Pathophysiology of
gastrointestinal system II18. 2. 2020
Prof.Anna Vašků1
Prof.Anna Vašků2
GIT physiology - repetition
̶ The gastrointestinal (GI) system is responsible for the digestion and absorption of ingested
food and liquids.
̶ the major factors affecting GI physiology and function are the intestinal microbiota, chronic
stress, inflammation, and aging with a focus on the neural regulation of the GI tract and an
emphasis on basic brain-gut interactions that serve to modulate the GI tract.
̶ GI diseases refer to diseases of the esophagus, stomach, small intestine, colon, and rectum.
̶ The major symptoms of common GI disorders include recurrent abdominal pain and bloating,
heartburn, indigestion/dyspepsia, nausea and vomiting, diarrhea, and constipation.
̶ GI disorders rank among the most prevalent disorders, with the most common including
esophageal and swallowing disorders, gastric and peptic ulcer disease, gastroparesis or
delayed gastric emptying, irritable bowel syndrome (IBS), and inflammatory bowel disease
(IBD).
̶ Pathophysiology knowledge the most important approach!
Prof.Anna Vašků3
GIT physiology - repetition
̶ The overall function of the GI tract is to digest ingested nutrients through complex processes
of digestive enzyme secretion and nutrient absorption. Luminal contents move along the GI
tract via smooth muscle peristalsis, while smooth muscle segmentation ensures adequate
contact time and exposure to the absorptive epithelial mucosal surface.
̶ The gut is capable of handling about 9 L of fluid per day, which is mainly absorbed by the
small intestine. This fluid movement can occur through paracellular or transcellular routes.
Paracellular pathway involves water movements coupled to nutrient absorption via alterations
in tight junction expression, while the transcellular route involves the passage of water
through apical and basolateral membranes of epithelial cells by passive diffusion, cotransport
with ions and nutrients, or through aquaporins.
̶ During intestinal absorption the epithelial barrier is specifically designed to protect against the
movement of potentially harmful antigenic, toxic, or infectious material across the GI mucosal
surface (Camilleri et al. 2012).
Prof.Anna Vašků4
GIT physiology - repetition
̶ To ensure effective digestion and proper GI tract health requires a complex
series of coordinated neural events accomplished by the central nervous
system (CNS), the nerve network within the gut itself known as the enteric
nervous system (ENS), and a whole host of GI endocrine peptides that target
specific cells and tissues that make up the GI tract.
̶ Specialized endoderm-derived epithelial cells termed enteroendocrine cells
(EECs) form the largest endocrine organ in the body and are widely
distributed throughout the GI tract. EECs play a key role in the control of GI
function including secretion, motility, and regulation of food intake,
postprandial glucose levels, and metabolism.
Prof.Anna Vašků5
GIT physiology - repetition
̶ The gut also performs important immune functions and a vast array of
inflammatory mediators can influence the recruitment of lymphocytes and
other immune cells to the gut wall including mast cells, and at the same time
modulate the activity of the gut neural networks. Additionally, the abundance
of microbiota residing in the human intestine estimated at 1014
microorganisms plays a pivotal role in the development of the enteric nervous
sytem (ENS), the overall health not only of the GI tract but also the entire
human body via mechanisms that include activation of the immune system,
and production of short-chain fatty acids (SCFAs) to promote colon cell health
as well as brain-gut interactions.
Prof.Anna Vašků6
Gut microbiota-brain axis. Five possible communication routes (–) between gut microbiota and brain:
intestinal mucosal barrier and blood-brain barrier is the important base for neuroendocrine-HPA axis
pathway , gut immune system , and gut microbiota metabolism system. Substances produced by
neuroendocrine-HPA axis pathway , gut immune system , and gut microbiota metabolism system, only
into the system circulation and brain through the intestinal mucosal barrier and blood-brain barrier system
can play effect of gut microbiota on the brain. HPA: Hypothalamic-pituitary-adrenal.
Wang HX, Wang YP. Gut Microbiota-brain Axis. Chin Med J (Engl). 2016;129(19):2373–2380.
doi:10.4103/0366-6999.190667
Prof.Anna Vašků7
Gut microbiota-brain axis
̶ gut microbiota-brain axis is a “bottom-up” term as opposed to a “top-down” term of “brain-gutmicrobiota
axis”, no matter what is called, its meaning refers to a bidirectional communication
network between gut and brain. Its composition includes gut microbiota and their metabolic
products, ENS, sympathetic and parasympathetic branches, neural-immune system,
neuroendocrine system, and central nervous system.
̶ Tthere might have possible five routes of communicating between gut microbiota and brain,
including the gut-brain's neural network, neuroendocrine-HPA axis, gut immune system,
some neurotransmitters and neural regulators synthesized by gut bacteria, and barriers
including intestinal mucosal barrier and blood-brain barrier. In this communicating network,
the brain affects gut movement, sensory and secretion function, and viscera signal from the
gut also affects brain function. For example, incoming and outgoing branches of VN play an
important role in gut message transmission. Vagal activation has anti-inflammatory effect.
