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ABSTRACT

The understanding of the effects of compounds on the gut microbiome is limited. In particular, it is unclear whether structurally similar compounds would have similar or distinct effects on the gut microbiome. Here, we selected berberine (BBR), an isoquinoline quaternary alkaloid, and 16 structural analogs and evaluated their effects on seven individual gut microbiomes cultured in vitro. The responses of the individual microbiomes were evaluated by metaproteomic profiles and by assessing butyrate production. We show that both interindividual differences and compound treatments significantly contributed to the variance of metaproteomic profiles. BBR and eight analogs led to changes in proteins involved in microbial defense and stress responses and enrichment of proteins from Verrucomicrobia, Proteobacteria, and Bacteroidetes phyla. It also led to a decrease in proteins from the Firmicutes phylum and its Clostridiales order which correlated to decrease proteins involved in the butyrate production pathway and butyrate concentration. Three of the compounds, sanguinarine, chelerythrine, and ethoxysanguinarine, activated bacterial protective mechanisms, enriched Proteobacteria, increased opacity proteins, and markedly reduced butyrate production. Dihydroberberine had a similar function to BBR in enriching the Akkermansia genus. In addition, it showed less overall adverse impacts on the functionality of the gut microbiome, including a better maintenance of the butyrate level. Our study shows that ex vivo microbiome assay can assess differential regulating effects of compounds with subtle differences and reveals that compound analogs can have distinct effects on the microbiome.  相似文献   
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ABSTRACT

Accumulating evidence points to Akkermansia muciniphila as a novel candidate to prevent or treat obesity-related metabolic disorders. We recently observed, in mice and in humans, that pasteurization of A. muciniphila increases its beneficial effects on metabolism. However, it is currently unknown if the observed beneficial effects on body weight and fat mass gain are due to specific changes in energy expenditure. Therefore, we investigated the effects of pasteurized A. muciniphila on whole-body energy metabolism during high-fat diet feeding by using metabolic chambers. We confirmed that daily oral administration of pasteurized A. muciniphila alleviated diet-induced obesity and decreased food energy efficiency. We found that this effect was associated with an increase in energy expenditure and spontaneous physical activity. Strikingly, we discovered that energy expenditure was enhanced independently from changes in markers of thermogenesis or beiging of the white adipose tissue. However, we found in brown and white adipose tissues that perilipin2, a factor associated with lipid droplet and known to be altered in obesity, was decreased in expression by pasteurized A. muciniphila. Finally, we observed that treatment with pasteurized A. muciniphila increased energy excretion in the feces. Interestingly, we demonstrated that this effect was not due to the modulation of intestinal lipid absorption or chylomicron synthesis but likely involved a reduction of carbohydrates absorption and enhanced intestinal epithelial turnover.

