寡果糖对人源菌群仔猪肠道菌群结构和宿主代谢的影响
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摘要
人的胃肠道中定植着一个非常复杂的微生物菌群,其结构和功能与宿主的健康和疾病有非常密切的关系。益生元是一类人不能消化的食物成分,通过被大肠中的细菌发酵,调节肠道菌群的结构和代谢,改善宿主健康。寡果糖是一种被普遍应用的益生元,很多研究表明它可以促进双歧杆菌的生长,但还没有研究在系统水平上调查寡果糖对肠道菌群的结构和代谢、以及宿主代谢的影响。若直接以人为对象进行研究,存在很多不便,如难以标准化受试者的饮食、采样困难以及伦理问题;很多研究采用人源菌群(Human Flora-associated, HFA)大鼠/小鼠为模型,并取得大量成果,但啮齿类动物消化道的解剖和生理特征与人的显著不同,所得结果有较大的局限性。而猪的消化系统的生理结构与人的相似性很高,更适合构建人肠道菌群的动物模型。因此,本实验室在前期的工作中建立了HFA仔猪模型,证明人的肠道菌群可以在原本无菌的仔猪肠道内定植。本论文以HFA仔猪为模型,用分子生态学的方法研究寡果糖对肠道菌群的组成的影响,并用基于核磁共振(NMR)的代谢组学方法调查寡果糖对肠道菌群代谢和宿主代谢的影响。
首先我们建立了针对人肠道菌群中最优势的细菌种群之一——柔嫩梭菌类群的类群特异性PCR-DGGE和克隆文库的方法。利用一对柔嫩梭菌类群特异性引物扩增得到239 bp的16S rRNA基因片段可以被DGGE很好地分离。11个健康人的粪便柔嫩梭菌类群DGGE图谱表明此类群的细菌组成具有宿主特异性;用DGGE对一个儿童的粪便柔嫩梭菌类群进行3年的监测,发现结构在前两年间有波动,而在第三年保持稳定。以一个成人的粪便总DNA为模板,用一个细菌通用的上游引物和一个柔嫩梭菌类群特异性的下游引物扩增1143 bp的16S rRNA基因片段,并克隆建库,挑取100个克隆。序列分析表明100个克隆均属于柔嫩梭菌类群;其中64%的克隆来自Faecalibacterium prausnitzii,6%来自Subdoligranulum variabile,2%是产丁酸细菌A2-207,28%来自未知菌种。通过对比克隆的239 bp片段在DGGE中的迁移位置和DGGE图谱中条带的位置,图谱中绝大多数条带的序列得到确定。结果表明柔嫩梭菌类群特异性DGGE和克隆文库是分析监测人肠道菌群中柔嫩梭菌类群的有效方法。
为研究寡果糖对人源肠道菌群结构的影响,我们采集一27岁的健康男性的新鲜粪便样品制备菌悬液,接种到剖腹产的无菌的仔猪的肠道中,构建了HFA仔猪。10只初生的HFA仔猪被平均分到对照组和益生元组,对照组仔猪食用基本食谱,益生元组仔猪在基本食谱的基础上每天饲喂一定量的寡果糖,如此持续至37日龄。在12日龄、17日龄、25日龄和37日龄收集每只仔猪的粪便样品,并提取粪便总DNA,分别用类群特异性PCR-DGGE和实时定量PCR方法在不同时间点比较两组仔猪的拟杆菌属、双歧杆菌属和柔嫩梭菌类群的组成和数量。在四个时间点都没有观察到寡果糖对双歧杆菌的促进作用,这可能是由于本研究中的HFA仔猪肠道中的双歧杆菌丰度较高,益生元不容易对它们的数量产生显著的提高作用。但寡果糖主要影响了其他细菌:在12日龄,两种未知拟杆菌的水平被提高;25日龄,寡果糖提高了Subdoligranulum variabile的水平,抑制了属于柔嫩梭菌类群的一种未知细菌;37日龄,拟杆菌属的数量被寡果糖显著降低。此工作表明,寡果糖可以影响双歧杆菌之外的肠道细菌。我们发现寡果糖可以刺激S. variabile的生长,已经有研究证明此细菌具有重要的生理功能,所以在今后的工作中有必要将它分离出来并进行功能分析,研究它与益生元和人体健康之间的关系。
接着,我们用基于NMR的代谢组学方法比较了HFA仔猪大肠不同区域内容物的代谢物组成,研究了大肠内菌群代谢的空间分布规律。用1H NMR图谱技术展示了10只37日龄的HFA仔猪的盲肠、近端结肠、远端结肠内容物和粪便中的生化组成,发现不同部位包含的代谢物种类相似,有很多细菌的代谢物,如短链脂肪酸、有机酸、酚酸、甲胺类物质、各种氨基酸等;也有来自食物、宿主分泌或来源尚未确定的物质,如碳水化合物、胆汁酸和核酸碱基。用多变量统计方法,主成分分析(Principle Component Analysis, PCA)、偏小二乘法(Partial Least Square Discrimination Analysis, PLS-DA)和正交偏小二乘法(Orthogonal Projection on Latent Structure, O-PLS)区分大肠不同区域的内容物和粪便的代谢物图谱,发现短链脂肪酸的含量从盲肠开始延大肠直至粪便逐渐降低,苯乙酸和3-羟基苯丙酸的含量在盲肠和近端结肠中明显高于远端结肠和粪便,支链氨基酸的含量从盲肠到粪便依次升高,糖苷类大分子的相对含量从盲肠到远端结肠逐渐升高。本研究表明,由于大肠不同部位的生理生态状况不同,肠道菌群的代谢活动也有差异。HFA仔猪大肠不同区段的内容物中代谢物的变化与文献报道的人类大肠内容物的生化组成的变化趋势相似,所以有潜力成为研究人肠道菌群代谢的有力模型。基于NMR的代谢组学方法可以快速展现肠道内容物的代谢物组成,反映肠道菌群代谢活动的概貌,可以用于监测肠道菌群的活动,研究外来干预(如益生元、益生素等)对菌群代谢的影响。粪便中的代谢物组成不完全等同于大肠内容物的情况,所以在下一步研究益生元对肠道菌群代谢的影响时,需要分析结肠内容物中的代谢物组成的变化。
为研究寡果糖对肠道菌群和宿主代谢的影响,5只对照组和5只益生元组仔猪在12日龄、17日龄、25日龄和37日龄的粪便,以及37日龄的近端结肠内容物、远端结肠内容物和尿液被采集。用NMR展示这些样品的生化组成,用正交偏小二乘法(Orthogonal Projection on Latent Structure, O-PLS)比较两组仔猪的NMR图谱。在4个时间点两组仔猪粪便的生化组成没有显著区别。在37日龄,益生元组仔猪的近端结肠内容物中含有较高含量的低聚糖、葡萄糖、乙酸、丙酸和核酸碱基;但寡果糖主要影响了HFA仔猪远端结肠内容物的代谢物组成,提高了低聚糖、葡萄糖、乙酸、乳酸、核酸碱基和多种氨基酸的含量,降低了胆汁酸的含量;益生元组仔猪的尿液中含有较高水平的丙氨酸、甘氨酸、肌酸、磷酸肌酸、乳酸、柠檬酸,但尿囊素和尿素的含量较低,一些由肠道菌群或者由肠道菌群和宿主共代谢产生的代谢物,如二甲胺、苯乙酰甘氨酸、三甲胺、三甲胺氧化物、马尿酸和4-羟苯基乳酸的含量在两组仔猪尿液中有差异。从这些代谢变化推断,寡果糖主要在HFA仔猪远端结肠内发挥益生元功效:寡果糖被结肠菌群发酵产生短链脂肪酸,从而影响了宿主的能量代谢;寡果糖调节菌群对氨基酸的代谢,影响了宿主的氨基酸代谢,改善宿主机体的氮平衡。寡果糖降低结肠中胆汁酸的现象说明它有一定预防结肠癌的作用。寡果糖对结肠菌群/宿主的核酸代谢也有影响,但其机理还需要进一步研究。基于1H NMR的代谢组学技术可以用于监测营养干预对肠道菌群和宿主代谢的影响。
