Project details

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Biliary atresia as a model for understanding the gut-liver axis

Keywords:
biliary atresia Gut Microbiota Composition gut-liver acis

Researchers:
dr. J.B.F. Hulscher
drs. D.B.E. van Wessel

Nature of the research:
Prospective cohort study

Fields of study:
surgery pediatrics microbiology

Background / introduction
In Biliary atresia (BA), an as yet unknown event induces bile duct obstruction within weeks after birth: first there is bile flow from liver to gut, then there is complete bile duct obstruction preventing bile flow, which is reversible surgically. This operation, the Kasai hepatoportoenterostomy, succeeds in ~50%. When bile flow cannot be restored, liver transplantation is inevitable. However, even in patients in whom bile flow is restored, liver disease progresses in ~50%, making transplantation necessary. Overall, some 70% of patients with BA will undergo liver transplantation in childhood (1-4).

The liver protects the body from bacteria and bacterial products that have crossed the gut barrier. Gut barrier disruption enhances (detrimental) bacterial exposure of the liver, while the liver influences gut microbiota and gut wall defenses via bile secretion and IgA production. Elucidating this reciprocal relation between bile, gut microbiota and gut barrier is urgently needed. Not only for the few BA patients who need liver transplantation in childhood, not only for the many adult patients with liver disease who suffer (and sometimes die) from severe gut-derived infections, but mainly for the multitude of patients with diseases like diabetes and atherosclerosis in whom gut-liver axis alterations are present (5-10).

While animal models are available, vigorous human data investigating the in-depth physiologic relation between bile, gut microbiota and gut barrier is virtually impossible because obtaining the essential human tissues is difficult. Human data are essential, as animal models can never completely substitute human data (e.g. because gut microbiota differ). BA offers an original and unique ‘model-disease’ to study the reciprocal effects of bile on gut wall and gut barrier, offering longitudinal data which is otherwise unobtainable yet essential for a fundamental understanding of the gut-liver axis as well as for therapy development for BA and other diseases associated with disturbed gut-liver axis.
Research question / problem definition
To confirm that in BA there is a ‘leaky gut’ leading to detrimental exposure of different organs to gut-derived products and that this leaky gut is due to changes in bile and/or microbiota.
Workplan
Samples are taken before, during and after the Kasai operation. Before and after the operation, blood and stool samples are collected. During the operation, jejunal, liver and lymph node biopsies are taken. During follow-up, blood and stool samples are taken at the outpatient clinic. The student will perform sampling of these materials. The student will be responsible for patient inclusion as well.
The student is allowed to choose the research project he/she likes. There are multiple possibilities for research projects. All will consist of a combination of clinical and laboratory work, thus offering the student a profound insight in translational science.
References
(1) Davenport M, De Ville de Goyet J, Stringer MD, Mieli-Vergani G, Kelly DA, McClean P, et al. Seamless management of biliary atresia in England and Wales (1999-2002). Lancet 2004 Apr 24;363(9418):1354-1357.

(2) de Vries W, de Langen ZJ, Groen H, Scheenstra R, Peeters PM, Hulscher JB, et al. Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008. J Pediatr 2012 Apr;160(4):638-644.e2.

(3) Verkade HJ, Bezerra JA, Davenport M, Schreiber RA, Mieli-Vergani G, Hulscher JB, et al. Biliary atresia and other cholestatic childhood diseases: Advances and future challenges. J Hepatol 2016 Sep;65(3):631-642.

(4) de Vries W, Homan-Van der Veen J, Hulscher JB, Hoekstra-Weebers JE, Houwen RH, Verkade HJ, et al. Twenty-year transplant-free survival rate among patients with biliary atresia. Clin Gastroenterol Hepatol 2011 Dec;9(12):1086-1091.

(5) Hartstra AV, Bouter KE, Backhed F, Nieuwdorp M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 2015 Jan;38(1):159-165.

(6) Cani PD. Gut microbiota and obesity: lessons from the microbiome. Brief Funct Genomics 2013 Jul;12(4):381-387.

(7) Haque TR, Barritt AS,4th. Intestinal microbiota in liver disease. Best Pract Res Clin Gastroenterol 2016 Feb;30(1):133-142.

(8) Quigley EM. Primary Biliary Cirrhosis and the Microbiome. Semin Liver Dis 2016 Sep;36(4):349-353.

(9) Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut 2016 Oct 8.

(10) Victor DW,3rd, Quigley EM. The Microbiome and the Liver: The Basics. Semin Liver Dis 2016 Sep;36(4):299-305.
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