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Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum Venetum flowers via enhancing immunity, reducing oxidative stress and regulating gut microbial in mice

ABSTRACT: Introduction: Emerging proof suggests that Apocynum venetum flowers polysaccharides (AVFP) has immunomodulatory effects in vitro. However, the action mechanism of AVFP is still unclear in vivo. The purpose of this study is to probe into the potential mechanism of AVFP on immunosuppressed mice through investigating organ index, cytokine levels, anti-oxidative stress capacity, transcriptomics and gut microbiota. Methods: Immunocompromised mouse model induced by cyclophosphamide (CXT) was divided into 6 groups. Enzyme-labeled method, HE, transcriptomics and high-throughput sequencing were used to detect the regulatory effects of AVFP on immunocompromised mice, as well as the function of AVFP on the concentration of short-chain fatty acids (SCFAs) by high-performance liquid chromatographic analysis (HPLC). Pearson was used to analyze the correlation between intestinal microbiota and biochemical indexes. Results: The experimental results illustrated that AVFP has protective effects against CXT-induced immunosuppression in mice via prominently increasing organ index, levels of anti-inflammatory factors in serum as well as enhancing antioxidant capacity of the liver. Meanwhile, it could also signally decrease the level of pro-inflammatory cytokines in serum, the activity of transaminase in serum and the content of free radicals in liver. Transcriptomics results discovered that AVFP could play a role in immune regulation via participating in NF-κB signaling pathway, regulating the immune-related genes Bcl3, Hp, Lbp, Cebpd, Gstp2 and Lcn2. Intestinal microbiota results illustrated that AVFP could increase abundance of beneficial bacteria, reduce abundance of harmful bacteria, while dramatically improved the content of SCFAs, modulated immune responses and improved host metabolism. Spearman analysis further assessed the correlation between gut microbiota and biochemical indicators. Conclusion: These findings demonstrated that AVFP could enhance the immune effects of the immunosuppressed mice and improve the body's ability to resist oxidative stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE267244 | GEO | 2024/05/31

REPOSITORIES: GEO

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Project description:Background and Aims: Many inflammatory diseases are associated with microbial dysbiosis, which may considerably alter the production of short-chain fatty acids (SCFAs). SCFAs are produced in the large bowel through bacterial fermentation of dietary fiber and play an important role in maintaining gut homeostasis. SCFAs, particularly acetate and butyrate, show beneficial immunomodulatory effects contributing to the prevention of inflammatory and allergic reactions. Thus, reduced production of SCFAs may impact on the mucosal immune responses critical to fighting pathogens. This study aims to determine the influence of SCFAs on a murine model of colonic bacterial infection. Methods: In the present study, we used acetate- (HAMSA) or butyrate- (HAMSB) yielding diets to deliver high concentrations of individual SCFAs to the large bowel of mice infected with C. rodentium. We assessed the effects of these SCFAs on clinical burden and gut pathogenicity in correlation with changes in bacteria growth, fecal microbiota composition, function and changes in the immunological profile. Results: Here we show in vitro that acetate and butyrate directly inhibited growth of the attaching and effacing (A/E) pathogen C. rodentium in a bacteriostatic manner. This correlated with reduced expression of Tir, a gene responsible for bacterial adherence and pathogenicity. Interestingly, HAMSA-fed mice presented reduced clinical scores during C. rodentium infection associated with high concentrations of fecal acetate. This was linked with compositional and functional changes in the microbiota when examining 16s sequencing and proteomics analysis. The HAMSA mediated is protection involved increased expression IL-22 and Muc-2 in the colon and increased numbers of CD8αα+ TCRγδ T cells in the colonic epithelium. These effects were dependent on GPR43, a metabolite-sensing GPCR that binds acetate. Conclusions: We established a promising new approach to moderate bacterial gut infections by manipulating the gut microbiota and mucosal immune tolerance through diets that yield the SCFA acetate.

Project description:The human gut microbiota is a complex microbial community with critical functions for the host, including the transformation of various chemicals. While effects on microorganisms has been evaluated using single-species models, their functional effects within more complex microbial communities remain unclear. In this study, we investigated the response of a simplified human gut microbiota model (SIHUMIx) cultivated in an in vitro bioreactor system in combination with 96 deep-well plates after exposure to 90 different xenobiotics, comprising 54 plant protection products and 36 food additives and dyes, at environmentally relevant concentrations. We employed metaproteomics and metabolomics to evaluate changes in bacterial abundances, the production of Short Chain Fatty Acids (SCFAs), and the regulation of metabolic pathways. Our findings unveiled significant changes induced by 23 out of 54 plant protection products and 28 out of 36 food additives across all three categories assessed. Notable highlights include azoxystrobin, fluoroxypyr, and ethoxyquin causing a substantial reduction (log2FC <-0.5) in the concentrations of the primary SCFAs: acetate, butyrate, and propionate. Several food additives had significant effects on the relative abundances of bacterial species; for example, acid orange 7 and saccharin led to a 75% decrease in Clostridium butyricum, with saccharin causing an additional 2.5-fold increase in E. coli compared to the control. Furthermore, both groups exhibited up- and down-regulation of various pathways, including those related to the metabolism of amino acids such as histidine, valine, leucine, and isoleucine, as well as bacterial secretion systems and energy pathways like starch, sucrose, butanoate, and pyruvate metabolism. This research introduces an efficient in vitro technique that enables high-throughput screening of the structure and function of a simplified and well-defined human gut microbiota model against 90 chemicals using metaproteomics and metabolomics. We believe this approach will be instrumental in characterizing chemical-microbiota interactions especially important for regulatory chemical risk assessments.

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Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum Venetum flowers via enhancing immunity, reducing oxidative stress and regulating gut microbial in mice

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