Establishment of COPD gut microbiota model with fecal microbiota transplantation and its evaluation_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Naijian ¹ ^# , DAI Zhouli ² ^# , CHEN Chiyong ² , ZHANG Jiahuan ¹ , HE Fang ³ , LI Jing ¹ , ZHOU Yumin ¹ , LI Bing ² ,  RAN Pixin ¹

1. The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, Guangzhou, Guangdong 510120, P. R. China;
2. The GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510120, P. R. China;
3. Basic Medical School, Guangzhou Medical University, Guangzhou, Guangdong 510120, P. R. China;

Corresponding author：

RAN Pixin, Email: pxran@gzhmu.edu.cn

Keywords：

Chronic obstructive pulmonary diseas; Fecal microbiota transplantation; Gut microbiota; Mice

DOI：

10.7507/1671-6205.202104004

Video：

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Objective To establisht a gut microbiota mice model for chronic obstructive pulmonary disease (COPD) with fecal microbiota transplantation (FMT) and its evaluation.Methods The mice received FMT from healthy individuals, COPD Ⅰ-Ⅱ subjects, or COPD Ⅲ–Ⅳ subjects. After microbiota depletion, the FMT was performed by a single oral administration of 100 μL per mouse every other day, for a total of 14 times in 28 days. On the 29^th day, the peripheral blood mononuclear cells were analyzed, the gut microbiota of mice before and after FMT was analyzed by 16S rRNA sequencing, and the mice model were evaluated.Results The operational taxonomic units, Chao 1 and Shannon indexes of mice all decreased significantly after antibiotic treatment (P<0.001), but increased significantly after FMT from healthy individuals, COPD Ⅰ-Ⅱ subjects, or COPD Ⅲ–Ⅳ subjects (P<0.05 or P<0.01). The abundance of Firmicutes, Proteobacteria and Actinobacteria in the guts of the mice in the healthy human FMT group, COPD Ⅰ-Ⅱ FMT group and COPD Ⅲ-Ⅳ FMT group were significantly different from those of the control group who only received phosphate buffer saline instead of FMT (P<0.05 or P<0.01). The auxiliary T lymphocytes and cytotoxic T lymphocytes were higher, but B lymphocytes decreased in the peripheral blood of the mice in the COPD Ⅰ-Ⅱ FMT group and COPD Ⅲ-Ⅳ FMT group (P<0.05 or P<0.01).Conclusion FMT can successfully establish a COPD gut microbiota research model.

Citation： LI Naijian, DAI Zhouli, CHEN Chiyong, ZHANG Jiahuan, HE Fang, LI Jing, ZHOU Yumin, LI Bing, RAN Pixin. Establishment of COPD gut microbiota model with fecal microbiota transplantation and its evaluation. Chinese Journal of Respiratory and Critical Care Medicine, 2021, 20(7): 465-471. doi: 10.7507/1671-6205.202104004 Copy

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2.	李乃健, 李冰, 冉丕鑫. 大气颗粒物对肺部微生态的影响及其在慢阻肺发病中的作用. 中国呼吸与危重监护杂志, 2018, 17(2): 1-4.
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15.	Lai HC, Lin TL, Chen TW, et al. Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut, 2021, 09: 2020-322599.
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17.	Britton GJ, Contijoch EJ, Mogno I, et al. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORγt+ regulatory T cells and exacerbate colitis in mice. Immunity, 2019, 50(1): 212-224.
18.	Sharon G, Cruz NJ, Kang DW, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell, 2019, 177(6): 1600-1618.
19.	Zheng DW, Dong X, Pan P, et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat Biomed Eng, 2019, 3(9): 717-728.
20.	Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol, 2016, 16(6): 341-352.
21.	Fan Y, Pedersen O, et al. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol, 2021, 19(1): 55-71.
22.	Marsland BJ, Trompette A, Gollwitzer ES, et al. The Gut–Lung Axis in Respiratory Disease. Ann Am Thorac Soc, 2015, 12 Suppl 2: S150-S156.
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24.	Li SS, Zhu A, Benes V, et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science, 2016, 352(6285): 586-589.
25.	Kennedy EA, King KY, Baldridge MT. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front Physiol, 2018, 9: 1534.
26.	Faner R, Cruz T, Agusti A. Immune response in chronic obstructive pulmonary disease. Expert Rev Clin Immunol, 2013, 9(9): 821-833.
27.	Brusselle GG, Joos GF, Bracke KR, et al. New insights into the immunology of chronic obstructive pulmonary disease. Lancet, 2011, 378(9795): 1015-1026.
28.	Wang H, Ying H, Wang S, et al. Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease. Clin Respir J, 2015, 9: 330-341.
29.	Cani PD, Jordan BF. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat Rev Gastroenterol Hepatol, 2018, 15(11): 671-682.
30.	Cox AJ, West NP, Cripps AW. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol, 2015, 3(3): 207-215.
31.	Chakradhar S. A curious connection: teasing apart the link between gut microbes and lung disease. Nat Med, 2017, 23(4): 402-404.

