Inflammatory bowel disease (IBD) results from complex interactions between intestinal microbiota and a genetically predisposed individual's immune system, leading to inappropriate immune activation and chronic inflammation. The two types of IBD are ulcerative colitis and Crohn's disease. IBD risk is influenced by both genetic and environmental factors that can disrupt the normal balance between the gut microbiome and the immune system, such as defects in autophagy and cellular stress responses. While genetic factors contribute to disease risk, they do not fully explain IBD cases, and environmental triggers like the modern hygiene environment and Western diet may promote low-grade intestinal damage and dysbiosis.

1. INFLAMMATORY BOWEL
DISEASE (IBD)

2. • Inflammatory bowel disease (IBD) is a chronic
condition resulting from complex interactions
between intestinal microbiota and host immunity
in genetically predisposed individuals that leads
to inappropriate mucosal immune activation.
The two disorders that comprise IBD are
ulcerative colitis and Crohn disease.

3. Epidemiology.
•Ulcerative colitis and Crohn disease mostfrequently present in
the teens and early 20s but can develop at any age.
•IBD is most common among Caucasians and in the United
States occurs three to five times more often among eastern
European Jews than the general population. This is at least
partly due to genetic factors
•IBD is most common in North America, northern Europe, and
Australia,but incidence worldwide is on the rise and is
becoming significant in Africa, South America, and Asia,
where prevalence was historically low.

4. •The hygiene hypothesis suggests that this increasing incidence
is related to improved food storage conditions, decreased food
contamination, and changes in gut microbiome composition
that result in inadequate development of regulatory processes
that limit mucosal immune responses. This in turn allows some
mucosa associated microbes to trigger persistent and chronic
inflammation in susceptible hosts.
•Other potential explanations for increased IBD prevalence
include the idea that preserva tives and other materials added
to processed foods induce low-grade mucosal damage that
predisposes to IBD.

5. Pathogenesis
•IBD results from a combination of abnormalities in immune
regulation, host-microbe interactions, and epithelial barrier
functions in genetically susceptible individuals.
•Over 200 IBD associated genetic polymorphism have been
identified, butthese accounts for less than 50% of disease risk
in crohn disease and make even smaller contribution to
ulcerative colitis.
•Eg, polymorphism of NOD2, the strongest risk gene for crohn
disease,are associated with only 10 fold increased risk of
disease.

6. •While genetic predisposition is important,
environmental factors are also critical to
pathogenesis. Genetic and environmental elements
that contribute to disease can be thought of in terms
of immunity, autophagy and cellular stress responses
and host microbial interactions

7. Mucosal immunity.
•A plethora of immune signaling and regulatory genes
including those encoding HLA molecules and cytokines have
been associated with IBD. In the case of the latter,
polymorphisms in genetic loci that include genes in both
proinflammatory
•Th1 polarization is present in both diseases, although there
is also evidence of Th2 activation in ulcerative colitis,
perhaps reflecting the underlying differences in genes
associated with disease.

8. • Th17 signaling is also important to IBD pathogenesis, as both
Crohn disease and ulcerative colitis are linked to
polymorphisms in the IL-23 receptor and other molecules
involved in Th17 signaling. These genetic data are consistent
with the observation that Th17 T-cell populations are
expanded within diseased intestine
• Overall, multiple genetic polymorphisms contribute to IBD
pathogenesis, and the specific genes involved vary between
Crohn disease and ulcerative colitis, among individuals, and,
in a few genes, across ethnic groups. For example, NOD2
polymorphisms have not been associated with Crohn disease
in Asian populations.

9. Autophagy and cellular stress responses.
•Genetic associations as well as molecular analyses indicate
that defects in autophagy and cellular stress responses
contribute to IBD pathogenesis.
•The most studied of these genes include ATG16L1 and IRGM,
both of which are involved in autophagosome formation.
•Autophagy is a normal homeostatic mechanism that clears
damaged organelles and is upregulated in response to
cellular stress including nutrient deprivation and endoplasmic
reticulum stress.

10. •Autophagy is also a means of clearing sources of reactive
oxygen species and intracellular pathogens
•The ATG16L1 mutation that is linked to Crohn disease
promotes ATG16L1 degradation, thereby limiting
autophagy.
• The precise pathways by which loss of ATG16L1 function
leads to disease are still being defined, but it is
noteworthy that Paneth cell granules, which contain
antibacterial peptides that are released into the crypt
lumen, are structurally and functionally abnormal in
patients and mice with ATG16L1 defects.

11. Host-microbial interactions.
•The gut microbiome, composed of bacteria, fungi, and
viruses, has been the subject of intense investigation over
the last decade.
•The microbiome is populated by a small number of species
at birth.
•This evolves to become a far more complex ecosystem with
many more species after weaning and through childhood.
•Microbial complexity then declines in old age.

12. •Microbes express proteins and other molecules and
generate metabolites that can protect against or promote
disease.
Eg; clostridia species stimulate development of regulatory
T cells
Bifidobacterium promote Th17 differentiation
•multiple species produce butyrate, whose activities include
enhancement of mucosal barrier function, increased
epithelial proliferation and immune regulation.

13. •Soluble microbial products activate host sensing
proteins, including surface TLRs and dectin receptors
and intracellular microbial associated pattern receptors,
e.g., NOD2.
•This is one means by which the microbiome can
modulate mucosal immunity
•Conversely, the immune system can markedly alter the
microbiome by mechanisms that include luminal
secretion of antimicrobial peptides and antibacterial
IgA.

14. •This interplay between microbes and the immune system
may contribute to the evolution of dysbiosis,
characterized by shifts in microbial populations and
reduced species diversity, in disease.
•Thus, although dysbiosis is often established at disease
presentation, it is difficult to differentiate between
microbial changes that trigger disease and those that are
caused by disease.

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