Positive effects of many gut microbiota and probiotics on brain function are dependent on the
vagal activity. Wang HX, Wang YP. Gut Microbiota-brain Axis. Chin Med J (Engl).
2016;129(19):2373–2380. doi:10.4103/0366-6999.190667
Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics
Gastroenterology. 2013 August;145(2):293-308.
Pathogenesis of diseases
The loss of universal helminth infection as occurred in earlier human evolution may alter the numbers or types of
bacterial and fungal commensals and thus affect normal mucosal tissue homeostasis. In susceptible or highly
exposed individuals, such alterations might alter the balance between immunotolerance, immunosurveillance and
nutrient extraction. This imbalance may contribute to the appearance of inflammatory systemic dysregulation at
mucosal surfaces, resulting in increases in asthma and allergic diseases, particularly in the setting of
environmental changes that have increased exposure to indoor allergens and pollutants, and even to increases in
obesity, which can be a risk factor for severe asthma.
Immunosurveillance is a term used to describe the processes by which
cells of the immune system look for and recognise foreign pathogens,
such as bacteria and viruses, or pre-cancerous and cancerous cells in the
body.
24.02.2020
11
Cell 2012; 148: 1258–1270
Development of gut microbiota
mikroflóry
24.02.2020
12
Cell 2012; 148: 1258–1270
ENS
̶ The relationship between the gut microbiota and ENS neurons is relatively complex.
̶ First, the microbiota can influence the development of the ENS, and this has
consequences on ENS activity and neurochemistry (such as neuronal
subpopulations).
̶ Second, gut bacteria can use different modes of communication to talk with ENS
neurons, including a direct “sensing” with intrinsic primary afferent neurons or the
release of numerous bacterial messengers (e.g., neurotransmitters, bioactive lipids,
gaseous factors). Along those lines, it is worth noting that the immune cells
infiltrating the gut epithelium may also communicate with the microbiota.
Glucagon‐like peptide‐1 (GLP‐1) is
̶ Glucagon‐like peptide‐1 (GLP‐1) is a key endocrine factor that
could participate in the control of the gut‐brain axis by gut
microbiota because of its location (i.e., released by intestinal L
cells).
̶ GLP‐1 could act on ENS neurons to modify the gut‐brain axis to
control food intake and glucose metabolism.
Endocannabinoid system (ECS)
̶ In the context of energy homeostasis, the endocannabinoid system (ECS) plays a major role.
̶ Endocannabinoids (eCBs) are bioactive lipids that are synthesized in and exert their action
on several organs involved in metabolism and appetite regulation.
̶ Depending on the action exerted by eCBs on the intestinal mucosa, they can be clustered as
a “gate opener” (anandamide) and “gate keeper” (palmitoylethanolamine, 2‐oleoylglycerol).
̶ Gut microbiota can modulate intestinal eCB tone. An “obesity microbiota” is associated with
an increased intestinal level of anandamide, thus increasing gut permeability.
Prof.Anna Vašků19
GIT pathophysiology
̶ A generally accepted hypothesis is that dysfunction of the bidirectional communication between the
brain and the gut in response to chronic stress activates the hypothalamic pituitary (HPA) axis and
autonomic nervous system and plays a role in the symptomatology of functional GI disorders such as
IBS. Inflammation of the gut mucosal surface has substantial effects on enteric and extrinsic afferent
neuronal function though complex changes in neuroimmune interaction.
̶ Although the effects of an intestinal inflammation on the CNS are not fully understood, patients with IBD
exhibit centrally mediated comorbidities including anxiety, depression, and fatigue, which strongly
suggests altered brain function in response to peripheral inflammation perhaps through alterations in
central immune-mediated mechanisms.
̶ Recent evidence points to changes in the gut microbiota playing a key role in GI disorders. Specifically,
disorders directly affecting the GI tract have been shown to exhibit microbial dysbiosis. Gut
inflammation causes marked alterations in the gut microbiota populations and may play a role in gutbrain
miscommunication. Another important factor altering the physiology of the GI tract is age. The
normal functioning of the gut is compromised as we age, with the elderly often complaining of
constipation, hemorrhoids, heartburn, decreased energy, and food allergies.
Prof.Anna Vašků20
Malabsorption
Malabsorption indicates impaired uptake of nutrients, ions or water along the
gastrointestinal tract which can occur with and without morphological changes of the small
intestinal mucosa. Thereby, disturbed digestion (maldigestion) and absorption
(malabsorption) can work alone or together (malassimilation).
Malabsorption occurs when a primary transport disorder (without morphological changes)
or a secondary transport defect due to morphological changes arises, when the absorptive
area is reduced or the transport of absorbed ingesta from the intestine is affected.
Depending on localization and extent of the disturbance the functional impairment is either
global, partial or compensated.
