肠道微生物群与2型糖尿病的研究进展

2型糖尿病(T2DM)的发病率在世界范围内迅速增加。然而,T2DM的发病机制尚不清楚。最近的证据表明肠道微生物群与肥胖和T2DM有关。有明确的证据表明肠道微生物通过对体质量、内毒素血症、胆汁酸代谢、促炎活性和胰岛素抵抗的调节而影响宿主。通过使用饮食、运动、益生菌、益生元和粪便微生物移植来调节肠道微生物群可能有助于改善宿主的葡萄糖代谢和胰岛素抵抗。但仍需要继续进行研究,以提高我们对肠道微生物群与T2DM关系的理解,并且为2型糖尿病的新治疗提供重要线索。     

肠道微生物及益生菌治疗对2型糖尿病的影响

2型糖尿病(type 2 diabetes mellitus,T2DM)是严重影响人类身体健康和生活质量的慢性疾病。研究发现其与肠道微生物的组成密切相关。随着目前肠道微生物的作用受到广泛关注,我们对2型糖尿病患者肠道菌群的变化有了更深入了解,许多功能强大的有益菌如阿克曼氏菌、柔嫩梭菌被发现,并发现由多种厌氧菌产生的不同短链脂肪酸对2型糖尿病患者的有益影响。补充有益菌和摄入益生菌制剂等通过调节肠道微生物群可能对预防和治疗2型糖尿病有效,但由于肠道微生物的复杂性和益生菌的局限性,需要进一步研究来评估益生菌的最佳剂量反应效应,并应用多组学方法提高基于微生物干预的个性化治疗,缓解和治疗2型糖尿病等代谢疾病。     

肠道菌群及其代谢产物与T2DM发病机制及干预措施*

2型糖尿病(type 2 diabetes mellitus,T2DM)是一种因胰岛素分泌不足或胰岛素抵抗而引起的慢性代谢疾病,T2DM患病人数的快速增长使治疗和预防T2DM成为世界上亟待解决的医学问题。随着微生物组学技术的进步,肠道菌群及其代谢产物与T2DM的研究亦逐渐深入,肠道菌群可能成为治疗和预防T2DM的靶点。肠道菌群及其代谢产物作用于T2DM的潜在机制,主要是参与体内炎症反应、增加肠道短链脂肪酸产量、调节肠道胆汁酸的代谢、调节支链氨基酸的代谢等。目前,治疗T2DM的药物可能会产生一些副作用,而基于肠道菌群干预T2DM的措施相对安全无害。例如,可通过严格控制的特定结构饮食长期摄入或增加益生菌的长期摄取控制血糖,或通过口服可影响肠道菌群生态结构的降糖药物(二甲双胍、阿卡波糖)有效地调控血糖水平。综述基于肠道菌群及其代谢产物诱发T2DM的潜在机制,研讨基于肠道菌群干预T2DM的措施,从肠道菌群的新视角探索治疗T2DM的新方法,为彻底治疗T2DM提供一种新可能。     

乳源性复合益生菌对2型糖尿病大鼠GLP 1的影响及调控机制

目的观察乳源性复合益生菌对2型糖尿病大鼠胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)的影响,并探讨其调控机制。方法采用高脂高糖饲养合并腹腔注射链脲佐菌素(Streptozotocin,STZ, 35 mg/kg)建立糖尿病大鼠模型(T2DM)。造模成功大鼠随机分为二甲双胍组(200 mg/kg)、低剂量复合益生菌组(1×10~8 CFU/d乳酸菌+1×10~6 CFU/d酵母菌)和高剂量复合益生菌组(1×10~(10) CFU/d乳酸菌+1×10~8 CFU/d酵母菌),以同周龄正常大鼠为正常对照组,灌胃4周。尾静脉采血测定空腹血糖、口服葡萄糖耐量;酶联免疫吸附法(ELISA)检测血清GLP-1和肽YY(PYY)水平;蛋白免疫印迹法(Western blot)检测结肠组织GLP-1蛋白表达;荧光定量PCR检测肠道菌群、G蛋白偶联受体(GPR43、GPR41)水平;气相色谱(GC)检测肠道短链脂肪酸(short chain fatty acids,SCFAs)含量。结果与模型组相比,高剂量复合益生菌能降低大鼠空腹血糖和口服糖耐量,增加肠道乳杆菌、双歧杆菌含量,提高肠道SCFAs含量,上调GPR43和GPR41 mRNA表达,促进胃肠激素GLP-1、PYY分泌,差异有统计学意义(均P0.05)。结论乳源性复合益生菌可显著促进T2D大鼠GLP-1的分泌,调节糖代谢,推测与调节肠道菌群-SCFAs-G蛋白偶联受体信号通路有关。     

