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CFTR dysregulation drives active selection of the gut microbiome


Autoři: Stacey M. Meeker aff001;  Kevin S. Mears aff001;  Naseer Sangwan aff002;  Mitchell J. Brittnacher aff003;  Eli J. Weiss aff003;  Piper M. Treuting aff001;  Nicholas Tolley aff001;  Christopher E. Pope aff004;  Kyle R. Hager aff003;  Anh T. Vo aff003;  Jisun Paik aff001;  Charles W. Frevert aff001;  Hillary S. Hayden aff003;  Lucas R. Hoffman aff003;  Samuel I. Miller aff003;  Adeline M. Hajjar aff001
Působiště autorů: Department of Comparative Medicine, University of Washington, Seattle, WA, United States of America aff001;  Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America aff002;  Department of Microbiology, University of Washington, Seattle, WA, United States of America aff003;  Department Pediatrics, University of Washington, Seattle, WA, United States of America aff004;  Departments of Medicine, Allergy and Infectious Disease, and Department of Genome Sciences, University of Washington, Seattle, WA, United States of America aff005;  Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America aff006
Vyšlo v časopise: CFTR dysregulation drives active selection of the gut microbiome. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008251
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008251

Souhrn

Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, we established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses. Our findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.

Klíčová slova:

Body weight – Cystic fibrosis – Diet – Gastrointestinal tract – Microbiome – Mouse models – Spleen – T cells


Zdroje

1. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066–73. doi: 10.1126/science.2475911 2475911.

2. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989;245(4922):1073–80. Epub 1989/09/08. doi: 10.1126/science.2570460 2570460.

3. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989;245(4922):1059–65. Epub 1989/09/08. doi: 10.1126/science.2772657 2772657.

4. Jackson AD, Goss CH. Epidemiology of CF: How registries can be used to advance our understanding of the CF population. J Cyst Fibros. 2018;17(3):297–305. Epub 2017/12/26. doi: 10.1016/j.jcf.2017.11.013 29275954.

5. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2017 Annual Data Report. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2017-Patient-Registry-Annual-Data-Report.pdf

6. Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A. Cystic fibrosis. Nat Rev Dis Primers. 2015;1:15010. Epub 2015/01/01. doi: 10.1038/nrdp.2015.10 27189798.

7. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251–4. Epub 1993/07/02. doi: 10.1016/0092-8674(93)90353-r 7686820.

8. Csanady L, Vergani P, Gadsby DC. Structure, Gating, and Regulation of the Cftr Anion Channel. Physiol Rev. 2019;99(1):707–38. Epub 2018/12/06. doi: 10.1152/physrev.00007.2018 30516439.

9. Rey MM, Bonk MP, Hadjiliadis D. Cystic Fibrosis: Emerging Understanding and Therapies. Annu Rev Med. 2019;70:197–210. Epub 2018/10/13. doi: 10.1146/annurev-med-112717-094536 30312551.

10. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16(1):45–56. Epub 2014/11/19. doi: 10.1038/nrg3849 nrg3849 [pii]. 25404111; PMCID: PMC4364438.

11. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891–904. doi: 10.1016/S0140-6736(09)60327-5 19403164.

12. Sathe MN, Freeman AJ. Gastrointestinal, Pancreatic, and Hepatobiliary Manifestations of Cystic Fibrosis. Pediatr Clin North Am. 2016;63(4):679–98. Epub 2016/07/30. doi: 10.1016/j.pcl.2016.04.008 [pii]. 27469182.

13. De Lisle RC, Borowitz D. The cystic fibrosis intestine. Cold Spring Harb Perspect Med. 2013;3(9):a009753. Epub 2013/06/22. cshperspect.a009753 [pii] doi: 10.1101/cshperspect.a009753 23788646.

14. Borowitz D. CFTR, bicarbonate, and the pathophysiology of cystic fibrosis. Pediatr Pulmonol. 2015;50 Suppl 40:S24–S30. Epub 2015/09/04. doi: 10.1002/ppul.23247 26335950.

15. Hoffman LR, Pope CE, Hayden HS, Heltshe S, Levy R, McNamara S, et al. Escherichia coli dysbiosis correlates with gastrointestinal dysfunction in children with cystic fibrosis. Clin Infect Dis. 2014;58(3):396–9. Epub 2013/11/02. cit715 [pii] doi: 10.1093/cid/cit715 24178246; PMCID: PMC3890337.