In conclusion, this study further dissects the mechanisms by which pasteurized A. muciniphila reduces body weight and fat mass gain. These data also further support the impact of targeting the gut microbiota by using specific bacteria to control whole-body energy metabolism.  相似文献   
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The gut and its bacterial colonizers are now well characterized as key players in whole-body metabolism, opening new avenues of research and generating great expectation for new treatments against obesity and its cardiometabolic complications. As diet is the main environmental factor affecting the gut microbiota, it has been suggested that fruits and vegetables, whose consumption is strongly associated with a healthy lifestyle, may carry phytochemicals that could help maintain intestinal homeostasis and metabolic health. We recently demonstrated that oral administration of a cranberry extract rich in polyphenols prevented diet-induced obesity and several detrimental features of the metabolic syndrome in association with a remarkable increase in the abundance of the mucin-degrading bacterium Akkermansia in the gut microbiota of mice. This addendum provides an extended discussion in light of recent discoveries suggesting a mechanistic link between polyphenols and Akkermansia, also contemplating how this unique microorganism may be exploited to fight the metabolic syndrome.  相似文献   
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Psoriasis is an immune‐mediated chronic inflammatory skin disease. Although its pathogenesis is not fully understood, Th17 cells and the cytokines they produce, such as IL‐17, IL‐22 and IL‐23, play critical roles in the pathogenesis of psoriasis. Evidence has demonstrated that psoriasis has some common features, including immune responses (due to Th17 cells) and inflammatory cytokine profiles, with systematic diseases including inflammatory bowel diseases (IBDs) and obesity. Recently, studies have demonstrated that the gut microbiota plays a crucial role in host homoeostasis and immune response, particular in Th17 cells, but the role of the gut microbiota in psoriasis remains unclear. To study the relationship between gut microbiota and psoriasis, we analysed microbiota profiles in psoriasis using a 16S rDNA sequencing platform, and we found that the abundance of Akkermansia muciniphila was significantly reduced in patients with psoriasis. A. muciniphila is believed to have an important function in the pathogenesis of IBD and obesity; therefore, A. muciniphila, which is an indicator of health status, may be a key node for psoriasis as well as IBD and obesity. Taken together, our study identified that gut microbiota signature and function are significantly altered in the gut of patients with psoriasis, which provides a novel angle to understanding the pathogenesis of psoriasis.  相似文献   
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目的 提取、鉴定嗜黏蛋白阿克曼菌(Akkermansia muciniphila, AKK)的脂多糖(lipopolysaccharide,LPS),初步探讨AKK的LPS对小鼠巨噬细胞的影响。 方法 试剂盒法提取AKK的LPS并纯化,ELISA法定量;BCA法、紫外分光光度法、SDS - PAGE和银染鉴定提取的LPS的纯度和结构;鲎试剂法检测LPS活性。体外培养小鼠巨噬细胞RAW 264.7,分为正常对照组、大肠杆菌(Escherichia coli,E.coli) LPS组和AKK LPS组。经LPS作用后,CCK - 8法检测细胞活性;RT - qPCR测定NF - κB、IL - 1β、IL - 6、TNF - α的mRNA表达水平。 结果 纯化的细菌LPS平均产率为7.14%,蛋白、核酸含量分别为0.005 6‰和2.12%;银染结果显示AKK的LPS条带分布与E.coli的LPS不同;鲎试剂测定其活性为7.10×107 EU/ml;部分干预浓度下,AKK LPS干预组细胞存活率低于E.coli LPS组;刺激6 h、12 h、24 h后,与正常对照组相比,AKK LPS干预组细胞内NF - κB的mRNA表达水平在干预6 h后显著上调,差异具有统计学意义(Z = - 3.606,P = 0.001);两种LPS干预组的IL - 1β、TNF - α、IL - 6 的mRNA表达水平在各时间点均高于对照组。 结论 提取的AKK的LPS纯度较高,生物活性良好; AKK 的LPS干预小鼠巨噬细胞,上调相关炎症因子IL - 1β、IL - 6、TNF - α及早期核转录因子NF - κB的转录表达。  相似文献   