降脂益生菌调节胆固醇代谢 改善小鼠非酒精性脂肪肝

目的研究一种由鼠李糖乳杆菌DM9054和植物乳杆菌86066构成的降脂益生菌组合对非酒精性脂肪性肝病(NAFLD)小鼠胆固醇代谢的影响及其可能机制。方法 24只雄性LDLR-/-小鼠随机分为对照组、模型组和益生菌干预组。高脂饮食(HFD)15周建立小鼠NAFLD模型,造模同时干预组给予鼠李糖乳杆菌DM9054联合植物乳杆菌86066灌胃,对照组和模型组给予等量生理盐水灌胃。实验过程中监测各组小鼠体重变化。实验结束后,检测小鼠血清甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL)和高密度脂蛋白胆固醇(HDL)的水平差异。检测小鼠肝脏组织病理变化。使用Realtime PCR检测小鼠肠道内法尼脂受体(FXR)mRNA、顶端膜钠依赖的胆汁酸转运体(ASBT)mRNA、纤维生长因子15(FGF-15)mRNA和三磷酸腺苷结合盒转运体G5(ABCG-5)mRNA表达水平。Western blot检测小鼠肝脏胆固醇7α-羟化酶(CYP7A1)、FXR、三磷酸腺苷结合盒转运体G8(ABCG-8)、清道夫受体BI(SR-BI)、3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMGCR)、胆盐输出泵(ABCB-11)、纤维生长因子受体4(FGFR-4)和胆固醇调节元件结合蛋白-2(SREBP-2)蛋白表达水平。结果与模型组相比,降脂益生菌干预组小鼠体重减轻(P0.05);小鼠血清TC、TG、LDL水平降低,HDL水平升高(P0.05);小鼠肝脏脂肪变性和炎性细胞浸润的现象显著减少;小鼠肠道ASBT mRNA和ABCG-5mRNA表达水平明显降低(Ps0.05),FGF-15mRNA表达水平明显升高(P0.05),FXR mRNA表达水平差异无统计学意义(P0.05);小鼠肝脏FGFR-4蛋白表达水平升高(P0.05),SREBP-2和HMGCR蛋白表达水平降低(Ps0.05),FXR、CYP7A1、SR-BI、ABCG-8和ABCB-11蛋白表达水平差异无统计学意义(Ps0.05)。结论降脂益生菌可能通过激活FXR-FGF15通路调节胆汁酸代谢;通过下调SREBP-2表达水平,抑制HMGCR表达,减少胆固醇的生成,从而起到改善非酒精性脂肪肝的作用。     

昂立1号~益生菌颗粒调节肠道菌群作用的研究

目的研究昂立1号益生菌颗粒调节肠道菌群作用。方法依照《保健食品检验与评价技术规范-2003版》之"调节肠道菌群作用检验方法"。结果该益生菌颗粒产品在30 d动物实验和14 d人体试验中,双歧杆菌和乳杆菌数量均有显著增加。结论该益生菌产品具有调节肠道菌群的保健作用。     

