1. What are IBD 2. Causes of IBD 3. Signs/ symptoms & complications of IBD 4. Crohn's disease- pathophysiology 5. Ulcerative colitis- pathophysiology 6. Preclinical models for IBD 7. DSS induced IBD 8. Terminalia chebula extracts

1. INFLAMMATORY BOWEL
DISEASES
PRIYANSHA SINGH (PC2021-14/226)
M.S.- PHARMACOLOGY & TOXICOLOGY
NIPER GUWAHATI

2. HISTORICALACCOUNTS OF I.B.D.
INTRODUCTION TO INFLAMMATORY BOWEL DISEASES
PATHOGENESIS OF I.B.D. (UC and CD)
CROHN’S DISEASE v/s ULCERATIVE COLITIS
PRECLINICAL MODELS FOR I.B.D.
DSS INDUCED MODEL FOR COLITIS
MOLECULAR TARGETS FOR I.B.D.
CURRENT THERAPEUTIC REGIME FOR I.B.D.
BENEFITS OF TERMINALIA CHEBULA IN I.B.D
CONCLUSION
REFERENCES
CONTENTS

3. HISTORICALACCOUNTS OF I.B.D.

4. Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic and recurrent inflammatory
disease that mainly relates to the intestinal tract.
Crohn’s disease is similar to UC, both of which have been classified as chronic IBD and which cause digestive disorders and
inflammation in the gastrointestinal tract.
Some of the symptoms of CD and UC include diarrhea, abdominal pain, rectal bleeding, and weight loss. They are mainly
characterized by inflammation. Both the diseases may occur in adolescents and adults and affect men and women equally. Despite
the similarity between the symptoms of these two diseases, there are some differences between the symptoms of CD and UC.
The exact cause of IBD remains indistinct, but it is generally accepted that its etiopathology is multifactorial, involving genetic
predisposition, mucosal barrier dysfunction, disturbances in the gastrointestinal microbiota, dysregulated immune responses,
environmental, and lifestyle factors.
The term inflammatory bowel disease (IBD) describes a group of disorders in which the intestines become inflamed. It has often been
thought of as an autoimmune disease, but research suggests that the chronic inflammation may not be due to the immune system attacking
the body itself. Instead, it is a result of the immune system attacking a harmless virus, bacteria, or food in the gut, causing inflammation that
leads to bowel injury.
INTRODUCTION TO INFLAMMATORY BOWEL DISEASES

5. Inflammatory Bowel Diseases (the reaction continues without control and damages the
intestinal wall, leading to diarrhea and abdominal pain.)
Environmental
Triggers
Immune System Disturbance
(bacteria, viruses, antigens --
triggers the body's immune
system to produce an
inflammatory reaction in the
intestinal tract. )
Genetic
Predisposition (gene
associated with
Crohn's disease, the
NOD2 gene)
ETIOLOGY OF I.B.D.

6. SYMPTOMS OF I.B.D.
Abdominal
cramps and
pain, Bloating
Diarrhea that
may be bloody
& Bowel
urgency
Severe urgency
to have a bowel
movement,
Fever, Weight
loss, Loss of
appetite
Iron deficiency
anemia due to
blood loss

7. COMPLICATIONS OF I.B.D.
Profuse intestinal bleeding
from the ulcers
(Haemorrhage of the
bowel)
Perforation, or rupture of
the bowel
Narrowing
(stenosis/stricture) and
obstruction of the bowel;
found in Crohn's
Fistulae (abnormal passages)
and perianal disease, disease
in the tissue around the anus.
These conditions are more
common in Crohn's than in
ulcerative colitis.
Toxic megacolon, which is an
extreme dilation of the colon
that is life-threatening. This is
associated more with
ulcerative colitis than Crohn's.
Malnutrition
Increases the risk of colon
cancer.
Abscess formation
IBD can also affect other
organs, someone with IBD
may have arthritis, skin
conditions, inflammation of
the eye, liver and kidney
disorders, or bone loss.
Of all the complications
outside the intestines,
arthritis is the most
common.
Joint, eye, and skin
complications often happen
together.
Lymphadenopathy

