4. Why we talk about Gut and
Liver ?
There is tight relationship
between the gut and liver
Embryological Anatomical Physiological
5.
6.
7. This axis refers to the reciprocal
regulation causing an
integrated system of-
Microbiota Diet
Genetic
background
Environm-
ental
factors
Immune homeostasis-
foods/
commensals/drugs/metabolites
Tolerance breakdown-
pathogenic organisms
8. As a frontline organ facing the
influx from gut mucosal barriers,
the liver continuously maintains
the balance
Hepatic
Kupffer
cells
MAIT
cells
HSECs Treg cells
Decreased
Cytokines
9. The protective
function of the
gut and liver
Gut barrier
Hepaetic
Kuffer cells
Biliary
MAIT cells
Vital for a
harmless
cooperation
between the liver
and the gut
Trinity of Barriers
10. Gut Barrier
The gut barrier is a functional
unit which prevents bacterial
adhesion and controls
paracellular trafficking.
11. A new entity has been recently discovered on the gut defense line, the gut-vascular
barrier
It prevents the translocation of the
bacteria/products from the gut to the
bloodstream
It is formed by the endothelial cells linked by
tight junctions in close contact with pericytes
and fibroblast
12. The disruption of the gut
barrier allow endotoxin,
Gram negative bacteria
and LPS, peptidoglycan
or
lipoteichoic acid to
translocate to the portal
system which
triggers inflammatory
responce
Endotoxin,
GNB and LPS,
peptidoglycan
or
lipoteichoic
acid
13. Hepatic Immunological Response to Gut Permeability
Small part of microbial associated
molecular patterns (MAMPs) eludes
the barrier and reaches the liver
parenchyma
The gut-barrier prevents the
translocation of microbial antigen into
the portal circulation
This is carried out by
Kupffer cells
Detected and destroyed
before reaching the
systemic circulation
In physiological settings
there is state of tolerance,
reducing the recruitment and
activation of T cells
which control effector T cells
proliferation and
their cytokine secretions
14. Protective barrier has been shown also on the biliary side and it is
represented by the Mucosal Associated Invariant T (MAIT) cells
These T cells express a conserved TCR alpha chain Va7.2-Ja33 and recognize vitamin B
metabolites of microbial origins via the MHC-related molecules
MAIT cells express chemokine receptors CCR6 and CXCR6 homing them close to the biliary
epithelial cells which express and secrete CCL20 and CXCL16
When exposed to bacterial products, MAITs degranulates, releasing IFN-gamma to protect
the biliary epithelium
MAIT cells
15. The failure of the gut barrier in
preventing the translocation of
MAMPs exposes the liver to an
increased volume of immune
stimuli
Hepatic Kupffer cells, HSECs and
biliary epithelial cells recognize
MAMPs via PRRs
Shapes the immune
liver milieu toward
an inflammatory
status
A “leaky gut”, alongside a
reduction in MAMPs
tolerance acts as central
player in chronic
inflammation in liver diseases
18. PSC in IBD : Indian Multicenter Data (n=48 PSC ,
12168 UC)
12168,
99.61% 42,
0.34%
6, 0.05%
48, 0.39%
IBD Patients without PSC UC Patients with PSC CD Patients with PSC
Sood A , et al in review
19. IBD whether UC or CD
• Is virtually Colonic,
• More right sided involvement
• Rectal Sparing
• Backwash Ileitis
PSC often runs a subclinical
course in female patients
and Crohn’s disease
20. The pathophysiology of PSC is unknown
However it is
suggested that there
is an autoimmune
component given its
association with the
presence of
autoantibodies such
as: ANCA, ANA
and ASMA
Ineffectiveness of
immunosuppressive
drugs.
But this factor has been questioned
There is a higher
prevalence of PSC in
men (contrary to most
immune-mediated
diseases more common
in females)
21. Another theory is that PSC is
a consequence of the
sustained inflammatory
response
as a product of bacterial
and viral translocation,
typical of IBD.
aberrant expression of gut
homing molecules such as
CCL25 and MadCAM-1 in
PSC liver, leading
to homing of CCR9 and
a4b7 expressing gut-primed
CD8 memory T-cells into
the liver
The aberrant gut
homing lymphocyte
hypothesis
22.
23.
24. CAUSAL ROLE FOR
THE GUT
MICROBIOME
Since the gastrointestinal tract harbors a rich and dense
microbiota, which is altered in IBD, a potential role of gut
microbiota for PSC has been proposed
Many observational studies have found that the gut
bacterial alpha diversity is lower in PSC than healthy
controls (HCs)
Overall bacterial community is different in PSC/PSC-IBD
A few bacterial taxa are fairly consistently altered in
the stool of PSC patients, Veillonella, in particular,
was higher in the stool of PSC patients than HCs in all
the studies in
25.