本研究用HFA仔猪为模型,调查了寡果糖对肠道菌群的组成和代谢以及宿主代谢的影响,为下一步研究菌群结构和菌群功能、菌群代谢和宿主代谢之间的关系提供有益的思路和线索。
Human gastrointestinal tract harbors a diverse and complex microbiota whose composition and activities play important roles in host health and disease. Prebiotics are non-digestible food ingredients that modulate the structure and metabolism of gut microbiota by being fermented by colonic bacteria and thus improve host health. Fructo-oligosaccharides (FOS) are one type of prebiotics which is widely applied in food industry. Many studies demonstrated FOS stimulated the growth of bifidobacteria, but few studies systematically investigated its effects on the composition and activities of gut microflora, as well as the host metabolism. Studying prebiotic effects directly on human beings may have such difficulties as standardizing the diets of volunteers, collecting biopsy samples, and ethical issues etc.; as a consequence, Human Flora-Associated (HFA) mice/rat models are widely used to produce useful results, but the anatomy and physiology of rodent digestive tracts are significantly different from those of human, so the HFA rodent models have low relevance to human biology. Compared to rodents, pigs share more similarities with human in anatomical and physiological characteristics of the digestive system, so they can be better candidates for developing HFA model. Our lab have established HFA piglet model by demonstrating that the human-originated gut microbiota can colonize in the gut of ex-germfree piglets. In this dissertation, using HFA piglet model, we assessed the impacts of FOS on the structure of gut microbiota with microbial ecological techniques, and investigated the influences of FOS on the metabolism of the gut microbiota and the host with NMR based metabonomic methods.
Before we studied the effects of FOS on the composition of gut microflora, a group-specific PCR-based denaturant gradient gel electrophoresis (DGGE) method was established and combined with group-specific clone library analysis to investigate the diversity of the Clostridium leptum subgroup in human feces. PCR products (239 bp in length) were amplified using C. leptum cluster-specific primers and were well separated by DGGE. DGGE patterns of fecal amplicons from 11 human individuals showed host-specific profiles; patterns of fecal samples collected from a child during 3 years demonstrated the structural succession