Prof.Anna Vašků21
Disease
Whipple's disease
Lamina propria
macrophages with PASpositive
material
Biopsy, PCR, EM
Intestinal lymphoma
Lymphoma cells in the
lamina propria and
submucosa
Biopsy, T-cell receptor
clonality
Intestinal
lymphangiectasia
Dilated lymphatic ducts
with partial villus atrophy
Biopsy
Eosinophilic
gastroenteritis
Eosinophilic infiltrates Biopsy
Amyloidosis Amyloidal deposits Biopsy
Crohn's disease
Skip lesions with detection
of granuloma
Biopsy
Infectious diseases
Detection of
microorganisms
Stool microbiology, serum
titre and PCR
Mastocytosis Mast cell infiltrates Biopsy, IgE
Coeliac disease
Villus reduction, crypt
hyperplasia, increased
intraepithelial lymphocytes
Biopsy, tissue
transglutaminase
antibodies, HLA-DQ2
Giardia lamblia infection Partial villus atrophy
Stool ELISA, indirect
immunofluorescence
Blind loop syndrome
Partial villus atrophy and
increased intraepithelial
lymphocyte count
H2-test (glucose),
quantitative culture from
small intestinal mucus
Vitamin-B12 deficiency
Macrocytotic anaemia,
ileal inflammation, gastric
resection or atrophic
gastritis
Serum vitamin B12,
parietal cell antibodies,
Schilling test, gastric pH
Radiation enteritis
Inflammation of the
intestine
Endoscopy
Zollinger–Ellison
syndrome
Ulcers and erosions of
gastric mucosa and small
intestinal partial villus
atrophy
Serum gastrin,
endoscopic ultrasound,
CT
Starvation, malnutrition or
parenteral nutrition
Mucosal hypotrophy (villus
and crypt reduction)
Biopsy
Malabsorption syndromes:
partial, global, compensated
Prof.Anna Vašků22
Coeliac disease
̶ Coeliac disease is a common cause of malabsorption in Caucasians, especially those of European
descent. Coeliac disease has variable manifestations, almost all of which are secondary to nutrient
malabsorption, and a varied natural history, with the onset of symptoms occurring at all ages.
̶ There is no functional test to diagnose coeliac disease. An early duodenal biopsy in combination with
specific antibodies (anti-gliadin, anti-endomysial, anti-tissue transglutaminase) is the diagnostic test of
choice. Furthermore, almost all patients with coeliac sprue express a distinct HLA-DQ2 allele
(DQA1*0501+DQB1*0201). Therefore, absence of this DQ2 allele virtually excludes the diagnosis.
̶ The gold standard of coeliac disease diagnosis is the presence of an abnormal small intestinal biopsy
and the clinical and histopathological response to the elimination of gluten from the diet.
̶ Since the diarrhoea in coeliac disease has several pathogenetic mechanisms, tests for (secondary)
lactase deficiency, fructose intolerance and rarely bile acid malabsorption are encouraged to guide the
patient and counsel him regarding the diet of choice or medical therapy. Some patients may obtain
temporary improvement with dietary lactose, fructose or fat restriction, while awaiting the full effects of
total gluten restriction. In some patients a therapeutic trial with cholestyramine with/without prior
SeHCAT test and/or stool fat test can be helpful when ileal involvement with bile acid diarrhoea is
suspected.
Prof.Anna Vašků23
Giardia lamblia infection
̶ In the Western world chronic infection with Giardia lamblia is
probably the most important infectious agent causing
malabsorption in the immunocompetent as well as in
immunocompromised people (mainly humoral defect of the
immune system).
̶ Diarrhoea is thought to result mainly from malabsorption due to a
partial villous atrophy and reduced disaccharidase activity,
although there is also a leak-flux and secretory component to this
type of diarrhoea.
Prof.Anna Vašků24
Whipple’s disease
̶ Whipple's disease is characterized by diarrhoea, steatorrhea, weight loss,
arthropathy and fever. It is caused by the ubiquitous bacterium Tropheryma
whipplei. New experimental approaches point to defects in T-cell and
macrophage immunity in these patients. The steatorrhea is generally
considered to be secondary to small intestinal mucosal injury and lymphatic
obstruction due to the massive infiltration of PAS-positive macrophages in the
lamina propria.
Prof.Anna Vašků25
Short bowel syndrome
̶ The short bowel syndrome (SBS) can appear clinically as a partial or global
malabsorption syndrome. The incidence of symptoms is variable.
̶ The exact definition of resection extent and the length of the remaining small
intestinal segment with or without colon are essential for the understanding of
the symptoms and therapy planning.
Prof.Anna Vašků26
Bacterial overgrowth
̶ Small bowel bacterial overgrowth (SBO) syndrome is characterized by diarrhoea, weight loss, bloating
and macrocytic anaemia and is caused by an increased number of colonic-type bacteria in the small
intestine.
̶ Physiologically, the number of bacteria in the small intestine is reduced by several mechanisms. Most
importantly, antegrade peristalsis prevents attachment of ingested microorganisms and an intact
ileocoecal valve inhibits retrograde ascension of bacteria into the small bowel from the colon with its
high bacterial content. Furthermore, gastric acid, bile and proteolytic enzymes destroy many
microorganisms or prevent them from entering the small intestine from the stomach. In addition, the
mucosal barrier with its mucus layer and anti-bacterial factors including the innate (e.g. defensins) and
acquired immune system (e.g. immunoglobulins) inhibit bacteria from overgrowth.
