Human Microbiota and Liver Transplant

Infection Clinical Trial

Official title:

Prospective Study To Characterize The Human Microbiota In Liver Transplantation And Its Impact On Early Outcome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02223468
• Other study ID #: Microta.LT.14
• Status: Completed
• Start date: January 2016
• Est. completion date: August 1, 2021

Study information

• Verified date: August 2021
• Source: Hospital Vall d'Hebron
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: August 1, 2021
• Est. primary completion date: August 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 68 Years

Eligibility

Inclusion Criteria:

• First liver transplant

• Patients aged 18-70 years

• Able to consent and agree in participate in the current study for one year

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

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

Locations

Country	Name	City	State
Spain	Institut de Recerca Hospital Vall d´Hebron	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Vall d'Hebron

Country where clinical trial is conducted

Spain, 

References & Publications (18)

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. Review. — View Citation

Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J; MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M'rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P. Enterotypes of the human gut microbiome. Nature. 2011 May 12;473(7346):174-80. doi: 10.1038/nature09944. Epub 2011 Apr 20. Erratum in: Nature. 2011 Jun 30;474(7353):666. Nature. 2014 Feb 27;506(7489):516. — View Citation

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. — View Citation

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. Epub 2005 Apr 14. — View Citation

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. — View Citation

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. Review. — View Citation

Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003 Feb 8;361(9356):512-9. Review. — View Citation

Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006 Feb 24;124(4):837-48. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

O'Hara AM, Shanahan F. Gut microbiota: mining for therapeutic potential. Clin Gastroenterol Hepatol. 2007 Mar;5(3):274-84. Review. — View Citation

Oh PL, Martínez 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. — View Citation

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. — View Citation

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. Review. — View Citation

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 1:4607-14. doi: 10.1073/pnas.1000092107. Epub 2010 Sep 8. Review. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Incidence of biopsy proven acute cellular rejection	If liver dysfunction is observed, percutaneous liver biopsy will be performed and histological severity will be searching following the Banff criteria	Evaluation at 3rd, 6th, 9th and 12th months post-trasplant
Secondary	Incidence of post-transplant infection requiring antibiotherapy (oral or endovenous)		Evaluation at 3rd, 6th, 9th and 12th months post-trasplant
Secondary	Incidence of Diabetes Mellitus de novo post-transplant		12 months post-trasplant
Secondary	Incidence of Obesity (BMI=30 kg/m2) post-transplant		12 months post-transplant
Secondary	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
Secondary	Patient and graft survival rates		Evaluation at 3rd, 6th, 9th and 12th months post-trasplant