药学学报, 2021, 56(4): 1100-1108
引用本文:
刘贵琴, 白雪, 段雅彬, 朱俊博, 杨建鑫, 王倩, 周杨, 顾文琦, 李向阳. 高原低氧环境对大鼠肠道菌群的影响[J]. 药学学报, 2021, 56(4): 1100-1108.
LIU Gui-qin, BAI Xue, DUAN Ya-bin, ZHU Jun-bo, YANG Jian-xin, WANG Qian, ZHOU Yang, GU Wen-qi, LI Xiang-yang. Changes in the intestinal flora of rats under high altitude hypoxia[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 1100-1108.

高原低氧环境对大鼠肠道菌群的影响
刘贵琴1#, 白雪2#, 段雅彬2, 朱俊博2, 杨建鑫2, 王倩3, 周杨3, 顾文琦3, 李向阳3,4*
1. 青海大学生态环境工程学院, 青海 西宁 810016;
2. 青海大学高原医学研究中心, 青海 西宁 810001;
3. 青海大学医学院, 青海 西宁 810001;
4. 青海大学三江源生态与高原农牧业国家重点实验室, 青海 西宁 810016
摘要:
探讨高原低氧环境对大鼠肠道菌群结构和多样性的影响。动物实验严格遵循青海大学医学院医学伦理委员会的规定。SD大鼠随机分为平原对照组、中度海拔缺氧组和高度海拔缺氧组,缺氧组大鼠分别于低氧暴露第3、7、15、30天测定粪便pH值,HE染色法观察小肠组织病理形态学变化,16S rDNA高通量测序技术对肠道菌群进行测序。与平原对照组相比,中度海拔缺氧组和高度海拔缺氧组大鼠粪便pH值均显著降低,高原低氧环境对小肠组织具有一定的影响,中度海拔缺氧组在低氧暴露第3天固有层和黏膜下层毛细血管轻度扩张充血,高度海拔缺氧组在低氧暴露第7天黏膜下层毛细血管扩张充血、黏膜固有层轻度水肿、淋巴管扩张。高原低氧环境下,大鼠肠道菌群的结构和多样性随低氧暴露时间延长发生显著改变。大鼠肠道菌群共检测出35个门、87个纲、205个目、337个科、638个属和256个种,其中厚壁菌门、梭菌纲、梭菌目、瘤胃菌科、阿克曼菌属和鼠乳杆菌相对丰度较高且具有统计学意义。与平原对照组相比,缺氧组大鼠肠道菌群在低氧暴露第15天差异最明显,中度海拔缺氧组中相对丰度较高差异菌有9个,以理研菌科_RC9_gut_group为主,高度海拔缺氧组中相对丰度较高的差异菌有19个,以瘤胃菌科为主。研究结果对明确肠道菌群与高原低氧的关系具有指导意义,为进一步研究高原低氧条件下疾病的形成和发展及药物代谢提供理论依据。
关键词:    高原      低氧      肠道菌群      16S rDNA      差异菌      多样性     
Changes in the intestinal flora of rats under high altitude hypoxia
LIU Gui-qin1#, BAI Xue2#, DUAN Ya-bin2, ZHU Jun-bo2, YANG Jian-xin2, WANG Qian3, ZHOU Yang3, GU Wen-qi3, LI Xiang-yang3,4*
1. College of Eco-Environmental Engineering, Qinghai University, Xining 810016, China;
2. Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China;
3. Medical College of Qinghai University, Xining 810001, China;
4. State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining 810016, China
Abstract:
The structure and diversity of the intestinal flora in rats exposed to high altitude hypoxia was investigated. Animal experiments strictly follow the regulations of Medical Laboratory Animal Ethics Committee of Qinghai University, School of Medicine. SD rats were randomly divided into a control group, a moderate altitude hypoxia group, and a high altitude hypoxia group. The pH value of the feces was measured and histopathological changes in the small intestine were determined by HE staining, and the intestinal flora were characterized by 16S rDNA high throughput sequencing technology on the 3rd, 7th, 15th, and 30th day of hypoxia exposure. Compared with the control group, the fecal pH value of rats in the moderate altitude hypoxia group and the high altitude hypoxia group was decreased significantly. The lamina propria and submucosa capillaries were slightly dilated and congested on the 3rd day in the moderate altitude hypoxia group. In the high altitude hypoxia group the submembrane capillaries were dilated and congested, the lamina propria of the mucosa showed mild edema, and the lymphatic vessels were dilated on the 7th day. The composition and diversity of intestinal flora in these rats changed significantly with prolonged exposure to the high altitude hypoxic environment. A total of 35 phyla, 87 classes, 205 orders, 337 families, 638 genera, and 256 species were annotated in the three groups of rats, including Firmicutes, Clostridia, Clostridiales, Ruminococcaceae, Akkermansia, and Lactobacillus_murinus. Compared with the control group, the intestinal flora of the hypoxic groups showed the most significant changes by the 15th day. There were 9 microbiota of gut microorganisms with relative abundance in the moderate altitude hypoxia group, of which Rikenellaceae_RC9_gut_group bacteria was the most common, there were 19 different microbiota of gut microorganisms with higher relative abundance in the high altitude hypoxia group, of which Ruminococcaceae bacteria was the most common. The results of this study indicate significant changes in the intestinal flora with high altitude hypoxia, and establish a foundation for further research on the initiation and development of diseases and drug metabolism in high altitude hypoxia.