̶ The pathopysiological basis for this syndrome can be any disturbance in the factors mentioned above.
In most cases, an intestinal stasis caused either by impaired peristalsis (functional stasis, e.g.
scleroderma, amyloidosis, diabetes) or by changes in intestinal anatomy (anatomic stasis, e.g. stricture,
blind loop, diverticula) predispose to bacterial overgrowth syndrome.
Prof.Anna Vašků27
Bacterial overgrowth
̶ The increased number of bacteria in the small intestine can cause several changes in small
intestinal function. First, bacteria deconjugate bile acids in the proximal small intestine which
are then not re-absorbed anymore leading to a decrease in the bile acid pool and a lack of
intraluminal bile acids. This leads to fat malabsorption with consequent steatorrhoe.
Furthermore, a variable degree of non-specific inflammation or epithelial defects are
sometimes noted due to bacterial proteases, exotoxins or invasive strains.
̶ As most bacteria require cobalamin for growth, increased concentrations of bacteria can lead
to cobalamin deficiency with megaloblastic anaemia and potentially neurologic changes. That
is why a typical laboratory feature is the combination of a low serum cobalamin level with an
elevated serum folate level, since bacteria frequently produce folate compounds that are then
absorbed.
Prof.Anna Vašků28
Carbohydrate malabsorption
̶ Carbohydrates represent the main source of energy in the diet and are present mainly in the form of starch,
disaccharides (saccharose and lactose) and glucose. Carbohydrates are absorbed in the small intestine as
monosaccharides. Therefore, carbohydrates must be digested by salivary and pancreatic amylase, gastric acid and
by the intestinal brush border disaccharidases (maltase, isomaltase, lactase, saccharase) to monosaccharides
(glucose, fructose and galactose).
̶ Absorption of glucose and galactose occurs via the transport protein SGLT1. The intestinal Na+-glucose
cotransporter SGLT1 uses sodium and electrical gradients across the apical enterocyte membrane to drive sugar
and water against their concentration gradients. Glucose and galactose are both handled by SGLT1, whereas
fructose is transported across the brush border by its own carrier, the facilitated fructose transporter GLUT5. All
three monosaccharides share a common exit on the basolateral membrane of the enterocyte through another
facilitated sugar transporter (GLUT2) into the portal blood. Furthermore, GLUT2 can also be inserted apically and
then represent a very dynamic high capacity low affinity pathway for monosaccharides.
̶ Malabsorbed monosaccharides generate an osmotic load that draws water and electrolytes into the lumen leading to
osmotic diarrhoea. In addition, non-absorbed sugars are a substrate for the intestinal microflora which produce
fatty acids and gases (methane, hydrogen, carbon dioxide) leading to bloating and flatulence. The increase in
luminal fatty acids leads to a lowered faecal pH which can be measured in infants in whom carbohydrate
malabsorption is suspected.
Prof.Anna Vašků29
Lactose intolerance
̶ Lactose is broken down by the brush border lactase into glucose and galactose. The enzyme lactase is invariably
present in humans (as well as in other mammalians) in the postnatal period but then physiologically disappears in
many populations, except for most of the Caucasians where lactase activity persists by about 80% throughout life.
̶ Clinically three different types of lactase intolerance syndromes can be distinguished, namely congenital, primary
and secondary lactase deficiency.
̶ The congenital lactase deficiency is an extremely rare autosomal-dominant inherited disease with a complete
absence of lactase activity immediately after birth.
̶ Primary lactase deficiency is a genetically determined relative or absolute absence of lactase which progressively
develops in childhood at various ages in different ethnic groups and is the most common type of lactose intolerance.
̶ Secondary lactase deficiency occurs in association with small-intestinal mucosal disease (e.g. infectious diarrhoea,
coeliac disease, Crohn's disease) with structural and consequently functional changes of the small intestinal
mucosa.
̶ Individuals with symptomatic lactose malabsorption develop one or more of the following symptoms after ingestion of
lactose-containing food: abdominal pain, diarrhoea, nausea, bloating, and/or flatulence. Development of symptoms
of lactose intolerance is related to the amount of lactose appearing in the small intestine and the activity of mucosal
lactase. Besides the amount of ingested lactose several other factors, e.g. rate of gastric emptying, intestinal transit
time and composition of microflora can influence the onset and severity of symptoms.
Prof.Anna Vašků30
Lactose intolerance
̶ A precise clinical history remains the most important approach to a
patient with suspected lactase deficiency and often reveals a
correlation between lactose ingestion and onset of symptoms. If
lactose malabsorption is suspected, a 2-week trial of lactose-free
diet is reasonable, under which the symptoms should ameliorate
or disappear. Then, the re-introduction of lactose into the diet with
recurrence of symptoms is considered diagnostic. Alternatively or
in more subtle cases the hydrogen breath test is the least invasive
and best diagnostic tool for the diagnosis of lactose
malabsorption.