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目的 前期研究发现脾虚证患者的肠道菌群发生显著变化,针对其中丰度明显改变的艾克曼菌ATCC BAA-835Akkermansia muciniphila ATCC BAA-835,AKK)和单形拟杆菌(Bacteroides uniformis,BU)建立实时荧光定量聚合酶链式反应(Quantitative real-time polymerase chain reaction, QPCR)检测方法,通过体外孵育和体内动物实验考察补中益气汤对其的影响。方法 采用模拟人体胃肠道代谢方法,将补中益气汤水煎剂与人工胃/肠液孵育后,与健康人群/脾虚证患者粪便共孵育,将粪便样品、24 h孵育样品进行微生物多样性测序;筛选AKK和BU特异性引物并建立其QPCR分析方法,检测补中益气汤与健康人群/脾虚证患者粪便共孵育后AKK和BU菌不同时间点的动态变化;采用番泻叶灌胃塑造脾虚证小鼠模型并给予补中益气汤治疗,考察补中益气汤对脾虚证小鼠体内AKK和BU菌含量的影响。结果 测序结果表明,健康人群和脾虚证患者肠道菌群结构存在明显差异,补中益气汤对粪便孵育液中肠道微生物具有一定的调节作用。方法学考察结果表明,建立的AKK和BU的QPCR定量检测方法重复性、稳定性良好,定量结果可靠。补中益气汤体外与健康人群/脾虚证患者粪便共孵育,其中AKK和BU呈现动态变化过程,其对健康人群/脾虚证患者粪便中AKK和BU均具有一定影响。孵育24 h,补中益气汤对脾虚证患者粪便样本中的AKK菌无显著影响,但可显著降低脾虚证患者粪便中BU菌含量(P<0.01)并恢复至健康人的水平。体内动物实验结果表明,补中益气汤体内可显著增加脾虚证小鼠粪便样本中AKK菌含量(P<0.01)并降低BU菌含量(P<0.01)。结论 补中益气汤体内外可直接调节BU菌含量,降低BU菌含量可能是其治疗脾虚证的分子作用机制之一。  相似文献   
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2型糖尿病的发生发展与肠道屏障功能受损导致的长期慢性低水平炎症反应密切相关,因此通过调整肠道菌群,保护肠黏膜屏障成为治疗2型糖尿病新思路。近年来研究表明,中药治疗2型糖尿病取得了很好的疗效,其机制与改善肠道菌群相关。Akkermansia muciniphila是一种以黏蛋白为培养基的优势菌种,定殖于回肠末端和结肠盲肠肠道黏液的外层,一方面能够为肠黏膜上皮细胞供能降解黏蛋白,保护肠上皮细胞,降低黏膜屏障通透性;另一方面优先利用黏蛋白,丰度过高对黏膜屏障具有削弱作用。A.muciniphila作为与肠黏膜屏障功能紧密相关的黏膜外层优势菌种,已经成为2型糖尿病治疗的一个潜在靶标。对A.muciniphila的生理特性及其与肠黏膜屏障、炎症的关系,以及中药干预作用的研究进展进行综述,以期为2型糖尿病治疗药物的研发提供一定线索。  相似文献   
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AIM: To investigated changes in intestinal Akkermansia muciniphila(A. muciniphila) and explored the mechanism underlying the therapeutic effects of Roux-en-Y gastric bypass(RYGB) surgery on type 2 diabetes in diabetic Goto-Kakizaki(GK) rats. METHODS: Male diabetic GK rats(n = 12) aged 8 wk were randomly assigned to the surgery group(GK-RYGB) or sham surgery group(GK-Sham)(n = 6 per group), and another 6 male Wistar rats aged 8 wk served as controls(WS-Sham). In the surgery group, RYGB surgery was conducted, and a sham operation was performed in both sham groups. Fasting blood glucose(FBG) levels before and after surgery, fasting levels of serum insulin and serum glucagon-like peptide-1(GLP-1) and levels 30 min after intragastric injection of glucose, and the amount of A. muciniphila in the stool were determined. Insulin and GLP-1 were measured by enzyme-linked immunosorbent assay, and A. muciniphila were detected by fluorescence-based quantitative polymerase chain reaction. RESULTS: The FBG was improved, and serum GLP-1 and insulin increased significantly(P < 0.05) in the GKRYGB group after surgery compared to levels before surgery and to levels in the GK-Sham group. Before surgery, the amounts of A. muciniphila in the GK-RYGB and GK-Sham groups were significantly lower than in the WS-Sham group(P < 0.05). After surgery, the amount of A. muciniphila in the GK-RYGB group increased markedly compared to that before surgery and to that in the GKSham and WS-Sham groups(P < 0.05). In addition, the A.muciniphila amount was positively related to GLP-1(r = 0.86, P < 0.05). CONCLUSION: Our results demonstrated RYGB surgery may increase GLP-1 secretion, elevate serum insulin after intragastric injection of glucose, and improve insulin resistance in diabetic GK rats, thereby contributing to a significant reduction in blood glucose. The increased amount of A. muciniphila after RYGB surgery may be related to elevated GLP-1 secretion.  相似文献   
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