16. Matamouros S, Hayden HS, Hager KR, Brittnacher MJ, Lachance K, Weiss EJ, et al. Adaptation of commensal proliferating Escherichia coli to the intestinal tract of young children with cystic fibrosis. Proc Natl Acad Sci U S A. 2018;115(7):1605–10. Epub 2018/01/31. doi: 10.1073/pnas.1714373115 29378945; PMCID: PMC5816161.

17. Manor O, Levy R, Pope CE, Hayden HS, Brittnacher MJ, Carr R, et al. Metagenomic evidence for taxonomic dysbiosis and functional imbalance in the gastrointestinal tracts of children with cystic fibrosis. Sci Rep. 2016;6:22493. doi: 10.1038/srep22493 26940651; PMCID: PMC4778032.

18. Dhaliwal J, Leach S, Katz T, Nahidi L, Pang T, Lee JM, et al. Intestinal inflammation and impact on growth in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2015;60(4):521–6. doi: 10.1097/MPG.0000000000000683 25539196.

19. Sutherland R, Katz T, Liu V, Quintano J, Brunner R, Tong CW, et al. Dietary intake of energy-dense, nutrient-poor and nutrient-dense food sources in children with cystic fibrosis. J Cyst Fibros. 2018;17(6):804–10. Epub 2018/05/05. doi: 10.1016/j.jcf.2018.03.011 29724576.

20. Garg M, Ooi CY. The Enigmatic Gut in Cystic Fibrosis: Linking Inflammation, Dysbiosis, and the Increased Risk of Malignancy. Curr Gastroenterol Rep. 2017;19(2):6. Epub 2017/02/06. doi: 10.1007/s11894-017-0546-0 [pii]. 28155088.

21. Yamada A, Komaki Y, Komaki F, Micic D, Zullow S, Sakuraba A. Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis. Lancet Oncol. 2018;19(6):758–67. Epub 2018/05/01. S1470-2045(18)30188-8 [pii] doi: 10.1016/S1470-2045(18)30188-8 29706374.

22. Chen J, Pitmon E, Wang K. Microbiome, inflammation and colorectal cancer. Semin Immunol. 2017;32:43–53. Epub 2017/10/07. S1044-5323(17)30024-6 [pii] doi: 10.1016/j.smim.2017.09.006 28982615.

23. Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, et al. An animal model for cystic fibrosis made by gene targeting. Science. 1992;257(5073):1083–8. doi: 10.1126/science.257.5073.1083 1380723.

24. Hodges CA, Grady BR, Mishra K, Cotton CU, Drumm ML. Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2011;301(3):G528–36. Epub 2011/06/11. ajpgi.00052.2011 [pii] doi: 10.1152/ajpgi.00052.2011 21659619; PMCID: PMC3174541.

25. Leung DH, Heltshe SL, Borowitz D, Gelfond D, Kloster M, Heubi JE, et al. Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life. JAMA Pediatr. 2017;171(6):546–54. Epub 2017/04/25. doi: 10.1001/jamapediatrics.2017.0206 2617992 [pii]. 28437538; PMCID: PMC5731827.

26. Hardin DS. GH improves growth and clinical status in children with cystic fibrosis—a review of published studies. Eur J Endocrinol. 2004;151 Suppl 1:S81–5. Epub 2004/09/02. doi: 10.1530/eje.0.151s081 15339250.

27. Lavelle GM, White MM, Browne N, McElvaney NG, Reeves EP. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences. Biomed Res Int. 2016;2016:5258727. Epub 2016/06/25. doi: 10.1155/2016/5258727 27340661; PMCID: PMC4908263.

28. Paik J, Pershutkina O, Meeker S, Yi JJ, Dowling S, Hsu C, et al. Potential for using a hermetically-sealed, positive-pressured isocage system for studies involving germ-free mice outside a flexible-film isolator. Gut Microbes. 2015;6(4):255–65. doi: 10.1080/19490976.2015.1064576 26177210; PMCID: PMC4615381.

29. Clarke LL, Gawenis LR, Bradford EM, Judd LM, Boyle KT, Simpson JE, et al. Abnormal Paneth cell granule dissolution and compromised resistance to bacterial colonization in the intestine of CF mice. Am J Physiol Gastrointest Liver Physiol. 2004;286(6):G1050–8. Epub 2004/01/13. doi: 10.1152/ajpgi.00393.2003 00393.2003 [pii]. 14715526.

30. Nielsen S, Needham B, Leach ST, Day AS, Jaffe A, Thomas T, et al. Disrupted progression of the intestinal microbiota with age in children with cystic fibrosis. Sci Rep. 2016;6:24857. Epub 2016/05/05. doi: 10.1038/srep24857 27143104; PMCID: PMC4855157.

