1. GI Pathophysiology 2016. 11. 01. Jaeyoung Chun, M.D. Pathophysiology
Thank you.
I will talk about gastrointestinal pathophysiology within next half an hour.

2. IBD IBS IBD : inflammatory bowel disease
There are two representative diseases in the lower GI tract including IBD and IBS. IBD means inflammatory bowel disease, a kind of chronic inflammatory disease. IBS means irritable bowel syndrome, a typical functional disorder. IBD is a different disease from IBS, but the pathophysiology of IBD and IBS has something in common.
IBD : inflammatory bowel disease
IBS : irritable bowel syndrome

3. Introduction : IBD Inflammatory bowel disease (IBD) Two major forms
Chronic relapsing inflammation of the digestive tract
Rare
Two major forms
Crohn’s disease (CD)
Ulcerative colitis (UC)
IBD is characterized by chronic relapsing inflammation of the digestive tract. The prevalence of IBD is very rare. It includes two major forms, CD and UC.

4. IBD : CD vs. UC
Involved in any part of the GI tract
Superficial inflammation
CD can induce transmural inflammation and affect any part of the GI tract in a non-continuous type. It is commonly associated with complications such as abscesses, fistulas and strictures. In contrast, UC is characterized by superficial inflammation limited to mucosa and/or submucosa. The inflammation of UC has continuous colonic involvement beginning in rectum. Patients with UC are at a higher risk of colorectal cancer than those with CD or general population.
Associated with complications such as strictures, fistulas and abscesses
At a higher risk of colorectal cancer

5. Introduction : IBS Irritable bowel syndrome (IBS)
Functional gastrointestinal disease
Very common
Change in bowel habits : diarrhea, constipation
Abdominal pain or discomfort relieved with bowel movement
IBS is very common and a functional gastrointestinal disease. Functional disease means there are no gross abnormal finding and organic damage in the intestinal tissue. So, the results of all tests to define the any organic problem in the GI tract are negative in patients with IBS.
The patients with IBS have change in bowel habits such as diarrhea or constipation, and abdominal pain or discomfort relieved with bowel movement.

6. IBD IBS Incidence Rare 5~20 / 100,000 Very common
67 / 1,000 person years
(20% prevalence)
Peak age of onset
20-30 & years NA
Sex (male : female)
1 : 1
1:2
Symptoms
Chronic relapsing GI symptoms
(abdominal pain, bowel habit change, etc)
Radiologic findings
Abnormal
Normal
Histologic findings
Chronic inflammation
Treatment
Anti-inflammatory drugs
Immunomodulatory drugs
Steroids
Biologic agents
Dietary modification
Probiotics
Anti-spasmodics
Anti-depressants
Prognosis
Lifelong disease
Complications (stricture, perforation, infection, or colorectal cancer)
Affect quality of life,
but not life threatening
This table summarizes the characteristics of both IBD and IBS. IBD shows double peak age of onset, 20s and 60s. But, there is no peak age of onset in IBS. IBD symptoms is similar as IBS symptoms. The results of radiology and histology are abnormal in IBD, but normal in IBS. Because IBD is an inflammatory disorder, the treatment of IBD is anti-inflammatory. However, the main treatment of IBS is drugs to control symptoms.

7. Crohn’s Disease Ulcerative Colitis Gastroenterology 2012;142:46-54
These figures show worldwide CD & UC incidence rates and/or prevalence. The red countries mean the highest incidence and prevalence of IBD, and the blue countries indicate the lowest incidence and prevalence of IBD.
In the past, IBD was well-known as a relatively common disease in developed countries including Canada or Europe. In Asia, it was very rare. Nowadays, the incidence and prevalence of IBD is rapidly increasing worldwide, especially in Asia. IBD seems to be a global disease.
Gastroenterology 2012;142:46-54

8. Incidence of IBD in Korea
Year of diagnosis
Incidence (/105)
4.2
3.1
Database from the Health Insurance and
Review Agency,
Population-based Cohort in the Songpa-Kangdong District, Seoul, Korea,
In the past, IBD was very rare in Asia. However, the incidence of IBD is rapidly increasing in Asia including Korea like this. Nowadays, about 7 per 100,000 persons are diagnosed with CD or UC every year in Korea.
Yang SK, Kim JS et al. Inflamm Bowel Dis 2008;14:542–549
Kim HJ et al. Inflamm Bowel Dis 2015;21:

9. IBD - Etiology Inflamm Bowel Dis 2015;21:912–922
Then, why is the incidence of IBD increasing in Korea? The pathophysiology of IBD still remains unclear, but recent progress in understanding the pathophysiology suggests that IBD is thought to result from the interplay of individual environmental triggers such as westernized diet and alterations in the gut microbiome that stimulate an aberrant immune response driving chronic intestinal inflammation in a genetically susceptible host.
Inflamm Bowel Dis 2015;21:912–922

10. IBD – Genetics 163 IBD risk loci Ann Gastroenterol 2014;27:294-303
The international IBD genetics consortium performed the largest meta-analysis including data from 15 different GWAS for both CD and UC, and summarized 163 independent IBD risk loci. These loci implicate a diverse array of genes involved in IBD pathogenesis that encompass multiple physiological processes, including innate immunity activated by microbe recognition, immune mediated functions and intestinal epithelial defense.
Ann Gastroenterol 2014;27:

11. Gut Microbiome We are more “bacteria” than “human”
10x the No. of human cells
150x the No. of human genome
Microbiome as “human organ”
Weighs ~1kg
Is more akin to immune system than liver

12. Gut Microbiome: Implication for Clinical Practice
Disease associated with dysregulated gut microbiome DM
Obesity
Metabolic syndrome
Stress/anxiety
Heart disease
Allergic disorders
Cancer
IBD & IBS
Many diseases may result if the gut microbiome is dysregulated. For examples, DM, obesity, metabolic syndrome, heart disease, allergic disorders, and cancers. Of course, the gut microenvironment can affect the development and perpetuation of the representative GI disorders including both IBD and IBS.

13. IBD & Gut Microbiota Evidence for role of microbiota in IBD
Patients with IBD have less diverse microbiome.
Antibiotics improve disease course in some IBD patients.
Animal models of IBD require presence of microbiota for inflammation.
Many genetic risk loci for IBD involve pathways for protection of host against gut microbiota.
Established association of diet, which impacts microbiome, and risk for IBD
To date, there are some evidences for role of microbiota in IBD. Patients with IBD have less diverse microbiome compared with general population. Antibiotics improve disease course in some IBD patients, but not all IBD patients. Animal models of IBD require presence of microbiota for inflammation. It means that intestinal inflammation is not detected in the germ-free mice. As I mentioned before, many genetic risk loci for IBD involve pathways for protection of host against gut microbiota. Finally, diet is associated with risk for IBD, and diet can impact gut microbiome.

14. This figure shows the complex interaction between immune system and gut microbiota in the pathogenesis of IBD. In steady state conditions, gut microbiota presents a favorable relationship with intestinal mucosal cells. A perfect balance between pro- and anti-inflammatory factors results in homeostasis. However, the alteration of the normal commensal community contributes to increase the risk of infection with consequent overgrowth of harmful pathogens. Pathogens are recognized by antigen presenting cells, inducing a T cell response and subsequent release of pro-inflammatory cytokines. Finally, epithelial cell damage developed in this way.
Pharmacol Ther 2015;149:

15. IBS Pathophysiology Am J Med 2015;128:817-827
This figure summarized a model of IBS pathophysiology. IBS is also thought to be a multifactorial disorder, deriving from many potential etiologic factors, including environmental, psychologic, and gut physiologic factors. This model highlights the complex, often bidirectional interplay of these factors in the pathogenesis of IBS. We will more focus on the alteration of gut microbiota and IBS pathophysiology in next slide.
Am J Med 2015;128:

16. IBS & Gut Microbiota Evidence for role of microbiota in IBS
Small intestinal bacterial overgrowth (SIBO) may initiate IBS symptoms.
Infectious gastroenteritis may trigger microinflammation (“postinfectious IBS”)
So, there are some evidences for role of gut microbiota in the pathophysiology of IBS. Small intestinal bacterial overgrowth (SIBO) may initiate IBS symptoms such as constipation or diarrhea. In addition, infectious gastroenteritis may trigger mild inflammation, so the patients with history of severe infection in the GI tract are at a high risk of IBS. We called it post-infectious IBS.
Am J Med 2015;128:

17. Brain-Gut-Enteric Microbiota Axis
This figure shows the pattern of bidirectional brain–gut–microbe interactions. First, the brain can influence enteric microbiota indirectly or directly. In contrast, communication from enteric microbiota to the host can occur conversely. And, disruption of this bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic GI disorders, including IBS and IBD.
EMS : emotional motor system
ANS : autonomic nervous system
Nat Rev Gastroenterol Hepatol 2009;6:

18. Brain-Gut-Enteric Microbiota Axis
So, communication from gut microbiota to the brain occurs through 1) production of neurotransmitter and neurotrophic factors, 2) protection of intestinal barrier and mucosal integrity, 3) modulation of enteric sensory afferents, 4) production of bacterial metabolites and 5) direct mucosal immune regulation. Conversely, brain can effect on gut microbiota through alteration in mucus production, motility, intestinal permeability or immune function. The dysregulated balance in the brain-gut-microbiota axis can induce IBD or IBS.
Ann Gastroenterol 2015;28:

19. Summary : IBD vs. IBS
IBD is rare, but chronic relapsing GI inflammation
IBS is very common, functional GI disorder
IBD & IBS are multifactorial disease
Genetic factor
Environmental factor : diet
Gut microbiota
Brain-gut-microbiota axis
In summary,
IBD is rare but chronic relapsing inflammation, and IBD patients have a lot of complications such as stricture, fistula, abscess or cancer. However, IBS is very common, functional GI disorder. IBS patients may experience severe symptoms including abdominal pain or diarrhea like IBD patients, but IBS is not life-threatening.
In terms of the pathophysiology, both IBD and IBS share the etiology including genetic, environmental, and microbiologic factors. And the complex interaction among these factors is very closely associated with the pathogenesis of both IBD and IBS.