8. PATHOPHYSIOLOGICAL OVERVIEW
OF I.B.D.
Both Crohn’s disease & Ulcerative colitis
share a common pathophysiology
Due to Impaired barrier function (increased
epithelial permeability) there is an increased
entry of commensal bacteria (antigen sampling in
lumen)
Translocation of microbial product, hence
activating immune cells.
Activation of immune cells stimulates the release of
Cytokines, TNF-a, IL-1 and IL-6 which results in chronic
inflammation and in the long run causes local and systemic
complications of IBD

9. Fig. 1- Pathophysiology behind I.B.D.

10. Fig. 2- A comparison between normal conditions v/s IBD

11. Increased Immune Response
Angiogenesis
Panneth cell necrosis
TNF-a/ TNFR
Release of protease- myofibril induced tissue destruction
in mucosal layer of intestine
Fig. 3- Result of TNF- a release aggravating IBD

12. CROHN’S DISEASE
 Crohn’s disease is one of the 2 major forms of IBD. Inflammation caused due to CD may effect any part of GIT tract, but it most
commonly involves the end of the small bowel (ileum) & the beginning of the colon.
 The inflammation is not continuous, inflamed segments are usually interrupted by normal healthy tissues. Most people experience
recurrent flares when the disease is active followed by symptom free periods of remission (skip lesions).
 CD is a Th1 cell-mediated disorder. Small bowel inflammation in CD exhibits an increased level of proinflammatory cytokines
such as interferon-gamma (IFN-γ) and IL-17A (produced by Th1 and Th17 cells, respectively)

13. CROHN’S DISEASE
Most people experience
recurrent flares when the
disease is active followed by
symptom free periods of
remission (skip lesions).
Symptoms may differ
according to the different
parts of the digestive tract
that are effected.
Most common signs
include- Diarrhea,
Abdominal pain/ tenderness,
loss of appetite, weight loss,
fatigue and fever etc.
Blood in stools
occur when the
colon is
involved.
Nausea/ vomiting occurs
when the stomach or the
first part of the small
intestine is effected.
About 1/3rd of patients
present with perianal
disease including abscess,
fistula & ulcers.
Extra-intestinal
manifestations (predominant
in children who also show
growth retardation)- joint,
skin and eyes

14. CROHN’S DISEASE
Inflammation in Crohn’s disease extends to the entire thickness of the intestinal wall.
Deep lesions in the mucosal wall often occur with areas of mucosal swelling creating a characteristic cobblestone
appearance.
Extensive inflammation may cause thickening of the bowel wall & hypertrophy of mesenteric fat wrapping around the
intestine.
Intestinal wall thickening together with scar formation, may block the flow of digestive content leading to bowel
obstruction. Ulcers can extend through bowel wall and form tunnels (fistulas) which may connect to the other loops of the
intestine, to the abdominal organs, muscles and even skin. A fistula may become infectious & form abscesses which can be
life threatening if not treated.
In longer term Crohn’s disease may increase the risks for colon cancers

15. Fig. 4- The uptake of luminal micro-flora stimulates APCs (e.g., dendritic cells and macrophages) which in turn produce proinflammatory
cytokines such as TNF-α, IL-6, and IL-23. Activated APCs facilitate subsequent differentiation of naïve CD4+ Th cells into Th1 and Th17 via
expression of master transcription factors. Inside the high endothelial venule, binding of α4β7-bearing lymphocytes to MAdCAM-1 causes entry
of more T cells into the lamina propria.