31. Mulcahy EM, Hudson JB, Beggs SA, Reid DW, Roddam LF, Cooley MA. High peripheral blood th17 percent associated with poor lung function in cystic fibrosis. PLoS One. 2015;10(3):e0120912. doi: 10.1371/journal.pone.0120912 25803862; PMCID: PMC4372584.

32. Tiringer K, Treis A, Fucik P, Gona M, Gruber S, Renner S, et al. A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am J Respir Crit Care Med. 2013;187(6):621–9. Epub 2013/01/12. doi: 10.1164/rccm.201206-1150OC rccm.201206-1150OC [pii]. 23306544.

33. Safe M, Gifford AJ, Jaffe A, Ooi CY. Resolution of Intestinal Histopathology Changes in Cystic Fibrosis after Treatment with Ivacaftor. Ann Am Thorac Soc. 2016;13(2):297–8. doi: 10.1513/AnnalsATS.201510-669LE 26848606.

34. Andersen DH. Cystic fibrosis of the pancreas and its relation to celiac disease—A clinical and pathologic study. Am J Dis Child. 1938;56(2):344–99. doi: 10.1001/archpedi.1938.01980140114013 ISI:000201769200013.

35. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A. 2008;105(52):20858–63. Epub 2008/12/17. 0808723105 [pii] doi: 10.1073/pnas.0808723105 19075245; PMCID: PMC2603261.

36. Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science. 2011;334(6053):255–8. Epub 2011/10/15. 334/6053/255 [pii] doi: 10.1126/science.1209791 21998396; PMCID: PMC3321924.

37. Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol. 2013;75:289–311. doi: 10.1146/annurev-physiol-030212-183744 23398152.

38. Flass T, Tong S, Frank DN, Wagner BD, Robertson CE, Kotter CV, et al. Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis. PLoS One. 2015;10(2):e0116967. doi: 10.1371/journal.pone.0116967 25658710; PMCID: PMC4319904.

39. van Elburg RM, Uil JJ, van Aalderen WM, Mulder CJ, Heymans HS. Intestinal permeability in exocrine pancreatic insufficiency due to cystic fibrosis or chronic pancreatitis. Pediatr Res. 1996;39(6):985–91. doi: 10.1203/00006450-199606000-00010 8725259.

40. Kushwah R, Gagnon S, Sweezey NB. Intrinsic predisposition of naive cystic fibrosis T cells to differentiate towards a Th17 phenotype. Respir Res. 2013;14:138. Epub 2013/12/19. doi: 10.1186/1465-9921-14-138 1465-9921-14-138 [pii]. 24344776; PMCID: PMC3890528.

41. Moss RB, Hsu YP, Olds L. Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes. Clin Exp Immunol. 2000;120(3):518–25. Epub 2000/06/09. cei1232 [pii] doi: 10.1046/j.1365-2249.2000.01232.x 10844532; PMCID: PMC1905557.

42. Brazova J, Sediva A, Pospisilova D, Vavrova V, Pohunek P, Macek M Jr., et al. Differential cytokine profile in children with cystic fibrosis. Clin Immunol. 2005;115(2):210–5. Epub 2005/05/12. S1521-6616(05)00037-9 [pii] doi: 10.1016/j.clim.2005.01.013 15885645.

43. Ooi CY, Syed SA, Rossi L, Garg M, Needham B, Avolio J, et al. Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation. Sci Rep. 2018;8(1):17834. Epub 2018/12/14. doi: 10.1038/s41598-018-36364-6 30546102; PMCID: PMC6292911.

44. Klindworth A, Pruesse E, Schweer T, Peplies J, Quast C, Horn M, 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. Epub 2012/08/31. doi: 10.1093/nar/gks808 gks808 [pii]. 22933715; PMCID: PMC3592464.

45. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. 2011. 2011;17(1):3. Epub 2011-08-02. doi: 10.14806/ej.17.1.200

46. Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13(7):581–3. Epub 2016/05/24. doi: 10.1038/nmeth.3869 nmeth.3869 [pii]. 27214047; PMCID: PMC4927377.

47. McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One. 2013;8(4):e61217. Epub 2013/05/01. doi: 10.1371/journal.pone.0061217 PONE-D-12-31789 [pii]. 23630581; PMCID: PMC3632530.

48. Parks DH, Tyson GW, Hugenholtz P, Beiko RG. STAMP: statistical analysis of taxonomic and functional profiles. Bioinformatics. 2014;30(21):3123–4. Epub 2014/07/26. doi: 10.1093/bioinformatics/btu494 25061070; PMCID: PMC4609014.

49. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological). 1995;57(1):289–300. citeulike-article-id:1042553 doi: 10.2307/2346101


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