Prof.Anna Vašků31
Glucose–galactose malabsorption
̶ Glucose–galactose malabsorption (GGM) is a very rare disease and is due to
a mutation in the SGLT1.
̶ The disease is characterized by severe diarrhoea in newborns when
individuals ingest carbohydrates that contain actively transported
monosaccharides (e.g. glucose or galactose) but not monosaccharides that
are not actively transported (e.g. fructose). The most reliable diagnostic test
for GGM is the hydrogen breath test. The H2 breath test for glucose or
galactose results in a great elevation in patients with GGM, while no such
increase is noted in controls or patients who eat fructose. Children with GGM
normalize on fructose-containing diets, but symptoms promptly return even in
adulthood after glucose provocation and the H2 breath test remains positive
Prof.Anna Vašků32
What is a Hydrogen Breath Test?
̶ A hydrogen breath test is used to measure how well certain
sugars such as lactose and fructose, are digested and absorbed
as well as diagnosing certain gastrointestinal conditions including
Intestinal Bacterial Overgrowth Syndrome (SIBO). Hydrogen is
produced when the bacteria in the colon is exposed to certain
unabsorbed sugars and carbohydrates.
Hydrogen breath testing is used for the following conditions:
• Lactose Intolerance
• Fructose Intolerance
• Small Intestinal Bacterial Overgrowth Syndrome (SIBO)
Prof.Anna Vašků33
What is the preparation for the tests?
̶ All 3 tests require the same prep:
• Discontinue all Proton Pump Inhibitors (PPI) which include Omeprazole, Lansoprazole, Dexlansoprazole,
Esomeprazole, Pantoprazole and Rabeprazole seven (7) days prior to the test.
• Discontinue H2 Blockers (Pepcid, Zantac, Tagamet, Axid, Rantidine, Famotidine) five (5) days prior to the breath
test.
• The day before your test, please limit your diet to the following foods ONLY:
• Baked or broiled chicken, fish or turkey with only salt and pepper seasoning if needed
• White bread only
• Plain steamed white rice
• Eggs
• Clear chicken or beef broth (no vegetable broth)
• Plain tofu with only salt and pepper seasoning if needed
• Coffee and Tea with no cream or sugar
• Avoid all other foods and drinks except water
• You should begin a complete fast (no food or drinks other than water) 12 hours prior to your breath test.
• On the day of your test, there is no smoking (including second hand smoke) at least 1 hour before or at any time
during the test.
• No sleeping or vigorous exercise for at least 1 hour before or at any time during the test.
• Nothing by mouth one (1) hour before you start your breath test. This means no water, gum, mints, smoking, etc.
Prof.Anna Vašků34
How is the breath test administered?
Each test is 3 hours in length and begins with a base line breath
sample. Then, depending on the test, you will drink a specialized
solution. Lactose and Fructose tests require 1 breath sample each
hour of the test. SIBO tests require a breath sample every 20
minutes. You will remain in the office throughout the entire 3 hours.
Prof.Anna Vašků35
Fructose intolerance (?)
̶ Fructose is taken up by the brush border transport protein GLUT 5 and as shown recently
also by GLUT2. Since fructose is rapidly cleared from the circulation, luminal uptake of
fructose is guaranteed. A true fructose malabsorption, as in lactase deficiency or in SGLT1
mutation, has not yet been reported. Fructose intolerance is rather defined as “any situation
in which free fructose is available to fermentative metabolism by luminal bacteria before it can
be absorbed across the small intestinal mucosa”.
̶ Fructose intolerance is not widely accepted as a disease and it rather represent intolerance
to a wide range of badly- or non-absorbed fermentable monosaccharides. Due to the
increasing load of fructose-containing solutions in the Western diet the capacity of the
fructose absorption system may be overloaded leading to symptoms of carbohydrate
malabsorption. On the other hand in chronic intestinal disease like irritable bowel disease,
inflammatory bowel disease or coeliac disease fructose malabsorption may play a role in
maintaining gastrointestinal symptoms despite adequate therapy. In this situation breath
testing might be applicable. Therapy should then be aimed at reducing the fructose content in
the diet.
Prof.Anna Vašků36
Malabsorption of specific nutrients, e.g.
iron, bile acids
Oral iron absorption test
̶ When iron deficiency with or without anaemia occurs a detailed work up following guidelines
should be performed including urine and faecal blood analysis, screening for coeliac disease
and in most cases endoscopy of the upper and lower GI tract.
Bile acid absorption test
̶ Bile acids are secreted with bile in the duodenum and are almost exclusively re-absorbed in
conjugated form in the distal ileum. Malabsorption of bile acids can be due to resection or
mucosal disease (e.g. ileitis terminalis) of this part of the small bowel. Bile acids entering the
colon can lead to the so called bile acid diarrhoea due to a direct action on colonocytes.
