Human Microbiota and Liver Transplant

NCT02223468 | Completed DMC

• 1 other identifier: Microta.LT.14
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The microbiota represents the collections of microbial communities that colonize a host. In health, the microbiota protects against pathogens and maturation of the immune system. In return, the immune system determines the composition of the microbiota. Altered microbial composition (dysbiosis) has been correlated with a number of diseases in humans. The real role of the microbiota in transplant recipients is still unknown even though we suspect that it may be affected directly or indirectly by immunosuppressive drugs and antimicrobial prophylaxis taken by transplant patients, as well as by inflammatory process secondary to ischemia/reperfusion injury. A number of studies have investigated the impact of liver transplantation on the intestinal microbiota. In a recent analysis of stool flora (Microb Ecol 2013; 65: 781-791) in 12 liver transplant recipients, changes in the microbiota were correlated to post-transplant infections. The authors suggested that the shift to pathogenic strains of bacteria due to the use of prophylactic antibiotics may be contributing to post-transplant complications. In a larger study, Wu et al (Hepatobiliary Pancreat Dis Int 2012; 11: 40-50) demonstrated marked changes in the gut microbiota post-transplantation with an increase in Enterobacteriaceae and Enterococcus, and reduction in Eubacteria, Bifidobacterium and Lactobacillus species. These changes, however, resolved over time such that by 6 months, at times when bacterial prophylaxis ends and immunosuppression is reduced. A better characterization of the impact of post-transplant therapy on the human microbiota has the potential to improve our understanding of the infection process and translate into development of new therapeutic strategies. The main goal of this study is to characterize intestinal microbiota and confirm the same bacterial DNA in peripheral blood and portal lymph nodes in patients affected with end-stage chronic liver disease, and to analyze its evolution from the moment of inclusion in waiting list throughout the first year after liver transplantation. For each patient, a healthy CONTROL with a similar age (± 10 years) will be selected from the same family setting, in whom just one sample will be obtained during the enrollment phase. The second goal is to analyze the potential associations between microbiota flora and transplant outcomes during the same period.

Conditions

Intestinal Microbiota; Complication of Transplanted Liver; Acute Rejection of Liver Transplant; Infection

Keywords

Intestinal Microbiota; Liver Transplant; Acute Rejection; Infection

Outcome Measures

Primary Outcomes (1)

• Analyses of changes in microbiota composition before and post-transplant

  Stool samples will be obtained from the liver transplant recipient following the time frame described above. A healthy CONTROL with a similar age (± 10 years) will be selected from the same family setting, in whom just one sample will be obtained during the enrollment phase

  Before transplant, 1st, 3rd, 7th, 14th and 28th post-transplant and 3rd, 6th, 9th and 12th months post-transplant

Secondary Outcomes (6)

• Incidence of biopsy proven acute cellular rejection

  Evaluation at 3rd, 6th, 9th and 12th months post-trasplant

• Incidence of post-transplant infection requiring antibiotherapy (oral or endovenous)

  Evaluation at 3rd, 6th, 9th and 12th months post-trasplant

• Incidence of Diabetes Mellitus de novo post-transplant

  12 months post-trasplant

• Incidence of Obesity (BMI≥30 kg/m2) post-transplant

  12 months post-transplant

• Incidence of renal dysfunction (creatinine ≥ 1.5mg/dL and/or MDRD formula Glomerular Filtrate Rate < 60 mL/min/1.73m2)

  Evaluation at 3rd, 6th, 9th and 12th months post-trasplant

Study Arms (1)

CASE-CONTROL

CASE: Liver transplant recipients (n=20) CONTROL: A healthy person with a similar age (±10 years) to the control selected from the same family setting (n=20)

Eligibility Criteria

• Age: 18 Years - 68 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adult liver transplant patients in Hospital Vall d´Hebron (Barcelona, Spain)

You may qualify if:

• First liver transplant
• Patients aged 18-70 years
• Able to consent and agree in participate in the current study for one year

You may not qualify if:

• Multiorgan transplantation and/or liver transplant from cardiac arrest donor and/or with ABO incompatibility.
• Uncontrolled concomitant infections (including HIV seropositivity) and/or diarrhoea, vomiting or active gastric ulcer.
• Fulminant hepatic insufficiency as first indication for liver transplant
• Hemodynamic instability prior to liver transplant.
• Recipient presenting present or previous neoplasia, except for non-metastatic basal of squamous cutaneous carcinoma or localized hepatocarcinoma with diameter \<5cm or \<3known lesions with diameter \<3cm.
• Significant comorbidity
• Breastfeeding or female patients at fertile age without negative pregnancy test and accepting the use of reliable fertility control method
• Any pretransplant antibiotherapy (oral or endovenous) or enrolled in any clinical assay

Sponsors & Collaborators

• Hospital Vall d'Hebron: lead

Study Sites (1)

Institut de Recerca Hospital Vall d´Hebron

Barcelona, 08035, Spain

Location

Related Publications (18)

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  PMID: 16497592 BACKGROUND

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  PMID: 21508958 BACKGROUND

• Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005 Jun 10;308(5728):1635-8. doi: 10.1126/science.1110591. Epub 2005 Apr 14.