益生菌对老年2型糖尿病患者的影响

目的探讨益生菌对老年2型糖尿病患者肠道菌群、肠道屏障功能及糖脂代谢水平的影响。方法选取2017年10月至2019年10月我院收治的200例2型糖尿病患者为研究对象。入选患者随机分为观察组和对照组,各100例。比较两组患者治疗前后肠道菌群变化情况,血清二胺氧化酶(DAO)、内毒素(ET)、D 乳酸(D lac)、糖化血红蛋白(HbA_1c)、空腹血糖(FPG)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL C)、高密度脂蛋白胆固醇(HDL C)水平。记录两组患者治疗过程中不良反应发生情况。结果治疗前,两组患者肠道双歧杆菌、乳杆菌、拟杆菌、肠球菌、肠杆菌及酵母菌数量比较差异无统计学意义(均P>0.05);治疗后,两组患者肠道双歧杆菌、乳杆菌、拟杆菌数量均显著增加,而肠球菌、肠杆菌及酵母菌数量显著降低,同时观察组患者变化幅度大于对照组(均P<0.05)。治疗前,两组患者血清DAO、ET、D lac、HbA_1c、FPG、TC、TG、LDL C、HDL C水平比较差异无统计学意义(均P>0.05)。治疗后,两组患者血清DAO、ET、D lac、HbA_1c、FPG、TC、TG、LDL C、HDL C水平均显著降低(P<0.05),同时观察组上述指标水平低于对照组(P<0.05)。观察组患者治疗过程中不良反应总发生率为9.0%,对照组为7.0%,两组比较差异无统计学意义(χ²=0.272,P=0.602)。结论益生菌可有效调节老年2型糖尿病患者肠道菌群,提高肠道屏障功能,控制糖脂代谢水平,安全性较高,具有较好的辅助治疗作用。     

益生菌降胆固醇功能研究进展

本文对益生菌在动物及人体上的降胆固醇功能及可能机理进行了综述。益生菌是一类能够对人体健康起到促进作用的活体微生物。现已发现某些乳杆菌、双歧杆菌和肠球菌属的一些菌株具有降低血清胆固醇水平的能力。由于实验动物和人体在生理学上存在差异,因此同一菌株在实验动物和人体上获得的结论可能不同。关于益生菌降胆固醇功能的机理,研究者提出了不同的假说。这些假说包括:(1)益生菌将胆固醇吸收至细胞膜或细胞质中;(2)益生菌将胆固醇吸附到细胞表面;(3)胆固醇和游离胆盐在酸性环境下发生共沉淀;(4)结合胆盐被益生菌的胆盐水解酶水解成了游离胆盐,后者具有较低的溶解度,不易被肠道回收;(5)胆酸被益生菌的荚膜胞外多糖黏附到了细胞表面;(6)益生菌发酵肠道食源性未消化的碳水化合物产生丙酸,后者能够抑制肝脏胆固醇的生物合成,从而导致血清胆固醇水平降低;(7)益生菌通过下调NPC1L1蛋白基因表达来降低小肠细胞对胆固醇的吸收;(8)益生菌抑制胆固醇乳化胶束的形成。这些假说将为我们认识益生菌的降胆固醇机制及潜在降胆固醇功能菌株的筛选提供了依据。     

基于消化酶和肠道益生菌作用的枇杷叶降血糖作用研究

目的：通过研究枇杷叶提取液消化前后对肠道益生菌的生长和代谢产生的影响，以及在消化过程中对消化酶活力的影响来探讨枇杷叶提取液的降血糖作用。方法：通过体外试验，考察了不同浓度的枇杷叶提取液对3种益生菌的增殖作用及对肠道消化酶的活性影响，并探讨了枇杷叶提取液经消化酶消化后对肠道益生菌的增殖作用。结果：（1）一定浓度的枇杷叶提取液对单独培养的双歧杆菌有显著的促进作用，但其对嗜酸乳杆菌的生长代谢无显著影响。（2）枇杷叶提取液经消化酶作用后对肠道益生菌的促生作用显著降低，甚至表现出抑制作用。（3）试验组代谢产物中的丙酸含量要明显高于对照组，而其他两种酸的含量差别并不显著。（4）浓度为6 g/L的枇杷叶提取液对蛋白酶活力的促进作用最为显著，而所研究的不同浓度枇杷叶提取液对胰淀粉酶活力均表现出抑制作用，对胰脂肪酶的活力无显著影响。结论：枇杷叶提取液可能是通过降低淀粉酶的活性及通过增加益生菌代谢产物中的丙酸含量来达到降低血糖浓度的目的。     