of the population in the first two years and its stability in the third year. A clone library was constructed with 100 clones, consisting of 1,143 bp inserts of 16S rRNA gene fragments that were amplified from one adult fecal DNA with one forward bacterial universal primer and one reverse group-specific primer. Eighty-six clones produced the 239 bp C. leptum cluster-specific amplicons and the remaining 14 clones did not but still phylogenetically belong to the subgroup. Sixty-four percent of the clones were from Faecalibacterium prausnitzii, 6% from Subdoligranulum variabile, 2% from the butyrate-producing bacterium A2-207 and 28% from unknown species. The identity of most bands in the DGGE profiles of the same adult was determined via comigration analysis with the 86 clones which included the 239 bp group specific fragments. These results suggest that DGGE combined with clone library analysis is an effective technique for monitoring and analyzing the composition of C. leptum cluster in human gut flora.
To study the influences of FOS on the structure of gut microbiota, fecal suspension was prepared from the fresh fecal sample collected from one healthy 27-year-old male adult donor and inoculated to ex-germfree piglets to produce HFA piglets. 10 newly born HFA piglets were evenly divided into 2 groups: 5 in control group being fed with basal diets, and 5 in prebiotic group having FOS added to the basal diets daily at the dose of 0.5 g/kg body weight/day. The feeding experiment lasted from day 1 to day 37 after the birth of piglets. Fecal samples on day 12, 17, 25 and 37 were collected from each piglet and fecal DNA was extracted. With group-specific PCR-DGGE and real-time PCR, the composition and amounts of Bacteroides genus, Bifidobcterium genus and C.leptum subgroup were compared between control and FOS-fed piglets. FOS did not change the composition or the amount of bifidobacteria, and the possible reason is the number of bifidobacteria in the gut of our HFA piglets was quite high, and thus it was difficult for FOS to produce significant bifidogenic effect. However, FOS mainly affected other bacteria: on day 12, two unknown bacteroides species were stimulated; on day 25, S. variabile was stimulated, and one unknown species from C.leptum subgroup was suppressed; on day 37, the amount of Bacteroides genus was decreased. Our work demonstrated that FOS can influence bacteria other than bifidobacteria in gut microbiota. We found for the first time that FOS stimulated the growth of S. variabile, which was revealed to actively interact with host metabolism, so it is necessary to isolate the bacteria in the future and study its relationship with prebiotics and host health.