  PMID: 15831718 BACKGROUND

• Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11971-5. doi: 10.1073/pnas.1002601107. Epub 2010 Jun 21.

  PMID: 20566857 BACKGROUND

• Wells JM, Rossi O, Meijerink M, van Baarlen P. Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4607-14. doi: 10.1073/pnas.1000092107. Epub 2010 Sep 8.

  PMID: 20826446 BACKGROUND

• Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol. 2012 Feb 1;590(3):447-58. doi: 10.1113/jphysiol.2011.219691. Epub 2011 Nov 28.

  PMID: 22124143 BACKGROUND

• Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003 Feb 8;361(9356):512-9. doi: 10.1016/S0140-6736(03)12489-0.

  PMID: 12583961 BACKGROUND

• O'Hara AM, Shanahan F. Gut microbiota: mining for therapeutic potential. Clin Gastroenterol Hepatol. 2007 Mar;5(3):274-84. doi: 10.1016/j.cgh.2006.12.009.

  PMID: 17368226 BACKGROUND

• Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011 Mar;23(3):255-64, e119. doi: 10.1111/j.1365-2982.2010.01620.x. Epub 2010 Nov 5.

  PMID: 21054680 BACKGROUND

• Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012 Sep 13;489(7415):231-41. doi: 10.1038/nature11551.

  PMID: 22972296 BACKGROUND

• Guarner F, Bourdet-Sicard R, Brandtzaeg P, Gill HS, McGuirk P, van Eden W, Versalovic J, Weinstock JV, Rook GA. Mechanisms of disease: the hygiene hypothesis revisited. Nat Clin Pract Gastroenterol Hepatol. 2006 May;3(5):275-84. doi: 10.1038/ncpgasthep0471.

  PMID: 16673007 BACKGROUND

• Oh PL, Martinez I, Sun Y, Walter J, Peterson DA, Mercer DF. Characterization of the ileal microbiota in rejecting and nonrejecting recipients of small bowel transplants. Am J Transplant. 2012 Mar;12(3):753-62. doi: 10.1111/j.1600-6143.2011.03860.x. Epub 2011 Dec 7.

  PMID: 22152019 BACKGROUND

• Xie Y, Luo Z, Li Z, Deng M, Liu H, Zhu B, Ruan B, Li L. Structural shifts of fecal microbial communities in rats with acute rejection after liver transplantation. Microb Ecol. 2012 Aug;64(2):546-54. doi: 10.1007/s00248-012-0030-1. Epub 2012 Mar 21.

  PMID: 22430504 BACKGROUND

• Wu ZW, Ling ZX, Lu HF, Zuo J, Sheng JF, Zheng SS, Li LJ. Changes of gut bacteria and immune parameters in liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2012 Feb;11(1):40-50. doi: 10.1016/s1499-3872(11)60124-0.

  PMID: 22251469 BACKGROUND

• Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant. 2005 Jan;5(1):125-30. doi: 10.1111/j.1600-6143.2004.00649.x.

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• Fricke WF, Maddox C, Song Y, Bromberg JS. Human microbiota characterization in the course of renal transplantation. Am J Transplant. 2014 Feb;14(2):416-27. doi: 10.1111/ajt.12588. Epub 2013 Dec 26.

  PMID: 24373208 BACKGROUND

• Alegre ML, Mannon RB, Mannon PJ. The microbiota, the immune system and the allograft. Am J Transplant. 2014 Jun;14(6):1236-48. doi: 10.1111/ajt.12760. Epub 2014 May 19.

  PMID: 24840316 BACKGROUND

• Lu H, He J, Wu Z, Xu W, Zhang H, Ye P, Yang J, Zhen S, Li L. Assessment of microbiome variation during the perioperative period in liver transplant patients: a retrospective analysis. Microb Ecol. 2013 Apr;65(3):781-91. doi: 10.1007/s00248-013-0211-6. Epub 2013 Mar 17.

  PMID: 23504024 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Stool samples Portal nodes Periphereal blood

MeSH Terms

Conditions

Infections

Study Officials

• Itxarone Bilbao, PhD/MD

  Department of HPB Surgery and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)

  PRINCIPAL INVESTIGATOR

• Chaysavanh Manichanh, PhD/MD

  Physiology and Pathophysiology of the Digestive Tract, Institut de Recerca Vall d´Hebron, Barcelona (Spain)

  STUDY CHAIR

• Cristina Dopazo, PhD/MD

  Department of HPB Surgery and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

• Francisco Guarner, PhD/MD

  Department of Gastroenterology Disease, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

• Mireia Caralt, PhD/MD

  Department of HBP Surgery and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

• Lluis Castells, PhD/MD

  Department of Internal Medicine, Liver Unit, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

• Jose Luis Lazaro, MD

  Department of HBP Surgery and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

• Fernando Azpiroz, PhD/MD

  Department of Gastroenterology Disease, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

• Ramón Charco, PhD/MD

  Department of HBP Surgery and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant in HPB Surgery and Transplants

Study Record Dates

• First Submitted: August 18, 2014
• First Posted: August 22, 2014
• Study Start: January 1, 2016
• Primary Completion: August 1, 2021
• Study Completion: August 1, 2021
• Last Updated: August 4, 2021

Record last verified: 2021-08

Locations

ES (1)