抗糖尿病药物的“肠道机制”

糖尿病已经成为困扰国民的健康问题之一。越来越多的证据表明,肠道菌群与2型糖尿病的发生、发展密切相关。近年来,治疗糖尿病的药物与肠道菌群的关系也引起人们的关注,2型糖尿病药物可以通过调节肠道菌群产生有益的代谢产物与宿主进行“分子对话”,调节机体的糖脂代谢等而达到降血糖的作用。本综述将近年来发表于国内外期刊的与抗糖药物“肠道机制”相关的论文进行归纳、分析与总结,旨在为研究抗糖尿病药物的作用机制提供新的思路,也为完善以肠道菌群为靶点的药物干预方案提供理论依据。     

益生菌在血糖调控中的作用

随着经济及生活水平的提高，营养过剩导致营养代谢疾病中2型糖尿病（type 2 diabetes mellitus，T2DM）发生率骤增。患者血糖升高及并发症严重降低生活质量，增加经济负担。现行降糖药存在局限性和副作用，而益生菌具有安全、经济和有效等特点，并且能够降血糖和减轻并发症等。益生菌在糖尿病预防、治疗和重塑肠道微生态健康方面具有良好的应用前景，逐渐成为糖尿病防治的研究热点。虽然益生菌有望攻克糖尿病，但是调控血糖的机制需要更加深入的研究。本文综述了益生菌调控血糖的应用及机制研究、发展趋势与前景及挑战，为调控血糖微生态制剂的开发提供理论基础。     

大豆蛋白源性肽调节糖脂代谢机制研究进展

大豆蛋白源性肽是大豆蛋白质经酸法或酶法水解后分离精制而得到的多肽混合物,是植物蛋白源性肽的重要来源,大豆蛋白源性肽通过抑制肠道胆固醇吸收、与胆固醇的相互作用、调节胆固醇代谢相关基因（用于降低胆固醇）、甘油三酯代谢相关基因、二肽基肽酶Ⅳ和葡萄糖代谢相关基因,在降低胆固醇、降低甘油三酯、抗肥胖、抑制脂肪酸合成酶和抗糖尿病等代谢调节方面具有重要作用。综述了大豆蛋白源性肽在体内外改善脂质和糖代谢方面的生理功能,并对大豆蛋白源性肽的前景进行了展望,以期为大豆蛋白源性肽的研究与应用提供参考。     

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes and related metabolic traits in an Iranian population

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been variably associated with insulin resistance and type 2 diabetes (T2D) in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that the K121Q variant might be associated with T2D and related metabolic traits in this population. The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 normoglycemic controls and 155 T2D patients. T2D patients had significantly higher values for systolic and diastolic blood pressure, BMI, glucose, cholesterol, triglyceride, LDL, apoB, insulin, and HOMA-IR, and lower levels of HDL than the normoglycemic subjects. The frequency of the Q allele did not differ between T2D and normoglycemic subjects (OR 0.96, 95% CI 0.90-2.00, P?=?0.70). The Q allele frequency was 16.5% in T2D and 15.2% in normoglycemic subjects. The ENPP1 genotype (KQ?+?QQ) was not associated with the systolic and diastolic blood pressure, glucose, triglyceride, cholesterol, LDL-C and HDL-C, apo B, BMI, HOMA-IR, and insulin levels in both normoglycemic and T2D groups. Our results suggest that the ENPP1 121Q allele might not be associated with T2D and related metabolic traits among Iranian subjects.     

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer''s patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.     

Intestinal cancer development in response to oral infection with high-fat diet-induced Type 2 diabetes (T2D) in collaborative cross mice under different host genetic background effects

Mammalian Genome - Type 2 diabetes (T2D) is a metabolic disease with an imbalance in blood glucose concentration. There are significant studies currently showing association between T2D and...     