We compared the biochemical composition of contents in different regions of the large intestine of HFA piglets with NMR based metabonomic techniques, and studied the spatial distribution of the gut microbiota metabolism in different regions along the large intestine. Metabolites present in aqueous extracts of contents from the caecum, proximal colon, distal colon and faeces of 10 HFA piglets were profiled by 1H NMR spectroscopy. Many compounds originating from bacterial activities were detected, including short chain fatty acids (SCFAs), organic acids, phenolic compounds, amino acids, and amines; besides, nucleobases, bile acids, choline and glycosides were also identified in profiles. Principle Component Analysis (PCA), Partial Least Square Discrimination Analysis (PLS-DA) and Orthogonal Projection on Latent Structure (O-PLS) analysis were used to differentiate NMR profiles of different regions and revealed that the biochemical composition in gut contents changed significantly in different regions of the large intestine of HFA piglets. The levels of SCFAs decreased distally from cecum to feces; phenylacetate and 3-hydroxyphenylpropionate predominated in cecum and proximal colon but not in distal colon and feces; the amounts of branch chain amino acids and glycosides increased distally along the large intestine. Our results suggest that the endogenous microbiota metabolize differently in different compartments of the large bowel due to varied environmental factors along the large bowel, such as substrate availability and host gut physiology, etc. The patterns of biochemical changes along the large intestine of HFA piglets showed to be similar to those in human colon as reported in the literature, so our HFA piglets potentially can become an effective in vivo model for studies on the metabolism of human gut microbiota. The 1H NMR-based metabonomic techniques has a great potential to be used to monitor the changes in the metabolic activities of colonic microbiota in response to interventions such as prebiotics, probiotics, antibiotics and diseases. Besides, the biochemical composition of feces is different from that of large intestinal contents, so it is necessary to analyze the metabolites in colonic content samples when study the effects of prebiotics on the metabolism of gut microbiota at next step.
In the last part, the influences of FOS on the metabolism of the gut microbiota and the host were studied with NMR-based metabonomic techniques. We collected feces from 5 control piglets and 5 FOS-fed piglets on day 12, 17, 25 and 37 after birth, as well as urine samples, and contents of proximal and distal colon from each animal on day 37. 1H NMR spectroscopy was applied to profile the metabolic composition of urine samples and aqueous extracts from feces and colonic contents. The Chemometric method, O-PLS was used to characterize the effects of FOS on the metabolism of the gut microflora and the host by comparing the NMR spectra of control and FOS-fed piglets. There is no statistically significant difference in fecal metabolite composition between two groups of piglets. In the proximal colon, FOS-fed piglets had higher levels of oligosaccharides, glucose, acetate, propionate and nucleobases than control animals. More marked differences between two groups were observed in distal colon: besides oligosaccharides, glucose, acetate, nucleobases, the quantities of lactate and amino acids were also increased by FOS treatment; the amount of bile acids was decreased. In the urine, FOS-fed piglets excreted more alanine, glycine, creatine and phosphocreatine, lactate, citrate, but less urea and allantoin; besides, FOS treatment also affected the quantities of some bacteria-origined metabolites in the urine such as dimethylamine, trimethylamine, trimethylamine N-oxide, phenylacetylglycine, hippurate and 4- hydroxyphenyl-lactate. As indicated by these results, FOS was fermented by the gut microbiota mainly in distal colon with the production of acetate and lactate, and the acids can be absorbed and utilized by the host as energy sources, and thus affected the energy metabolism of the host; FOS also modulated the amino acid metabolism of gut microbiota, and thus influenced the amino acid metabolism of the host and improved its N-balance; FOS was indicated to have a preventative effect on colon cancer by decreasing the amounts of bile acids in distal colon. The mechanism for the influence of FOS on the nucleic acid metabolism of the gut microbiota/host need to be further studied. The 1H NMR-based metabonomic techniques can be used to monitor the metabolic responses of colonic microbiota and the host to interventions such as prebiotics, probiotics, antibiotics and diseases.