Key words:    plateau    hypoxia    intestinal flora    16S rDNA    differential microbiota of gut microorganisms    diversity   
收稿日期: 2020-09-29
DOI: 10.16438/j.0513-4870.2020-1628
基金项目: 国家自然科学基金资助项目(81760673,81460568);青海省创新平台建设专项(2021-ZJ-T03).
通讯作者: 李向阳,Tel:86-971-5362082,Fax:86-971-5362383,E-mail:qhmclxy@163.com
Email: qhmclxy@163.com
相关功能
PDF(1348KB) Free
打印本文
0
作者相关文章
刘贵琴  在本刊中的所有文章
白雪  在本刊中的所有文章
段雅彬  在本刊中的所有文章
朱俊博  在本刊中的所有文章
杨建鑫  在本刊中的所有文章
王倩  在本刊中的所有文章
周杨  在本刊中的所有文章
顾文琦  在本刊中的所有文章
李向阳  在本刊中的所有文章

参考文献:
[1] Bonkowsky JL, Son JH. Hypoxia and connectivity in the developing vertebrate nervous system[J]. Dis Model Mech, 2018, 11:dmm037127.
[2] Simon MC, Liu LP, Barnhart BC, et al. Hypoxia-induced signaling in the cardiovascular system[J]. Annu Rev Physiol, 2008, 70:51-71.
[3] Hocker AD, Stokes JA, Powell FL, et al. The impact of inflammation on respiratory plasticity[J]. Exp Neurol, 2017, 287:243-253.
[4] Hogberg N, Carlsson PO, Hillered L, et al. Intraluminal intestinal microdialysis detects markers of hypoxia and cell damage in experimental necrotizing enterocolitis[J]. J Pediatr Surg, 2012, 47:1646-1651.
[5] Longhi MS, Moss A, Jiang ZG, et al. Purinergic signaling during intestinal inflammation[J]. J Mol Med (Berl), 2017, 95:915-925.
[6] Adak A, Maity C, Ghosh K, et al. Alteration of predominant gastrointestinal flora and oxidative damage of large intestine under simulated hypobaric hypoxia[J]. Z Gastroenterol, 2014, 52:180-186.
[7] Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease[J]. Curr Opin Gastroenterol, 2015, 31:69-75.
[8] Willyard C. When drugs unintentionally affect gut bugs[J]. Nat Rev Drug Discov, 2018, 17:383-384.
[9] Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults[J]. PLoS One, 2010, 5:e9085.
[10] Gomes AC, Hoffmann C, Mota JF. The human gut microbiota:metabolism and perspective in obesity[J]. Gut Microbes, 2018, 9:308-325.
[11] Zhang FX, Wu WM, Deng ZY, et al. High altitude increases the expression of hypoxia-inducible factor 1α and inducible nitric oxide synthase with intestinal mucosal barrier failure in rats[J]. Int J Clin Exp Pathol, 2015, 8:5189-5195.
[12] Possemiers S, Grootaert C, Vermeiren J, et al. The intestinal environment in health and disease:recent insights on the potential of intestinal bacteria to influence human health[J]. Curr Pharm Des, 2009, 15:2051-2065.
[13] Zhang W, Jiao LF, Liu RX, et al. The effect of exposure to high altitude and low oxygen on intestinal microbial communities in mice[J]. PLoS One, 2018, 13:e0203701.
[14] Sun YM, Zhang JH, Zhao AP, et al. Effects of intestinal flora on the pharmacokinetics and pharmacodynamics of aspirin in high-altitude hypoxia[J]. PLoS One, 2020, 15:e0230197.
[15] Power SE, O'Toole PW, Stanton C, et al. Intestinal microbiota, diet and health[J]. Br J Nutr, 2014, 111:387-402.
[16] Li L, Zhao X. Comparative analyses of fecal microbiota in Tibetan and Chinese Han living at low or highaltitude by barcoded 454 pyrosequencing[J]. Sci Rep, 2015, 5:14682-14692.
[17] Rausch LK, Hofer M, Pramsohler S, et al. Adiponectin, leptin and visfatin in hypoxia and its effect for weight loss in obesity[J]. Front Endocrinol (Lausanne), 2018, 9:615-621.
[18] van Welden S, Selfridge AC, Hindryckx P. Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD[J]. Nat Rev Gastroenterol Hepatol, 2017, 14:596-611.
[19] Xu H, Wang JQ, Cai J, et al. Protective effect of Lactobacillus rhamnosus GG and its supernatant against myocardial dysfunction in obese mice exposed to intermittent hypoxia is associated with the activation of Nrf2 pathway[J]. Int J Biol Sci, 2019, 1511:2471-2483.