Prof.Anna Vašků37
Protein-losing enteropathy
Protein-losing enteropathy is not a specific disease but rather a syndrome that is characterized by
hypoproteinaemia and peripheral oedema in the absence of proteinuria, defects in protein synthesis or
protein malnutrition. It can occur in numerous gastrointestinal and non-gastrointestinal diseases. These
diseases causing protein-losing enteropathy can be classified into three groups according to the mucosal
alterations:
(1)
mucosal ulceration, such that the protein loss primarily represents exudation across ulcerations, e.g.
ulcerative colitis, Crohn’s disease, gastrointestinal carcinomas or peptic ulcer.
(2)
non-ulcerated mucosa, but with evidence of mucosal changes so that the protein loss represents loss
across epithelia with altered permeability, e.g. coeliac disease, Ménétrier’s disease, collagenous
colitis and Whipple's disease.
(3)
lymphatic dysfunction, representing either primary lymphatic disease or secondary to partial lymphatic
obstruction
Prof.Anna Vašků38
Protein-losing enteropathy
The diagnosis of protein-losing enteropathy is
suggested by the presence of peripheral oedema
and low serum albumin levels in the absence of
protein malnutrition and renal or hepatic disease.
Schulzke JD, Tröger H, Amasheh M. Disorders of intestinal secretion and absorption.
Best Pract Res Clin Gastroenterol. 2009;23(3):395–406.
doi:10.1016/j.bpg.2009.04.005
Prof.Anna Vašků39
Inflammatory bowel diseases
̶ Inflammatory bowel diseases (IBD), mainly consisting of Crohn’s disease (CD), ulcerative
colitis (UC), and IBD-unclassified (IBDU), are chronic relapsing and remitting diseases
resulting in uncontrolled inflammation of the gastrointestinal (GI) tract.
̶ The distribution of the diseases varies geographically, but the majority of patients are
diagnosed with UC (approximately 55%), followed by CD and IBDU.
̶ The treatment aims to relieve and prevent GI tract inflammation and has until the 1990s
consisted of anti-inflammatory and immunosuppressive drugs or surgical procedures (e.g.,
removal of the colon, limited resections). The introduction and development of biological
treatment options during the last two decades likely have improved the natural disease
course of IBD and possibly decreased surgery rates. However, the majority of the patients
will, despite treatment, alternate between periods of remission and periods of active disease.
Because of the unpredictable disease course and onset in patients of young age, IBD
represents a major physical and psychological burden on patients.
Weimers P, Munkholm P. The Natural History of IBD: Lessons
Learned. Curr Treat Options Gastroenterol. 2018;16(1):101–111.
doi:10.1007/s11938-018-0173-3
Prof.Anna Vašků40
Inflammatory bowel diseases - etiology
̶ The etiology of these diseases is unknown, but that genetic, environmental,
and intestinal microbial factors play an important role in the development of
IBD has been scientifically verified.
̶ The prevalence of IBD has increased during the last decades and it is
estimated to be five million patients affected by the disease globally. With an
increasing prevalence and the need for expensive medical treatments, IBD
represents a significant strain on the health care system.
Weimers P, Munkholm P. The Natural History of IBD: Lessons
Learned. Curr Treat Options Gastroenterol. 2018;16(1):101–
111. doi:10.1007/s11938-018-0173-3
Prof.Anna Vašků41
Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory
bowel disease. J Allergy Clin Immunol. 2020;145(1):16–27.
doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků42
IBD
̶ Inflammatory bowel disease (IBD) is a chronic immune-mediated
disease affecting the gastrointestinal tract. IBD consists of 2
subtypes: ulcerative colitis and Crohn disease. IBD is thought to
develop as a result of interactions between environmental,
microbial, and immune-mediated factors in a genetically
susceptible host. Of late, the potential role of the microbiome in
the development, progression, and treatment of IBD has been a
subject of considerable interest and enquiry. Indeed, studies in
human subjects have shown that the gut microbiome is different in
patients with IBD compared with that in healthy control subjects.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory
bowel disease. J Allergy Clin Immunol. 2020;145(1):16–27.
doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků43
IBD
̶ Other evidence in support of a fundamental role for the
microbiome in patients with IBD includes identification of
mutations in genes involved in microbiome-immune interactions
among patients with IBD and epidemiologic observations
implicating such microbiota-modulating risk factors as antibiotic
use, cigarette smoking, levels of sanitation, and diet in the
pathogenesis of IBD. Consequently, there has been much interest
in the possible benefits of microbiome-modulating interventions,
such as probiotics, prebiotics, antibiotics, fecal microbiota
transplantation, and gene manipulation in the treatment of IBD.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and
inflammatory bowel disease. J Allergy Clin Immunol.
2020;145(1):16–27. doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků44
Disease course
̶ The clinical course of UC and CD is unpredictable and is
characterized by times of remission and times of active
disease with characteristic symptoms of abdominal pain,
diarrhea, and weight loss.
̶ Despite many similarities between the two diseases,
disease phenotype and progression differ significantly.