HFA piglet model was utilized in our study to systematically study the effects of the prebiotic ingredient FOS on the gut microbiota and host metabolism. Our results will provide helpful insight and guidance to understanding the relationship among the composition and metabolism of the gut microbiota, and the metabolism of host.
首先我们建立了针对人肠道菌群中最优势的细菌种群之一——柔嫩梭菌类群的类群特异性PCR-DGGE和克隆文库的方法。利用一对柔嫩梭菌类群特异性引物扩增得到239 bp的16S rRNA基因片段可以被DGGE很好地分离。11个健康人的粪便柔嫩梭菌类群DGGE图谱表明此类群的细菌组成具有宿主特异性;用DGGE对一个儿童的粪便柔嫩梭菌类群进行3年的监测,发现结构在前两年间有波动,而在第三年保持稳定。以一个成人的粪便总DNA为模板,用一个细菌通用的上游引物和一个柔嫩梭菌类群特异性的下游引物扩增1143 bp的16S rRNA基因片段,并克隆建库,挑取100个克隆。序列分析表明100个克隆均属于柔嫩梭菌类群;其中64%的克隆来自Faecalibacterium prausnitzii,6%来自Subdoligranulum variabile,2%是产丁酸细菌A2-207,28%来自未知菌种。通过对比克隆的239 bp片段在DGGE中的迁移位置和DGGE图谱中条带的位置,图谱中绝大多数条带的序列得到确定。结果表明柔嫩梭菌类群特异性DGGE和克隆文库是分析监测人肠道菌群中柔嫩梭菌类群的有效方法。
为研究寡果糖对人源肠道菌群结构的影响,我们采集一27岁的健康男性的新鲜粪便样品制备菌悬液,接种到剖腹产的无菌的仔猪的肠道中,构建了HFA仔猪。10只初生的HFA仔猪被平均分到对照组和益生元组,对照组仔猪食用基本食谱,益生元组仔猪在基本食谱的基础上每天饲喂一定量的寡果糖,如此持续至37日龄。在12日龄、17日龄、25日龄和37日龄收集每只仔猪的粪便样品,并提取粪便总DNA,分别用类群特异性PCR-DGGE和实时定量PCR方法在不同时间点比较两组仔猪的拟杆菌属、双歧杆菌属和柔嫩梭菌类群的组成和数量。在四个时间点都没有观察到寡果糖对双歧杆菌的促进作用,这可能是由于本研究中的HFA仔猪肠道中的双歧杆菌丰度较高,益生元不容易对它们的数量产生显著的提高作用。但寡果糖主要影响了其他细菌:在12日龄,两种未知拟杆菌的水平被提高;25日龄,寡果糖提高了Subdoligranulum variabile的水平,抑制了属于柔嫩梭菌类群的一种未知细菌;37日龄,拟杆菌属的数量被寡果糖显著降低。此工作表明,寡果糖可以影响双歧杆菌之外的肠道细菌。我们发现寡果糖可以刺激S. variabile的生长,已经有研究证明此细菌具有重要的生理功能,所以在今后的工作中有必要将它分离出来并进行功能分析,研究它与益生元和人体健康之间的关系。
接着,我们用基于NMR的代谢组学方法比较了HFA仔猪大肠不同区域内容物的代谢物组成,研究了大肠内菌群代谢的空间分布规律。用1H NMR图谱技术展示了10只37日龄的HFA仔猪的盲肠、近端结肠、远端结肠内容物和粪便中的生化组成,发现不同部位包含的代谢物种类相似,有很多细菌的代谢物,如短链脂肪酸、有机酸、酚酸、甲胺类物质、各种氨基酸等;也有来自食物、宿主分泌或来源尚未确定的物质,如碳水化合物、胆汁酸和核酸碱基。用多变量统计方法,主成分分析(Principle Component Analysis, PCA)、偏小二乘法(Partial Least Square Discrimination Analysis, PLS-DA)和正交偏小二乘法(Orthogonal Projection on Latent Structure, O-PLS)区分大肠不同区域的内容物和粪便的代谢物图谱,发现短链脂肪酸的含量从盲肠开始延大肠直至粪便逐渐降低,苯乙酸和3-羟基苯丙酸的含量在盲肠和近端结肠中明显高于远端结肠和粪便,支链氨基酸的含量从盲肠到粪便依次升高,糖苷类大分子的相对含量从盲肠到远端结肠逐渐升高。本研究表明,由于大肠不同部位的生理生态状况不同,肠道菌群的代谢活动也有差异。HFA仔猪大肠不同区段的内容物中代谢物的变化与文献报道的人类大肠内容物的生化组成的变化趋势相似,所以有潜力成为研究人肠道菌群代谢的有力模型。基于NMR的代谢组学方法可以快速展现肠道内容物的代谢物组成,反映肠道菌群代谢活动的概貌,可以用于监测肠道菌群的活动,研究外来干预(如益生元、益生素等)对菌群代谢的影响。粪便中的代谢物组成不完全等同于大肠内容物的情况,所以在下一步研究益生元对肠道菌群代谢的影响时,需要分析结肠内容物中的代谢物组成的变化。
