Liver diseases associated with

inflammatory bowel disease

David Adams

Centre for Liver Research University of Birmingham and NIHR Biomedical Research Centre.

Extraintestinal Manifestations of inflammatory bowel

disease

Joints

•Type 1 and 2 Arthropathy•Orchard, Wordsworth and Jewell

•Ankylosing spondylitis

Liver

•Primary sclerosing cholangitis

•Autoimmune hepatitis

Eye

•Uveitis

•Iritis

•Episcleritis

Skin

•Erythema Nodosum

•Pyoderma Gangrenosum

Lung

• Bronchiectasis

• Bronchiolitis

• Interstitial lung disease

Broome U et al. Gut 1996

Chapman,R.W. Gut 1991

Diseases

associated with

active bowel

disease

Pyoderma gangrenosum

Pyoderma gangrenosum

Erythema nodosum

Episcleritis

Arthropathies

associated with IBDParallel IBD activity

Type 1 Pauciarticular

Ankylosing spondylitis

Independent of IBD

activity

Type 2 Polyarticular

Orchard & Jewell Gastro 1999

Autoimmune liver disease and IBD

PSC or autoimmune hepatitis • 3-10% of patients with IBD• >80% PSC patients have microscopic IBD

Broome et al 1995; Loftus et al 2005; Jorgensen 2012

PSC

T cell mediated destruction of hepatocytes

AIHPSC

• 15% risk of cholangiocarcinoma and CRC

• 36% die or progress to liver transplantation

• No effective treatmentGoode et al Hepatology 2018

The colitis of PSC has distinct features disease and runs a

course that is independent of liver disease

•PSC can develop after colectomy for UC

•UC can develop after liver transplant for PSC

Pan-colonic inflammation

High risk of colon cancer

Backwash ileitis

Right-sided

predominanceMild

inflammation

Rectal sparing Loftus et al Gut 2005;

Jorgensen KK 2011 IBD

Marelli 2011 Gut

Boonstra K IBD 2012

IBD PSC

Do mucosal lymphocytes drive liver disease ?

Hypothesis:

Gut activated lymphocytes in IBD enter the liver and contribute to

liver inflammation in PSC.

Trichinella spiralis new born larvae (NBL) and

the hepato-enteric immune response

Liver tolerance to

new borne larvae

Effector CD4 cells Effector CD4 cells No effector CD4 cells

IL-10 deficient

Severe Hepatitis to

new borne larvae

NBL

NBL NBL

Liver tolerance to

new borne larvae

Bliss,SK JI 2007

IL-10 deficient

UNDER THE RIGHT CONDITIONS T CELLS ACTIVATED IN THE GUT CAN

CAUSE LIVER DISEASE

In the absence regulatory T cells dysfunctional immune

regulation leads to immune mediated gut and liver disease

IL2Ra-/- mice develop autoimmune cholangiopathy and colitis

Willerford et al. Immunity 1995

Wakabayashi et al. Hepatology 2006

GWAS studies in PSC suggest defects in immune

regulatory genes including IL2RA

Melum et al Nat Gen 2011

Mesenteric lymph node Intestinal mucosal vessels

CCL25

CCR9

a4b7

MAdCAM-1

Gut-tropic T-cell

Stagg et al Eur J Immunol 2002

Mora, Eksteen et al Science 2006

KEY:

MAdCAM-1:

Mucosal Addressin Cell Adhesion

Molecule-1

VAP-1: Vascular Adhesion

Protein-1

Intestinal specific lymphocyte recruitment

Skin lymph nodeSkin vessels

CCL17 CCl28

CCR4 CCR10

CLA

E-selectin

Gut-tropic T-cell

Mesenteric lymph node

Intestinal mucosal vessels

Hepatic sinusoids

CCL25

CCR9

a4b7

MAdCAM-1

Gut-tropic T-cell

Trivedi et al. J. Autoimmunity 2013

Enterohepaticlymphocyte recirculation

PSC

CCL25MAdCAM-1

Eksteen et al J Exp Med 2004 Liaskou et al Gastro 2014

MADCAM-1 and CCL25 are detected in the PSC liver

0 20 40 60 80 100

CD LPLCD PBLNL LILN PBL

PBC LILPSC PBL

PSC LIL

20% of T cells in the liver have a gut phenotype

Bile duct

CCR9+CD3+ CD28-

Mesenteric lymph node

Intestinal mucosal vessels

Hepatic sinusoids

CCL25

CCR9

a4b7

MAdCAM-1

Gut-tropic T-cell

Trivedi et al. J. Autoimmunity 2013

KEY:

MAdCAM-1:

Mucosal Addressin Cell Adhesion

Molecule-1

VAP-1: Vascular Adhesion

Protein-1

CCL25

MAdCAM-1

Enterohepaticlymphocyte recirculation

PSC

VAP-1

What induces the liver to express gut homing

molecules in AIH/PSC?

VASCULAR ADHESION PROTEIN-1

VAP-1

(SSAO)

RGD motif

Endothelium

Lymphocyte

Amine

Aldehyde

NH3

H2O2

?

VAP-1:Ligand

interaction

VAP-1 is an endothelial adhesion molecule which recruits

effector cells to the liver AND an amine oxidase.

Amines from

food and wine

and bacteria

Salmi Science 1991; McNab Gastro 1996; Smith JEM 1998 Jalkanen and Salmi EMBOJ 2001

Weston et al J Clin Invest 2015

VAP-1 expression & enzyme activity is increased in

PSC liver

Palak J Trivedi et al. Gut 2018

RGD motif

Endothelium

Lymphocyte

Amine

Aldehyde

NH3

H2O2

?

NFkB Activation

VAP-1:Ligand

interaction

The enzyme activity of VAP-1 activates liver endothelium

TRANSCRIPTION OF

CHEMOKINES AND ADHESION

MOLECULES

Lalor Hepatology 2007; Liaskou Hepatology 2011

MADCAM-1

Methylamine feeding of VAP-1 transgenic mice

induces increased expression of endothelial

adhesion molecules including MADCAM-1

Liaskou et al Hepatology 2011

Lia Liaskou

Mesenteric lymph node

Intestinal mucosal vessels

Hepatic sinusoids

CCL25

CCR9

a4b7

MAdCAM-1

Gut-tropic T-cell

Trivedi et al. J. Autoimmunity 2013

CCL25

MAdCAM-1

Enterohepaticlymphocyte recirculation

PSC

VAP-1

What activates VAP-1 leading to expression of gut

homing molecules in the liver?

VASCULAR ADHESION PROTEIN-1

MAdCAM-1

Ethylamine

0 2000 4000 6000 80000

5

10

15

Concentration (mmol)

Ve

locity

(n

mo

l H2O

2/m

in)

Phenethylamine

0 500 1000 1500 20000

5

10

15

Concentration (mmol)

Ve

locity

(n

mo

l H2O

2/m

in)

Dopamine

0 100 200 300 4000

20

40

60

80

100

Concentration (mmol)

Ve

locity

(n

mo

l H2O

2/m

in)

Methylamine

0 500 1000 1500 20000

5

10

15

20

Concentration (mmol)

Ve

loci

ty (n

mo

l H2O

2/m

in)

Cysteamine

0 50 100 150 2000

20

40

60

80

Concentration (mmol)

Ve

loci

ty (n

mo

l H2O

2/m

in)

Benzylamine

0 200 400 6000

5

10

15

Concentration (mmol)

Ve

loci

ty (n

mo

l H2O

2/m

in)

What are the natural amine substrates that

activate VAP-1?

Kcat/Km: 2.7e+6 Kcat/Km: 4.5e+6 Kcat/Km: 5.1e+7

Kcat/Km: 3.8e+7 Kcat/Km: 5.4e+7 Kcat/Km: 2.6e+7

Trivedi et al. Gut 2018

Cysteamine

Cysteamine induces MADCAM-1 and increases mucosal lymphocyte adhesion to liver endothelium

Trivedi et al. Gut 2018

Adhesion of mucosal lymphocytesExpression of MADCAM-1

**

MA = Methyl amine

CA = Cysteamine

Cysteamine and mucosal inflammation

Colonic epithelium generates cysteamine via vanin-1

• Vanin-1 overexpression = increased cysteamine & colitis

– Cysteamine depletion abrogates colitis– Berruyer et al JEM 2006, Martin et al. 2004 J. Clin. Inv.