16. PATHOPHYSIOLOGY OF CROHN’S DISEASE

17. ULCERATIVE COLITIS

18. COMPLICATIONS OF ULCERATIVE COLITIS
Complications include the increased risk for colon cancer, toxic/ fulminant colitis, toxic megacolon (severe
violent diarrhea, high fever, abdominal pain and signs of peritonitis).
Toxic colitis results into the inflammation reaching upto the smooth muscle layer of the intestinal wall thus
resulting in the paralysis of colon muscle which may lead to colon dilatation and perforation

19. Fig. 5- Pathophysiology of Ulcerative Colitis

20. PATHOPHYSIOLOGY OF ULCERATIVE COLITIS

21. Interleukin (IL)-13 produced by T
helper type 2 (Th2) cells and non-
classical natural killer T cells (NKT
cells) also mediates UC as it
synergizes with tumor necrosis factor
alpha (TNF-α) to regulate the
expression of genes responsible for
the formation of tight junction entero-
epithelial cells.
IL-13 also disturbs the
membrane integrity by
increasing the rate of cell
apoptosis (which intensifies
upon exposure to TNF-α), and
by changing the protein
composition of the tight
junctions. An impairment of
tight junctions increases gut
permeability, leading to an
enhanced influx of luminal
antigens.
Antigen-presenting cells (APC) such as
macrophages and dendritic cells become
activated upon recognizing non-
pathogenic bacteria (commensal
microbiota) through Toll-like receptors
(e.g., Toll-like receptor 2 (TLR2) and
TLR4)
Activated APCs in turn
initiate differentiation
of naïve CD4+ (cluster
of differentiation 4) T-
cells into different
subsets of effector T
helper cells such as
Th2, Th9, and
regulatory T cells
(Treg) in UC.
In the inflamed lamina propria of
UC patients, the expression of
IL-4, which is a signature
cytokine of Th2 cells, is
dominated by high-level
expression of other Th2-
associated cytokines such as IL-5
and IL-13, and the Th2 master
transcription factor GATA
binding protein 3 (GATA3).
Thus, UC is predominantly a
Th2-mediated immune disorder,
but considering the low-level
expression of IL-4, the role of
Th2 cells as a whole in UC
remains inconclusive. IL-9-
producing Th9 cells are also
associated with UC as they
prevent mucosal wound healing
and disrupt protective functions
of the mucus layer.
High levels of mucosal
addressin cell adhesion
molecule-1 (MAdCAM-1)
causes increased
recruitment of gut-
associated lymphocytes to
healthy gastrointestinal
tract and sites of
inflammation, implicating
its role in the pathogenesis
of IBD
PATHOPHYSIOLOGY OF ULCERATIVE COLITIS

22. ULCERATIVE COLITIS v/s CROHN’S DISEASE
PARAMETER ULCERATIVE COLITIS CROHN’S DISEASE
ONSET Acute or Subacute Insidious
EXTENSION Affects only the colon Can affect any part of the GIT from the mouth to anus
RECTAL INVOLVEMENT Always Rare
DISTRIBUTION OF
DISEASE
Continuous areas of inflammation Patchy areas of inflammation
SKIP LESIONS Absent Present
COBBLESTONE
APPEARANCE
Absent Present
DEPTH OF INFLAMMATION Shallow, mucosal May be transmural, deep into the tissues
DIARRHEA Bloody Usually not bloody
ABDOMINAL MASS Absent May be present
FISTULA FORMATION Rare Common
BILE DUCT INVOLVEMENT Higher rates of PSC Lower rates of PSC
CANCER RISK Higher than Crohn Lower than UC
SMOKING Lower risk for smokers Higher risk for smokers

23. ULCERATIVE COLITIS v/s CROHN’S DISEASE

24. PRECLINICAL MODELS FOR I.B.D.
IN VITRO
MODELS
FOR I.B.D.
Caco-2 cell
line
HT29 cell
line
Organoids
Co-culture
of
Caco-2/HT2
9-MTX
T84 cell
line