为研究寡果糖对肠道菌群和宿主代谢的影响,5只对照组和5只益生元组仔猪在12日龄、17日龄、25日龄和37日龄的粪便,以及37日龄的近端结肠内容物、远端结肠内容物和尿液被采集。用NMR展示这些样品的生化组成,用正交偏小二乘法(Orthogonal Projection on Latent Structure, O-PLS)比较两组仔猪的NMR图谱。在4个时间点两组仔猪粪便的生化组成没有显著区别。在37日龄,益生元组仔猪的近端结肠内容物中含有较高含量的低聚糖、葡萄糖、乙酸、丙酸和核酸碱基;但寡果糖主要影响了HFA仔猪远端结肠内容物的代谢物组成,提高了低聚糖、葡萄糖、乙酸、乳酸、核酸碱基和多种氨基酸的含量,降低了胆汁酸的含量;益生元组仔猪的尿液中含有较高水平的丙氨酸、甘氨酸、肌酸、磷酸肌酸、乳酸、柠檬酸,但尿囊素和尿素的含量较低,一些由肠道菌群或者由肠道菌群和宿主共代谢产生的代谢物,如二甲胺、苯乙酰甘氨酸、三甲胺、三甲胺氧化物、马尿酸和4-羟苯基乳酸的含量在两组仔猪尿液中有差异。从这些代谢变化推断,寡果糖主要在HFA仔猪远端结肠内发挥益生元功效:寡果糖被结肠菌群发酵产生短链脂肪酸,从而影响了宿主的能量代谢;寡果糖调节菌群对氨基酸的代谢,影响了宿主的氨基酸代谢,改善宿主机体的氮平衡。寡果糖降低结肠中胆汁酸的现象说明它有一定预防结肠癌的作用。寡果糖对结肠菌群/宿主的核酸代谢也有影响,但其机理还需要进一步研究。基于1H NMR的代谢组学技术可以用于监测营养干预对肠道菌群和宿主代谢的影响。
本研究用HFA仔猪为模型,调查了寡果糖对肠道菌群的组成和代谢以及宿主代谢的影响,为下一步研究菌群结构和菌群功能、菌群代谢和宿主代谢之间的关系提供有益的思路和线索。
Human gastrointestinal tract harbors a diverse and complex microbiota whose composition and activities play important roles in host health and disease. Prebiotics are non-digestible food ingredients that modulate the structure and metabolism of gut microbiota by being fermented by colonic bacteria and thus improve host health. Fructo-oligosaccharides (FOS) are one type of prebiotics which is widely applied in food industry. Many studies demonstrated FOS stimulated the growth of bifidobacteria, but few studies systematically investigated its effects on the composition and activities of gut microflora, as well as the host metabolism. Studying prebiotic effects directly on human beings may have such difficulties as standardizing the diets of volunteers, collecting biopsy samples, and ethical issues etc.; as a consequence, Human Flora-Associated (HFA) mice/rat models are widely used to produce useful results, but the anatomy and physiology of rodent digestive tracts are significantly different from those of human, so the HFA rodent models have low relevance to human biology. Compared to rodents, pigs share more similarities with human in anatomical and physiological characteristics of the digestive system, so they can be better candidates for developing HFA model. Our lab have established HFA piglet model by demonstrating that the human-originated gut microbiota can colonize in the gut of ex-germfree piglets. In this dissertation, using HFA piglet model, we assessed the impacts of FOS on the structure of gut microbiota with microbial ecological techniques, and investigated the influences of FOS on the metabolism of the gut microbiota and the host with NMR based metabonomic methods.