Lactoferrin Dampens High-Fructose Corn Syrup-Induced Hepatic Manifestations of the Metabolic Syndrome in a Murine Model

Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.     

Duodenal Mucosa: A New Target for the Treatment of Type 2 Diabetes

ObjectiveAfter a high-fat and high-sugar diet, the duodenal mucosa of rodents proliferate and trigger the signal of insulin resistance, which may be the cause of type 2 diabetes (T2D). In response to this phenomenon, researchers have designed the duodenal mucosal resurfacing (DMR) procedure, mainly through the hydrothermal ablation procedure, to restore the normal mucosal surface, thereby correcting this abnormal metabolic signal. This article aims to understand the changes in duodenum before and after the onset or treatment of T2D, and the potential mechanisms of DMR procedure.MethodsA literature search of PubMed and Web of Science was conducted using appropriate keywords.ResultsBoth animal and clinical studies have shown that the villus thickness, intestinal cells, glucose transporters, enteric nerves, and gut microbiota and their metabolites in the duodenum undergo corresponding changes before and after the onset or treatment of T2D. These changes may be related to the pathogenesis of T2D. DMR procedure may produce beneficial glycemic and hepatic metabolic effects by regulating these changes.ConclusionThe duodenum is an important metabolic signaling center, and limiting nutrient exposure to this critical region will have powerful metabolic benefits. The DMR procedure may regulate glycemic and hepatic parameters through various mechanisms, which needs to be further confirmed by a large number of animal and clinical studies.     

益生菌在血糖调控中的研究进展

随着经济的快速发展和人们生活方式的改变,糖尿病等代谢性疾病的发病率在全球范围急剧上升,特别是在我国形势尤其严峻。以往研究结果表明,肠道微生物与人体健康密切相关,糖尿病患者的菌群结构与健康人群存在显著差别。益生菌疗法由于具有低成本、高安全性和高可靠性的特点,在疾病预防和重塑肠道微生态健康方面具有良好的应用前景,逐渐成为糖尿病防治的研究热点。本文系统地阐述了血糖调控益生菌的基础研究和应用开发进展,为血糖调控益生菌制剂及相关功能性食品的开发提供理论参考和指导依据。     

Euterpe oleracea Mart. (açaí) seed extract associated with exercise training reduces hepatic steatosis in type 2 diabetic male rats

Type 2 diabetes mellitus contributes to an increased risk of metabolic and morphological changes in key organs, such as the liver. We aimed to assess the effect of the açaí seed extract (ASE) associated with exercise training on hepatic steatosis induced by high-fat (HF) diet plus streptozotocin (STZ) in rats. Type 2 diabetes was induced by feeding rats with HF diet (55% fat) for 5 weeks, followed by a single low dose of STZ (35 mg/kg i.p.). Control and diabetic groups were subdivided into four groups that were fed with standard chow diet for 4 weeks. Control (C) group was subdivided into Sedentary C, Training C, ASE Sedentary C and ASE Training C. Diabetic (D) group was subdivided into Sedentary D, Training D, ASE Sedentary D and ASE Training D. ASE (200 mg/kg/day) was administered by intragastric gavage, and the exercise training was performed on a treadmill (30 min/day; 5 days/week). Treatment with ASE associated with exercise training reduced the blood glucose (70.2%), total cholesterol (81.2%), aspartate aminotransferase (51.7%) and hepatic triglyceride levels (66.8%) and steatosis (72%) in ASE Training D group compared with the Sedentary D group. ASE associated with exercise training reduced the hepatic lipogenic proteins’ expression (77.3%) and increased the antioxidant defense (63.1%), pAMPK expression (70.2%), cholesterol transporters (71.1%) and the pLKB1/LKB1 ratio (57.1%) in type 2 diabetic rats. In conclusion, ASE treatment associated with exercise training protects against hepatic steatosis in diabetic rats by reducing hepatic lipogenesis and increasing antioxidant defense and cholesterol excretion.