25. DSS INDUCED ULCERATIVE
COLITIS IN MICE
 DSS is induced in mice is of a concentration ~ 3-5% DSS (w/v) (36,000- 50,000 Da) is
added to the drinking water for a period of 5-8 successive days. In rats the concentration
is almost the same (2-5% DSS w/v) with duration upto 9 days. The animal should
develop acute/ chronic colitis depending upon the dosing and the frequency.
 Body weights may slightly increase during the first three days and begin to decrease
gradually with the initiation of bleeding. There is no hard and fast rule that DSS should
be given for 7 days, rather it is up to the investigator to determine when mice should be
sacrificed based on significant body weight loss and bloody diarrhea.
 ADVANTAGE- DSS model is one of the most widely used ones amongst all in vivo
preclinical models reason being chronic colitis induced by DSS resembles the clinical
course of human ulcerative colitis- features such as cryptitis and crypt abscesses due to
transepithelial neutrophil migration and also because of its simplicity plus its
reproducibility. As there are no special skills required for DSS administration,
investigators can easily employ multiple groups to test disease susceptibility between
genetic backgrounds or evaluate the efficacy of prophylactic or therapeutic strategies
 In optimal conditions, disease induction occurs within 3-7 days following DSS
administration. During this period, severe colonic bleeding occurs, mimicking the
superficial inflammation seen in ulcerative colitis. Fig. 6- DSS induced damage

26. HOW DOES DSS INDUCE COLITIS IN
PRECLINICAL MODEL
DSS
Impaired cytoskeletal structure
of colonic epithelium
Mitochondrial dysfunction
Infiltration of inflammatory cells
Increased oxidative stress & reduction of anti-
oxidative property
Induction of cell cycle arrest and apoptosis
COLITIS
Fig. 7- Summarized DSS colitis model

27. PATHOPHYSIOLOGY OF DSS INDUCED COLITIS
 Induction of indirect intestinal inflammation due to epithelial injury limited to the gut mucosa—disruption of the epithelial monolayer
lining causes the entry of gut microbiome and antigens followed by immune cell activation in the underlying tissues.
 Disease manifestations: weight loss, bloody diarrhea, colon shortening, crypt abscesses are formed; symptoms in the large intestines are
more pronounced than in the small intestines.
 Immune cells: lesions infiltrated by immune cells such as neutrophils and macrophages near the damaged segment; switches from Th1-
Th17-mediated acute inflammation to Th2-mediated in chronic colitis exhibiting Th1/Th2 cytokine profile changes.
 Cytokine and Chemokines: increased TNFα, IL-6, IL-17, and Keratinocyte Chemoattractant (KC) in the acute state; increase in IL-4, IL-
10, and concomitant decrease in TNFα, IL-6, IL-17; increase in myeloperoxidase activity.
Pathways involved- activation of NF-kB and JAK- STAT pathways for activation of pro- inflammatory genes facilitating the release of
iNOS, COX-2, IL-6 and TNF-a. and DSS also stimulates the increase in oxidative stress which further results in cell injury and
inflammation

28. PATHOLOGICAL FINDINGS OF DSS INDUCED
COLITIS
Fig. 8- Eight week old C57BL6 mice were given 2.5% DSS in drinking water for 7 days. Control mice were given water only. On day 8,
mice were sacrificed and monitored for colitis. A. Gross picture of colons. B. Endoscopic examination of colons. C. H&E stained colonic
sections. Arrows indicate: 1. Shortened and bleeding colons, 2. Enlarged spleen, 3. Superficial inflammation, 4. Epithelial erosion and
immune cell infiltration in DSS-treated mice. There is also a difference in body weight due to the administration of DSS.

29. Fig. 9- Imbalance created by DSS in mucosal layer and epithelium

30. Fig. 10- Pathways followed by DSS as it gets
absorbed into the intestine

31. ROLE OF Terminalia chebula IN I.B.D.
Manish K. Gautam et. al. performed a preclinical experiment to evaluate healing effect of 50% ethanolic extract of Terminalia
chebula fruit pulp (TCE) on trinitrobenzene sulfonic acid (TNBS, intra-colonic route) induced colitis in rats.
 TCE (600 mg/kg, oral) was studied in TNBS-induced colitis for its effects on fecal output, food and water intake and body weight
changes, histology, antibacterial activity and levels of free radicals (nitric oxide and lipid peroxidation), antioxidants (superoxide
dismutase; catalase and reduced glutathione) and acute inflammatory marker (myeloperoxidase) in colonic tissue.
TNBS administration increased colonic mucosal damage and inflammation (macroscopic and microscopic) and stool output but
decreased body weight which was reversed by TCE treatment.
TCE showed significant antibacterial activity and enhanced the antioxidants but decreased free radicals and myeloperoxidase
activities affected in TNBS colitis.
Thus, Terminalia chebula dried fruit pulp extract healed colitis by promoting antioxidant status and decreasing intestinal bacterial
load, free radicals and myeloperoxidase responsible for tissue damage and delayed healing.