Before we studied the effects of FOS on the composition of gut microflora, a group-specific PCR-based denaturant gradient gel electrophoresis (DGGE) method was established and combined with group-specific clone library analysis to investigate the diversity of the Clostridium leptum subgroup in human feces. PCR products (239 bp in length) were amplified using C. leptum cluster-specific primers and were well separated by DGGE. DGGE patterns of fecal amplicons from 11 human individuals showed host-specific profiles; patterns of fecal samples collected from a child during 3 years demonstrated the structural succession of the population in the first two years and its stability in the third year. A clone library was constructed with 100 clones, consisting of 1,143 bp inserts of 16S rRNA gene fragments that were amplified from one adult fecal DNA with one forward bacterial universal primer and one reverse group-specific primer. Eighty-six clones produced the 239 bp C. leptum cluster-specific amplicons and the remaining 14 clones did not but still phylogenetically belong to the subgroup. Sixty-four percent of the clones were from Faecalibacterium prausnitzii, 6% from Subdoligranulum variabile, 2% from the butyrate-producing bacterium A2-207 and 28% from unknown species. The identity of most bands in the DGGE profiles of the same adult was determined via comigration analysis with the 86 clones which included the 239 bp group specific fragments. These results suggest that DGGE combined with clone library analysis is an effective technique for monitoring and analyzing the composition of C. leptum cluster in human gut flora.
To study the influences of FOS on the structure of gut microbiota, fecal suspension was prepared from the fresh fecal sample collected from one healthy 27-year-old male adult donor and inoculated to ex-germfree piglets to produce HFA piglets. 10 newly born HFA piglets were evenly divided into 2 groups: 5 in control group being fed with basal diets, and 5 in prebiotic group having FOS added to the basal diets daily at the dose of 0.5 g/kg body weight/day. The feeding experiment lasted from day 1 to day 37 after the birth of piglets. Fecal samples on day 12, 17, 25 and 37 were collected from each piglet and fecal DNA was extracted. With group-specific PCR-DGGE and real-time PCR, the composition and amounts of Bacteroides genus, Bifidobcterium genus and C.leptum subgroup were compared between control and FOS-fed piglets. FOS did not change the composition or the amount of bifidobacteria, and the possible reason is the number of bifidobacteria in the gut of our HFA piglets was quite high, and thus it was difficult for FOS to produce significant bifidogenic effect. However, FOS mainly affected other bacteria: on day 12, two unknown bacteroides species were stimulated; on day 25, S. variabile was stimulated, and one unknown species from C.leptum subgroup was suppressed; on day 37, the amount of Bacteroides genus was decreased. Our work demonstrated that FOS can influence bacteria other than bifidobacteria in gut microbiota. We found for the first time that FOS stimulated the growth of S. variabile, which was revealed to actively interact with host metabolism, so it is necessary to isolate the bacteria in the future and study its relationship with prebiotics and host health.
