孕期给予益生菌或益生元可预防大鼠雄性子代成年后的高血压发生

Hsu etal. Nutrients (2018)

DOI 10.3390/nu10091229

孕期给予益生菌或益生元可预防大鼠雄性子代成年后的高血压发生

Maternal Administration of Probiotic orPrebiotic Prevents Male Adult Rat Offspring against Developmental Programmingof Hypertension Induced by High Fructose Consumption in Pregnancy and Lactation

Abstract

Excessive intake of fructose is associatedwith hypertension. Gut microbiota and their metabolites are thought to beassociated with the development of hypertension. We examined whether maternalhigh-fructose (HF) diet-induced programmed hypertension via altering gutmicrobiota, regulating short-chain fatty acids (SCFAs) and their receptors, andmediating nutrient-sensing signals in adult male offspring. Next, we aimed todetermine whether early gut microbiota-targeted therapies with probiotic Lactobacillus casei and prebiotic inulincan prevent maternal HF-induced programmed hypertension. Pregnant rats received60% high-fructose (HF) diet, with 2 × 108 CFU/day Lactobacillus casei via oral gavage(HF+Probiotic), or with 5% w/w long chain inulin (HF+prebiotic) duringpregnancy and lactation. Male offspring (n = 7–8/group) were assigned to fourgroups: control, HF, HF+Probiotic, and HF+Prebiotic. Rats were sacrificed at 12weeks of age. Maternal probiotic Lactobacilluscasei and prebiotic inulin therapies protect against hypertension in maleadult offspring born to fructose-fed mothers. Probiotic treatment preventsHF-induced hypertension is associated with reduced plasma acetate level anddecreased renal mRNA expression of Olfr78. While prebiotic treatment increasedplasma propionate level and restored HF-induced reduction of Frar2 expression.Maternal HF diet has long-term programming effects on the adult offspring’s gutmicrobiota. Probiotic and prebiotic therapies exerted similar protectiveeffects on blood pressure but they showed different mechanisms on modulation ofgut microbiota. Maternal HF diet induced developmental programming ofhypertension, which probiotic Lactobacilluscasei or prebiotic inulin therapy prevented. Maternal gutmicrobiota-targeted therapies could be reprogramming strategies to prevent thedevelopment of hypertension caused by maternal consumption of fructose-richdiet.

妊娠期高果糖饮食已被证明会对妊娠和产后生活造成不良影响。流行病学表明过量摄取果糖与许多常见疾病有关，包括高血压。尽管最近的研究表明，富含果糖的饮食与肠道菌群失调之间存在联系，然而摄入益生菌益生元能否改善由高果糖饮食引起的高血压目前尚不明确。本文研究了母体高果糖饮食是否通过改变肠道微生物群，调节短链脂肪酸（scfas）及其受体，以及调节营养感应信号诱导了成年雄性后代的程序性高血压。同时，研究了通过干酪乳杆菌（益生菌）和菊粉（益生元）的早期靶向肠道微生物群的治疗是否可以预防母体高果糖饮食诱导的程序性高血压。

研究对象：12至16周大的怀孕 SpragueDawley (SD)大鼠及其雄性后代

研究方法：将妊娠期SD大鼠随机分为4组(n = 3/组)，喂养方法如下:

(1)对照组，在妊娠和哺乳期(共有六个星期)给予正常的鼠粮；

(2)HF组，在整个妊娠和哺乳期给予鼠粮加60%的高果糖(HF)饲料；

(3)HF+益生元组，在妊娠和哺乳期给予60%HF饲料加5% w/w 长链菊粉；

(4)HF +益生菌组，在妊娠和哺乳期给予60%HF饲料加干酪乳杆菌（2×108 CFU /天）。

大鼠的雄性后代被分为7至8只一组，并在12周龄时处死，采集粪便样本、肝素化血样和肾脏样本进行后续分析。

检测方法：采用16S rRNA基因V3-V4区测序检测肠道微生物的组成；采用气相色谱-质谱法测定血浆醋酸盐、丁酸盐和丙酸盐的含量等。

实验结论：

1. 孕期给予干酪乳杆菌（益生菌）或菊粉（益生元）治疗可预防高果糖饲料喂养的雄性子代成年后高血压的发生；

2. 孕期高果糖诱导的程序性高血压与血浆醋酸盐水平升高，肾Frar3、Frar2 mRNA表达降低，以及多个营养感知信号(Sirt4、Prkag2、Pparg2)降低有关；

3. 益生菌治疗可预防HF诱导的高血压，这可能与血浆醋酸盐水平降低、肾内Olfr78 mRNA表达降低有关；

4. 益生元干预可提高血浆丙酸盐水平，恢复Ffar2表达；

5. 孕期高果糖饮食对后代成年后的肠道菌群产生长期影响，包括嗜碱菌属丰度的降低和乳酸菌属丰度的增加；

6. 益生菌和益生元疗法显示了相似的降压效果，但他们对肠道微生物有不同的调节机制。

Figure 4. Effect of maternal high-fructose(HF) diet, probiotic Lactobacillus casei,and prebiotic inulin on gene expression of (A) relative abundances of the gutmicrobiota at the genus level. Linear discriminant analysis (LDA), along witheffect size measurements, was applied to identify enriched bacterial genera.Most enriched and depleted genera (LDA score (log10) > 1.0) in the (B) HF(red) vs. control (green), (C) HF+Probiotic (red) vs. HF (green), and (D)HF+Prebiotic (red) vs. HF (green). N = 7–8/group.

图4。母体高果糖（HF）饮食、益生菌干酪乳杆菌和益生元菊粉对属级肠道微生物群（a）相对丰度基因表达的影响。采用线性判别分析法（LDA）结合效应大小测定法，对富集菌属进行鉴定。（b）HF（红色）与对照（绿色），（c）HF+益生菌（红色）与HF（绿色），（d）HF+益生菌（红色）与HF（绿色），（d）HF+益生菌（红色）与HF（绿色）中最丰富和最贫瘠的属（LDA评分（log10）>1.0）。n=7–8/组。

Figure 5. Effect of maternal high-fructose(HF) diet, probiotic Lactobacillus casei,and prebiotic inulin on gene expression of (A) Relative abundances of the gutmicrobiota at the species level; (B) the Akkermansiamuciniphila; (C) the Bacteroidesacidifaciens; (D) the Prevotellaalbensis; and (E) the Ruminococcusalbus. N = 7–8/group. * p < 0.05 versus control; # p < 0.05 versusHF.

图5. 母体高果糖（HF）饮食、益生菌干酪乳杆菌和益生菌菊粉对（a）物种水平肠道微生物群相对丰度的基因表达的影响；（b）Akkermansia muciniphila；（c）Bacteroides acidifaciens；（d）Prevotella albensis；和（e）Ruminococcus albus。n=7–8/组。* 与对照组相比，P<0.05；#P<0.05与HF组。

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