Thus, while CD can affect the whole GI tract causing
transmural inflammation, UC are confined to the mucosal
and occasionally the submucosal layer of the colon.
Prof.Anna Vašků45
Ulcerative colitis
̶ Aproximately one third of the patients are diagnosed with proctitis, one third
with left sided colitis, and one third with pancolitis. However, the proportions
may vary with geography and population; thus, proctitis is described more
frequently in some Asian cohorts and left-sided colitis in some European
cohorts Since UC is a dynamic and sometimes unpredictable disease, the
disease course may progress over time and the proportion of patients with
extensive colitis might increase to 46% after a few years.
Weimers P, Munkholm P. The Natural History of IBD:
Lessons Learned. Curr Treat Options Gastroenterol.
2018;16(1):101–111. doi:10.1007/s11938-018-0173-
3
Prof.Anna Vašků46
Crohn’s disease
̶ Since inflammation and lesions caused by CD can affect any segment of the GI tract, the
location of the disease as well as treatment options differs from UC. At the time of diagnosis,
roughly one third of the patients have ileocolonic disease, one third have isolated ileal
disease, one third have isolated colonic disease, and a minority have isolated upper GI
inflammation.
̶ The course of CD is considered to be more stable regarding disease extension compared to
UC, with only 20% with isolated disease (ileal or colonic) developing ileocolonic disease after
a few years.
̶ Approximately 25–41% of the patients presents a stricturing or penetrating disease
phenotype at diagnosis. The behavior (inflammatory, stricturing, penetrating) of CD is
dynamic, and the cumulative risk of developing stricturing or penetrating phenotype is
approximately 50% after 10–20 years of disease duration.
̶ An important aspect of the penetrating phenotype is the development of fistulas.
Prof.Anna Vašků47
Pathophysiology of IBD
̶ Gut microbiota composition is known to be important in
maintaining health and mediating disease
̶ Dysbiosis, a change in the normal microbial ecology, occurs in the
intestine in the context of IBD
̶ Gut inflammation in IBD is characterized by a reduced diversity of
microbiota, which could render the host more susceptible to
colonization with pathogens or pathobionts
̶ Environmental factors probably have a major role in IBD; antibiotic
use, childbirth mode, breastfeeding, air pollution, NSAID use,
hypoxia or high altitude, diet and urban environments have been
studied
Prof.Anna Vašků48
Genetic, environmental, and immune-mediated microbiome
interactions in the pathogenesis of IBD. Genetic mutations
and environmental factors act as inciting triggers and lead
to an impaired immune response to gut microbiota,
resulting in a proinflammatory state.
Toll-like receptors (TLR) and NOD-like receptors (NLRs) on
dendritic cells, macrophages, and epithelial cells interact
with the microbiota and lead to differentiation of TH17 cells,
type 3 innate lymphoid cells (ILC3s), and TH1 cells, which
secrete proinflammatory cytokines. This in turn causes
inflammation, epithelial barrier dysfunction, and bacterial
translocation. Microbiota changes, including decreased
diversity and increased instability of the gut microbiota
composition over time, decreases in Firmicutes species, and
increases in Proteobacteria species, are seen in association
with IBD. In healthy subjects bacteria sensed by TLRs and
NLRs lead to production of IgA-secreting B cells and
differentiation of regulatory T (Treg) cells under the
influence of TGF-β and AhR signaling. IgA produced from B
cells neutralizes pathogenic bacteria, and IL-10, an antiinflammatory
cytokine produced by regulatory T cells, acts
to maintain gut homeostasis.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and
inflammatory bowel disease. J Allergy Clin Immunol.
2020;145(1):16–27. doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků49
̶ Many of the genetic mutations associated with IBD are related to
immune function and, specifically, interactions between the
immune system and the microbiome. These genes include
nucleotide oligomerization domain 2 (NOD2), autophagy-related
16-like 1 (ATG16L1), caspase recruitment domain–containing
protein 9 (CARD9), and C-type lectin domain family 7 member
A (CLEC7A). NOD2 encodes an intracellular pattern recognition
receptor that interacts with the peptidoglycan found in both grampositive
and gram-negative bacteria.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and
inflammatory bowel disease. J Allergy Clin Immunol.
2020;145(1):16–27. doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků50
NOD2
̶ NOD2 is expressed in intestinal epithelial cells, functions as a defensive
factor against intracellular bacteria, and contributes to the immune response
to commensal microbes. In human subjects mutations in NOD2 are
associated with a decrease in levels of IL-10, an anti-inflammatory cytokine,
and increased numbers of mucosa-associated bacteria. Patients with NOD2
mutations have microbiota that are characterized by decreased abundance of
Faecalibacterium species and increased abundance of Escherichia species.
In patients with CD, NOD2 is associated with ileal disease, an increased risk
of postoperative recurrence after ileocecal resection, and a more aggressive
fistulizing and fibrostenotic disease phenotype.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and
inflammatory bowel disease. J Allergy Clin Immunol.