We compared the biochemical composition of contents in different regions of the large intestine of HFA piglets with NMR based metabonomic techniques, and studied the spatial distribution of the gut microbiota metabolism in different regions along the large intestine. Metabolites present in aqueous extracts of contents from the caecum, proximal colon, distal colon and faeces of 10 HFA piglets were profiled by 1H NMR spectroscopy. Many compounds originating from bacterial activities were detected, including short chain fatty acids (SCFAs), organic acids, phenolic compounds, amino acids, and amines; besides, nucleobases, bile acids, choline and glycosides were also identified in profiles. Principle Component Analysis (PCA), Partial Least Square Discrimination Analysis (PLS-DA) and Orthogonal Projection on Latent Structure (O-PLS) analysis were used to differentiate NMR profiles of different regions and revealed that the biochemical composition in gut contents changed significantly in different regions of the large intestine of HFA piglets. The levels of SCFAs decreased distally from cecum to feces; phenylacetate and 3-hydroxyphenylpropionate predominated in cecum and proximal colon but not in distal colon and feces; the amounts of branch chain amino acids and glycosides increased distally along the large intestine. Our results suggest that the endogenous microbiota metabolize differently in different compartments of the large bowel due to varied environmental factors along the large bowel, such as substrate availability and host gut physiology, etc. The patterns of biochemical changes along the large intestine of HFA piglets showed to be similar to those in human colon as reported in the literature, so our HFA piglets potentially can become an effective in vivo model for studies on the metabolism of human gut microbiota. The 1H NMR-based metabonomic techniques has a great potential to be used to monitor the changes in the metabolic activities of colonic microbiota in response to interventions such as prebiotics, probiotics, antibiotics and diseases. Besides, the biochemical composition of feces is different from that of large intestinal contents, so it is necessary to analyze the metabolites in colonic content samples when study the effects of prebiotics on the metabolism of gut microbiota at next step.
In the last part, the influences of FOS on the metabolism of the gut microbiota and the host were studied with NMR-based metabonomic techniques. We collected feces from 5 control piglets and 5 FOS-fed piglets on day 12, 17, 25 and 37 after birth, as well as urine samples, and contents of proximal and distal colon from each animal on day 37. 1H NMR spectroscopy was applied to profile the metabolic composition of urine samples and aqueous extracts from feces and colonic contents. The Chemometric method, O-PLS was used to characterize the effects of FOS on the metabolism of the gut microflora and the host by comparing the NMR spectra of control and FOS-fed piglets. There is no statistically significant difference in fecal metabolite composition between two groups of piglets. In the proximal colon, FOS-fed piglets had higher levels of oligosaccharides, glucose, acetate, propionate and nucleobases than control animals. More marked differences between two groups were observed in distal colon: besides oligosaccharides, glucose, acetate, nucleobases, the quantities of lactate and amino acids were also increased by FOS treatment; the amount of bile acids was decreased. In the urine, FOS-fed piglets excreted more alanine, glycine, creatine and phosphocreatine, lactate, citrate, but less urea and allantoin; besides, FOS treatment also affected the quantities of some bacteria-origined metabolites in the urine such as dimethylamine, trimethylamine, trimethylamine N-oxide, phenylacetylglycine, hippurate and 4- hydroxyphenyl-lactate. As indicated by these results, FOS was fermented by the gut microbiota mainly in distal colon with the production of acetate and lactate, and the acids can be absorbed and utilized by the host as energy sources, and thus affected the energy metabolism of the host; FOS also modulated the amino acid metabolism of gut microbiota, and thus influenced the amino acid metabolism of the host and improved its N-balance; FOS was indicated to have a preventative effect on colon cancer by decreasing the amounts of bile acids in distal colon. The mechanism for the influence of FOS on the nucleic acid metabolism of the gut microbiota/host need to be further studied. The 1H NMR-based metabonomic techniques can be used to monitor the metabolic responses of colonic microbiota and the host to interventions such as prebiotics, probiotics, antibiotics and diseases.
HFA piglet model was utilized in our study to systematically study the effects of the prebiotic ingredient FOS on the gut microbiota and host metabolism. Our results will provide helpful insight and guidance to understanding the relationship among the composition and metabolism of the gut microbiota, and the metabolism of host.
引文
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