[20] Xu CL, Sun R, Qiao XJ, et al. Protective effect of glutamine on intestinal injury and bacterial community in rats exposed to hypobaric hypoxia environment[J]. World J Gastroenterol, 2014, 20:4662-4674.
[21] Png CW, Linden SK, Gilshenan KS, et al. Mucolytic bacteria with increase prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria[J]. Am J Gastroenterol, 2010, 105:2420-2428.
[22] Wang L, Christophersen CT, Sorich MJ, et al. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism[J]. Appl Environ Microbiol, 2011, 77:6718-6721.
[23] Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity[J]. Proc Natl Acad Sci U S A, 2013, 110:9066-9071.
[24] Macchione IG, Lopetuso LR, Ianiro G, et al. Akkermansia muciniphila:key player in metabolic and gastrointestinal disorders[J]. Eur Rev Med Pharmacol Sci, 2019, 2318:8075-8083.
[25] Zhou KQ. Strategies to promote abundance of Akkermansia muciniphila, an emerging probiotics in the gut, evidence from dietary intervention studies[J]. J Funct Foods, 2017, 33:194-201.
[26] Sommer F, Anderson JM, Bharti R, et al. The resilience of the intestinal microbiota influences health and disease[J]. Nat Rev Microbiol, 2017, 15:630-638.
[27] Brown E, Taylor CT. Hypoxia-sensitive pathways in intestinal inflammation[J]. J Physiol, 2018, 596:2985-2989.
[28] Vandenplas Y, Carnielli VP, Ksiazyk J, et al. Factors affecting early-life intestinal microbiota development[J]. Nutrition, 2020, 78:110812.
[29] Wang H, Zhang W, Zuo L, et al. Intestinal dysbacteriosis contributes to decreased intestinal mucosal barrier function and increased bacterial translocation[J]. Lett Appl Microbiol, 2014, 58:384-392.
[30] Wu X, Vallance BA, Boyer L, et al. Saccharomyces boulardii ameliorates Citrobacter rodentium-induced colitis through actions on bacterial virulence factors[J]. Am J Physiol Gastrointest Liver Physiol, 2008, 294:G295-G306.
[31] Gao XJ, Li T, Wei B, et al. Intestinal flora mediated changes and mechanisms of intestinal CYP3A and P-glycoprotein in rats with ulcerative colitis[J]. Acta Pharm Sin (药学学报), 2017, 52:34-43.
[32] Li ZJ, Chen XG, Zhang S. The role of the intestinal microflora dysbiosis in chronic kidney disease[J]. Acta Pharm Sin (药学学报), 2020, 55:2777-2784.
[33] Narula N, Kassam Z, Yuan Y, et al. Systematic review and meta-analysis:fecal microbiota transplantation for treatment of active ulcerative colitis[J]. Inflamm Bowel Dis, 2017, 23:1702-1709.
[34] Roxas JL, Viswanathan VK. Modulation of intestinal paracellular transport by bacterial pathogens[J]. Compr Physiol, 2018, 82:823-842.
[35] Wojtal KA, Cee A, Lang S, et al. Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans[J]. Am J Physiol Gastrointest Liver Physiol, 2014, 307:G673-G688.
[36] Westerterp KR. Energy and water balance at high altitude[J]. News Physiol Sci, 2001, 16:134-137.
[37] Li XY, Liu YN, Yuan M, et al. Effect of high altitude hypoxia on the activity and protein expression of drug metabolizing enzymes CYP2C9 and 2C19[J]. Acta Pharm Sin (药学学报), 2012, 47:188-193.
[38] Li XY, Liu YN, Li YP, et al. Pharmacokinetics of sulfamethoxazole in healthy Han volunteers living at plain and in native Han and Tibetan healthy volunteers living at high altitude[J]. Acta Pharm Sin (药学学报), 2011, 46:1117-1122.
[39] Zhang JL, Li XY. A review of drug metabolism under hypoxia environment at high altitude[J]. Acta Pharm Sin (药学学报), 2015, 50:1073-1079.
[40] Li XY, Wang XJ, Li YP, et al. Effect of exposure to acute and chronic high-altitude hypoxia on the activity and expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in rats[J]. Pharmacology, 2014, 93:76-83.
[41] Duan YB, Zhu JB, Yang JX, et al. Regulation of high-altitude hypoxia on the transcription of CYP450 and UGT1A1 mediated by PXR and CAR[J]. Front Pharmacol, 2020, 11:574176.
[42] Liu GQ, Li XY. Intestinal flora and drug metabolism under high altitude hypoxia conditions[J]. J Pharm Res (药学研究), 2019, 38:714-718.
相关文献:
1.孙月梅, 张雅婷, 张娟红, 李雪, 王荣, 李文斌.药物微生物组学研究进展[J]. 药学学报, 2020,55(10): 2314-2321
2.张娟玲, 李向阳.高原低氧影响药物代谢的研究进展[J]. 药学学报, 2015,50(9): 1073-1079
3.李向阳, 刘永年, 袁 明, 李永平, 杨应忠, 朱俊博.高原低氧对药物代谢酶CYP2C9和2C19活性及蛋白表达的影响[J]. 药学学报, 2012,47(2): 188-193