necrosis factor-α and leukotriene B4, which helped combat inflammatory responses. Moreover, butyrate treatment exerted remarkable positive influences that mediate an increase in 6-keto-PGF-1α (a degradation product of prostacyclin), trefoil factor 2, MUC5AC and fibroblast growth factor-7 levels to promote gastric mucosal repair. The expression of specific receptor GPR109A for butyrate was upregulated, with no significant difference noted in the expression of GPR43 or GPR41. Overall, the present findings revealed that butyrate exerted therapeutic effects by upregulating mucosal repair factors and stimulating protective responses against oxidation and inflammation. GPR109A may be the key receptor for butyrate therapy.
Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was verified by the results of fecal microbiota transplantation (FMT) treatment but eliminated by using antibiotics to deplete gut bacteria. Detailedly, 16S rRNA and metagenomic sequencing identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria, which was confirmed by the increase of GABA synthesis key enzymes, glutamic acid decarboxylase (GAD) and putrescine aminotransferase (PAT), in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated by the results from GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, and GABA was identified as a key metabolite.
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