Cysteamine released by proteobacteria/firmicutes

Changes in the enteric microbiome in liver

disease

PSC-IBD versus IBD & controls:

– Reduced Prevotella & Roseburia

– virtual absence of Bacteroides

compared with IBD and controls.

– Increases in

– Proteobacteria Escherichia,

– Firmicutes Clostridia, Veillonella

– Quarashi et al Gut 2017.

• PSC:

– Firmicutes Veillonella increased– Kummen et al Gut 2016

Cysteamine released by proteobacteria/firmicutes

Escherichia, Salmonella, Vibrio, Helicobacter,

Veillonella, Clostridia

Mesenteric

lymph node

Intestinal mucosal vessels

Hepatic sinusoids

VAP-1

CCL25

CCR9

a4b7

MAdCAM-1

Gut-

tropic

T-cell

CCL25

MAdCAM-1

Enterohepatic

lymphocyte recirculation

VAP-1

Bacteria-derived amine substrate

NFkBH202

HSEC

MAdCAM-1

Trivedi and Adams 2013

INFLAMED GUT

And DYSBIOSIS

Portal vein

Blocking Lymphocyte Localization to the Gastrointestinal Mucosa as a

Therapeutic Strategy for Liver Disease and Inflammatory Bowel Diseases

Rodrigo Mora Gastroenterology 2011

Studies using vedolizumab to treat IBD and PSC

No Patients Outcome Population

Prospective controlled trials needed for proof of concept

Mesenteric

lymph node

Intestinal mucosal vessels

Hepatic sinusoids

VAP-1

CCL25

CCR9

a4b7

MAdCAM-1

Gut-

tropic

T-cell

CCL25

MAdCAM-1

Enterohepatic

lymphocyte recirculation

VAP-1

Bacteria-derived amine substrate

NFkBH202

HSEC

MAdCAM-1

Trivedi and Adams 2013

INFLAMED GUT

And DYSBIOSIS

Portal vein

Blockade of VAP-1 in PSC

Single arm, two-stage, multi-centre, phase II clinical trial

investigating safety and activity of BTT1023, a human

monoclonal antibody targeting vascular adhesion protein

(VAP-1), in the treatment of patients with primary sclerosing

cholangitis (PSC)

BUTEO

Mesenteric

lymph node

Intestinal mucosal vessels

Hepatic sinusoids

VAP-1

CCL25

CCR9

a4b7

MAdCAM-1

Gut-

tropic

T-cell

CCL25

MAdCAM-1

Enterohepatic

lymphocyte recirculation

VAP-1

Bacteria-derived amine substrate

NFkBH202

HSEC

MAdCAM-1

Trivedi and Adams 2013

INFLAMED GUT

And DYSBIOSIS

Portal vein

Hoel et al Sci Rep 2018

Dysbiosis & endothelial dysfunction

Faecal microbiota transplantation associated with

clinical response and a loss of cysteamine producing

proteobacteria in children with IBD

Safety, Clinical Response, and Microbiome Findings Following Fecal

Microbiota Transplant in Children With Inflammatory Bowel Disease.

Goyal A et al Inflamm Bowel Disease 2018

Donor Recipient 1 week 1 month 6 month

Proteobacteria

CREDITS

Collaborators• Kristiina Aalto, Marika Karikoski, Sirpa

Jalkanen, Marko Salmi (Turku)

• Mike Briskin (Merrimack Pharma)

• Uli von Andrian and Rodrigo Mora (Harvard)

• Dave Smith, Antero Kallio, Jani Vainio,

Biotie Therapies

• Mark Pallen (UEA)

THE UNIVERSITY OF BIRMINGHAMBirmingham

Palak Trivedi

Lia Liaskou

Trish Lalor

Chris Weston

Allister Grant

Bertus Eksteen

Alice Miles

Nabil Quarashi

Gideon Hirschfield

Stefan Hubscher

European Commission

The patients for donating samples and

our surgeons for collecting them