1. Budden KF, Gellatly SL, Wood DL, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol, 2017, 15(1): 55-63.
2. 李乃健, 李冰, 冉丕鑫. 大气颗粒物对肺部微生态的影响及其在慢阻肺发病中的作用. 中国呼吸与危重监护杂志, 2018, 17(2): 1-4.
3. Mjösberg J, Rao A. Lung inflammation originating in the gut. Science, 2018, 359(6371): 36-37.
4. Hurst JR, Sin DD. Chronic obstructive pulmonary disease as a risk factor for cardiovascular disease. a view from the SUMMIT. Am J Respir Crit Care Med, 2018, 198(1): 2-4.
5. Rutten EPA, Lenaerts K, Buurman WA, et al. Disturbed intestinal integrity in patients with COPD: effects of activities of daily living. Chest, 2014, 145: 245-252.
6. Bowerman KL, Rehman SF, Vaughan A, et al. Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease. Nat Commun, 2020, 11(1): 5886.
7. Zhou Y, Zhong NS, Li X, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med, 2017, 377(10): 923-935.
8. Li C, Zhou Y, Liu S, et al. Tiotropium discontinuation in patients with early-stage COPD: a prospective observational cohort study. ERJ Open Res, 2019, 5(1): 00175-2018.
9. Singh D, Agusti A, Anzueto A, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD Science Committee Report 2019. Eur Respir J, 2019, 53(5): 1900164.
10. Miller M R, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J, 2005, 26(2): 319-338.
11. Schuijt TJ, Lankelma JM, Scicluna BP, et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut, 2016, 65(4): 575-583.
12. 6S Metagenomic Sequencing Library Preparation. San Diego, CA: Illumina. Updated 2014. Retrieved July 15, 2016, from https://www.illumina.com/.
13. Klindworth A1, Pruesse E, Schweer T, et al. Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res, 2013, 41(1): e1.
14. Rocafort M, Noguera-Julian M, Rivera J, et al. Evolution of the gut microbiome following acute HIV-1 infection. Microbiome, 2019, 7(1): 73.
15. Lai HC, Lin TL, Chen TW, et al. Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut, 2021, 09: 2020-322599.
16. Li N, Yang Z, Liao B, et al. Chronic exposure to ambient particulate matter induces gut microbial dysbiosis in a rat COPD model. Respir Res, 2020, 21(1): 271.
17. Britton GJ, Contijoch EJ, Mogno I, et al. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORγt+ regulatory T cells and exacerbate colitis in mice. Immunity, 2019, 50(1): 212-224.
18. Sharon G, Cruz NJ, Kang DW, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell, 2019, 177(6): 1600-1618.
19. Zheng DW, Dong X, Pan P, et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat Biomed Eng, 2019, 3(9): 717-728.
20. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol, 2016, 16(6): 341-352.
21. Fan Y, Pedersen O, et al. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol, 2021, 19(1): 55-71.
22. Marsland BJ, Trompette A, Gollwitzer ES, et al. The Gut–Lung Axis in Respiratory Disease. Ann Am Thorac Soc, 2015, 12 Suppl 2: S150-S156.
23. Young RP, Hopkins RJ, Marsland B, et al. The Gut-Liver-Lung Axis. Modulation of the Innate Immune Response and Its Possible Role in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol, 2016, 54(2): 161-169.
24. Li SS, Zhu A, Benes V, et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science, 2016, 352(6285): 586-589.
25. Kennedy EA, King KY, Baldridge MT. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front Physiol, 2018, 9: 1534.
26. Faner R, Cruz T, Agusti A. Immune response in chronic obstructive pulmonary disease. Expert Rev Clin Immunol, 2013, 9(9): 821-833.
27. Brusselle GG, Joos GF, Bracke KR, et al. New insights into the immunology of chronic obstructive pulmonary disease. Lancet, 2011, 378(9795): 1015-1026.
28. Wang H, Ying H, Wang S, et al. Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease. Clin Respir J, 2015, 9: 330-341.
29. Cani PD, Jordan BF. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat Rev Gastroenterol Hepatol, 2018, 15(11): 671-682.
30. Cox AJ, West NP, Cripps AW. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol, 2015, 3(3): 207-215.
31. Chakradhar S. A curious connection: teasing apart the link between gut microbes and lung disease. Nat Med, 2017, 23(4): 402-404.

Chinese Journal of Respiratory and Critical Care Medicine

Establishment of COPD gut microbiota model with fecal microbiota transplantation and its evaluation

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