32. RESULTS OF Terminalia chebula ON I.B.D.
Decrease in fecal output on administration of TCE Increase in body weight on administration of TCE
Effects of TCE on TNBS-induced rat colonic mucosal damage score, weight and adhesions.

33. HISTOLOGICAL RESULTS OF Terminalia chebula ON I.B.D.
Histology of colon of NS rats showed normal and clear structure with intact mucosa, submucosa and muscularis externa. TNBS colitis rats showed eroded mucosa,
crypt destruction with severe cryptitis, lympho-plasmacytic infiltrate and transmural inflammation while, TNBS-induced colitis rats treated with TCE or SS showed
improvement in the structures with near intact lamina propria with mild lymphoplasmacytic infiltrate and submucosa with mild lymphomononuclear aggregate.
Histolgical section of rat colon stained with H & E stain (x100). (a) NS+CMC showing normal structure and clear with intact mucosa and sub mucosa. (b)
TNBS+CMC showing ulcerated and eroded mucosa shown by white arrow, crypt destruction with severe cryptitis shown by yellow arrow, lymphoplasmacytic
infiltrate shown by red arrow and transmural inflammation (predominantly-lymphocytes and plasma cells) shown by brown arrow. (c) TNBS+ TCE showing
regenerative mucosa with mild crypt distortion and mild lympho-plasmacytic infiltrate in the lamina propria with oedematous submucosa and (d) TNBS+ SS
showing intact mucosa with minimal lymphoplasmacytic infiltrate in the lamina propria

34. ANTIOXIDANT & ANTIMICROBIAL
ACTIVITY OF TCE
 Effect on free radicals- TNBS enhanced both LPO and NO expressed as nmol/mg protein compared to NS (normal saline) rats. TCE and SS showed reversal
of levels of both LPO and NO near to the NS level.
 Effect on antioxidants- TNBS treated animals showed significant decrease in SOD, CAT and GSH levels in the colonic mucosal incubates when expressed as
mU (SOD and CAT) or nmol (GSH) per mg protein compared to NS group. TCE and SS treatments reversed the above changes in SOD, CAT and GSH levels
in TNBS-induced colitis near to normal NS group.
 Effect on myeloperoxidase- TNBS treated animals showed significant increase in MPO level in the colonic mucosal incubates when expressed as mU/ mg
protein compared to normal NS rats. TCE and SS reversed the above changes in MPO level near to normal NS group.
 TCE did not show any acute toxicity manifestation like increased motor activity, salivation, colonic convulsion, coma and death in mice, observed up to a
period of two week.
Antimicrobial susceptibility and MIC- In-vitro antimicrobial susceptibility test against gram negative intestinal bacteria like E. coli, S. boydii, S. sonnie and S.
flexneri with TCE (200 mg/ml) as indicated by zone of inhibition >10 mm.
The above effects of TCE could be attributed to various active constituents namely phenolic compounds, triterpinoids, tannins, and flavonoids which are
commonly known for their antioxidant activity. Extensive immune activation and breakdown of the intestinal barrier provides bacteria access to the gut
mucosal immune system, resulting in uncontrolled inflammation and dysbiosis. TCE exhibited considerable level of inhibition against the intestinal organisms
as reported earlier for herbal products and this could be due presence of certain phytochemical including flavonoid in TCE. The antibacterial effect could be
contributory factors in helping healing of colitis induced by TNBS. TCE was also found to have no acute toxicity even with five times of the optimal effective
dose administered to mice indicating its safety on use.