26. Genetic Risk
Studies have shown an increased association of PSC
and specific HLA haplotypes, raising the possibility of
a genetic risk in the development of this disease
Both HLA histocompatibility complex class I and class
II have been described in the setting of PSC
Susceptibility to PSC has been associated with HLA-
B8, -DR3, -DR2, -DR6, and -DQ
31. Clinical Gastroenterology and Hepatology 2020;18:179–187
102 patients on Vedolizumab
• No evidence for a biochemical
response to vedolizumab
• Vedolizumab seems to be safe
in patients with PSC and IBD
32. MANIPULATING GUT
MICROBIOME
WITH
VANCOMYCIN IN PSC
The microbiota plays an important role in the
pathogenesis and the progression of PSC.
Antibiotics, such as vancomycin, was utilized in clinical
trials to modify intestinal microbiota flora.
Trial data demonstrated that vancomycin could improve
liver biochemistry in PSC patients
33. There was
improvement in LFT
The convergence of both agents on
antibacterial activity on clostridial
organisms, the bacteria
primarily responsible for bile acid
metabolism, is postulated mode of
action for the therapeutic effects seen
with these agents in PSC
34. POTENTIAL ROLE OF
REGULATORY
T CELL THERAPY IN
PSC
IL-2 infusion
therapy
expand Tregs
The increase in Tregs result in
reduction of pro-
inflammatory IL-17 cytokines
and increase in anti-
inflammatory IL-10
production by hepatic
lymphocytes
35. Low dose IL-2 infusion
therapies have been
carried out in
human autoimmune
diseases (e.g T1DM, SLE)
and a majority of findings
resulted in a decrease in
disease severity
Although this has not
yet been tried in
autoimmune liver diseases
36. The final common pathway in
IBD and
its extra-intestinal complications
is a destructive
influx of inflammatory cells
37. But why particular tissues are
targeted and how
inflammatory complications
can occur many years after
the intestinal inflammation
has resolved
38. Extra-intestinal
expression of endothelial
adhesion molecules that
are usually restricted to
the gut leads to the
recruitment of mucosal
memory and/or effector
T cells
Because memory T cells are long-
lived, extra-intestinal disease may
develop many years after clinically
apparent inflammation in the bowel
This also explains why extra-intestinal
disease can develop in patients with
sub-clinical IBD or even in patients
whose colons have been surgically
removed
39. Non-Alcoholic Fatty Liver Disease
There are some emerging data suggesting an increase in prevalence of NAFLD in
IBD patients compared to the general population
Some have attributed this to a general increase of metabolic syndrome or the
increasingly successful IBD therapy in achieving remission and improved nutritional
status
However, the pathogenesis of NAFLD in the IBD population may be more
complex involving factors, such as chronic inflammation, drug-induced
hepatotoxicity, steroid exposure, malnutrition and gut dysbiosis
40.
41. Cholelithiasis
Parente F, Pastore L, et al; Incidence and risk factors for gallstones in patients with inflammatory bowel disease: a large casecontrol study. Hepatology 2007
Patients with CD have double the risk of developing cholelithiasis while UC show no
difference
A prevalence of 11%-34% has been estimated in CD.
The involvement of the ileum leads to a reduction in the reabsorption of bile salts, with
the consequent alteration in the enterohepatic circulation and secondarily an increase in
biliary cholesterol saturation
The risk is related to the degree and extent of ileal involvement and the number of
intestinal resections
43. IBD predisposes to
thrombosis by inducing
episodes of acute and chronic
intestinal inflammation,
leading to a
.
Clinical risk factors, such as
,
, and placement
of
also contribute to thrombotic
risk.
44. Hepatitis B Virus Reactivation
Immunosuppressive therapies has been associated with HBV reactivation
All candidates for immunosuppressive therapy should be screened for HBsAg, anti-
HBs and anti-HBc prior to immunosuppression treatment
The risk of HBV reactivation hasbeen classified as high (>10%), moderate (1–10%) or
low (<1%)
Vaccination of HBV seronegative patients is recommended (4 doses (2ml) at 0, 1, 2,
and 6 months)
48. Granulomatous Hepatitis
It is an infrequent manifestation in patients with IBD, being mainly described in CD
Has a good prognosis, it improves with the control of the CD
A prevalence of less than 1% has been reported and is characterized by the presence
of non-caseating hepatic granulomas
49.
50.
51. Núñez F P, Hepatobiliary manifestations in inflammatory bowel disease: A practical approach. World J
Hepatol 2022
52. Intimate
relationship-
Embryological,
Anatomical
& Physiological
Continuous
flow of
commensals,
food antigens &
xenobiotics to
the liver
The protective
function
Gut barrier
Hepaetic Kuffer
cells
Biliary MAIT
cells
Mucosal
memory
T cells are
recruited to the
liver
Aberrant
expression of
gut-homing
molecules,
MADCAM1
and CCL25
Disruption of
the gut barrier
allow endotoxin,
GNB and LPS
to translocate to
the portal
system which
triggers
inflammatory
responce