35. CURRENT DRUGS FOR I.B.D.
Drug Name Compound Class Drug Class R.O.A. Half
Life
Target Mechanism of Action Major Side Effects
Mesalamine 5-aminosalicylic acid
derivatives
5-Aminosalicylic
acid derivative
Oral ~ 25 h UC, CD Inhibits the NF-Kβ pathway,
intestinal epithelial cell injury
apoptosis.
Dizziness, rhinitis, sinusitis,
nasopharyngitis, back pain,
abdominal pain, skin rash,
eructation, constipation.
Certolizumab
pegol (CZP)
A recombinant
humanized Fab′
fragment of a
monoclonal antibody
Cytokines/growth
factors/
immunosuppressant
Sub-Q 14 days CD Selectively neutralizes TNF-α. Upper respiratory infection, urinary
tract infection, arthralgia, rash
Golimumab From genetically
engineered mice with
human anti-TNF
antibody
Biologic agent,
TNF blocking
agent
IV 2
weeks
UC Inhibits TNF-α activity by
binding to its receptor.
Respiratory infections
(nasopharyngitis), decreased
neutrophils, and microbial
infections.
Tofacitinib Small molecule
derived from
n-acylpiperidines
JAK-inhibitor Oral ~3−6 h UC Inhibits JAK family of
proteins (JAK-1, 2, 3 &
TYK2), while in UC, it is via
inhibition of JAK-1
subsequently down regulate
IL-6 and IFN-γ
Nasopharyngitis, headache,
skin rash, diarrhea, herpes
zoster infection, upper
respiratory tract infection,
increased creatine phosphate
Adalimumab Anti-TNF-α
monoclonal
antibody
Cytokines/growth
factors
Sub-Q 2
weeks
UC, CD Binds to TNF-α and
prevent from binding its
receptor and inhibit
subsequent inflammatory
responses.
Headache, skin rash, upper
respiratory tract infection,
sinusitis, antibody
development.

36. NOVEL BOTANICALS FOR I.B.D.
UNDERGOING CLINICALTRIALS
Name Plant Disease/Condition Target/ Objective Clinical Phase
Berberine Coptis chinensis UC Assess the safety of berberine (berberine chloride) for
UC patients in clinical remission while receiving
maintenance therapy with mesalamine
Phase I
Epigallocatechin 3-
gallate
Camellia sinensis
(Green tea)
Mild to moderately
active UC
Determine the Safety of an oral dose of green tea extract
(Polyphenon E®) as a preliminary evidence to support its
efficacy in UC.
Phase II
Curcumin
(1,7-Bis(4-hydroxy3-
methoxyphenyl)-1,
6-heptadiene-3,
5-dione)
C. longa • Both UC and CD
• CD
• UC
• Determine the tolerability of curcumin in pediatric
IBD patients.
• Study the effect of curcumin combined with
thiopurines in the prevention of post-operative
recurrence of CD.
• Evaluate the efficacy of combined therapy of
curcumin + 5ASA versus 5ASA alone on mild to
moderate UC patients.
Phase I
Phase III
Phase III

37. Fig. – Discovery and development of novel dugs and novel therapeutic targets for the treatment of IBD. These novel drugs include agents that target
leukocyte trafficking, Interleukin (IL) 23, Janus kinases (JAK), Sphingosine 1 phosphate (S1P) and Smad7, an inhibitor of the immunosuppressive cytokine
transforming growth factor β1 (TGF-β1)
NOVEL THERAPEUTIC AGENTS FOR I.B.D.
UNDERGOING CLINICAL TRIALS

38. Fig. - New therapeutic approaches in IBD with their specific targets- Modulation of barrier function, gut microbiota, matrix modelling, macrophage &
lymphocyte activation, homing and retention, as well as angiogenesis, are emerging as novel therapeutic targets. This schematic diagram shows the target,
proposed mechanisms and agent in development.

39. CONCLUSION
 Crohn’s disease & Ulcerative colitis are 2 major forms of IBD
 Both the diseases have distinctive pathophysiology & they are caused due to genetic,
environmental factors, diet, immune system imbalance etc.
There are various in vitro & in vivo screening models present for screening of therapeutic agents
for I.B.D.s
 Terminalia Chebula extracts are most widely used due to their desired effects and anti toxic
activity. Whereas new botanicals and biological drugs are also into clinical trials

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41. THANK YOU