2020;145(1):16–27. doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků51
Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory
bowel disease. J Allergy Clin Immunol. 2020;145(1):16–27.
doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků52
To the previous picture
̶ Role of NOD2 in bacteria-host interactions in patients with IBD.
NOD2 encodes an intracellular pattern recognition receptor that
interacts with peptidoglycan of gram-positive and gram-negative
bacteria. NOD2 is involved with regulation of both pathogenic and
commensal bacteria. Mutations in NOD2 lead to decreased levels
of anti-inflammatory cytokines, such as IL-10, and an increase in
mucosal bacteria. In human subjects with NOD2 mutations, there
is an enrichment of Escherichia species and a depletion of
Faecalibacterium species. In patients with CD, NOD2 is
associated with ileal disease and an aggressive disease
phenotype with stricturing and fistulizing disease activity.
Prof.Anna Vašků53
IBD and environmental factors
̶ number of environmental factors have been associated with the development
of IBD. Alteration of the gut microbiota, or dysbiosis, is closely linked to
initiation or progression of IBD, but whether dysbiosis is a primary or
secondary event is unclear. Nevertheless, early-life events such as birth,
breastfeeding and exposure to antibiotics, as well as later childhood events,
are considered potential risk factors for IBD. Air pollution, a consequence of
the progressive contamination of the environment by countless compounds,
is another factor associated with IBD, as particulate matter or other
components can alter the host's mucosal defences and trigger immune
responses.
Prof.Anna Vašků54
Breast-feeding is protective against the
development of IBD.
̶ The oligosaccharides in breast milk have prebiotic effects that
contribute to the establishment of the infant gut microbiota. In
addition, human milk oligosaccharides have been found to inhibit
the adhesion of enteropathogenic E coli, Vibrio cholerae, and
Salmonella fyris to epithelial cells.
̶ Infants who are breast-fed have a lower incidence of
gastrointestinal tract infections. Breast-feeding has been shown to
lead to an increased abundance of Firmicutes and Actinobacteria
compared with formula-fed infants.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory
bowel disease. J Allergy Clin Immunol. 2020;145(1):16–27.
doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků55
Breast-feeding is protective against the
development of IBD.
̶ human breast milk is microbially diverse and has both
probiotic and prebiotic effects. Breast milk contains Lactobacillus
rhamnosus, Lactobacillus gasseri, Lactococcus lactis,
Leuconostoc mesenteroides, and Bifidobacteria. Microbiota in
breast milk promote immune tolerance, prevent infection, and play
a role in the maintenance of the epithelial barrier through an
immune-mediated influence on intestinal microbiota composition.
Glassner KL, Abraham BP, Quigley EMM. The
microbiome and inflammatory bowel disease. J
Allergy Clin Immunol. 2020;145(1):16–27.
doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků56
Dietary changes
̶ Dietary changes, if sufficiently drastic, can alter the intestinal
microbiome in as little as 24 hours. Animal-based diets lead to
increased abundance of bile-tolerant bacteria, including Alistipes,
Bilophila, and Bacteroides species, and a decreased abundance
of Firmicutes. In contrast, plant-based diets lead to increased
abundance of Firmicutes. Certain diets have been associated with
an increased risk for IBD.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and
inflammatory bowel disease. J Allergy Clin Immunol.
2020;145(1):16–27. doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků57
Dietary changes
̶ Patients with IBD were found less likely to have consumed unpasteurized
milk or eaten pork.
̶ Diets high in total fats, omega-6 fatty acids, and meat were associated with
an increased risk of IBD, whereas higher fiber and fruit intakes were
associated with a decreased risk for CD, and a high intake of vegetables was
associated with a decreased risk for UC.
̶ These findings can be explained by diet-induced shifts in the microbiome,
such as the decreased abundance of Firmicutes with animal-based diets.
Decreased abundance of Faecalibacterium prausnitzii, a member of the
Firmicutes phylum with anti-inflammatory effects, has been associated with
CD.
Prof.Anna Vašků58
Cigarette smoking
̶ Cigarette smoking has a complex interaction, with IBD being
apparently protective against UC but negatively affecting the
natural history of CD.
Glassner KL, Abraham BP, Quigley EMM. The microbiome
and inflammatory bowel disease. J Allergy Clin Immunol.
2020;145(1):16–27. doi:10.1016/j.jaci.2019.11.003
Prof.Anna Vašků59
Cigarette smoking
̶ there is evidence that the gut microbiota of current and former smokers differs
from that of nonsmokers, with a relative increase in the numbers of
Bacteroidetes and decrease in Firmicutes and Proteobacteria in one of these
studies. In a study evaluating the microbiota of cigarette smokers before and
after smoking cessation, cigarette smokers had a lower abundance of
Bifidobacterium species compared with nonsmoking control subjects, and
increases in Bifidobacterium species were seen after smoking cessation.
There was also a decrease in Bacteroides species after smoking cessation.
Some of the differences seen in the gut microbiota of cigarette smokers
mirror those seen in patients with CD and those with UC, suggesting a
potential link between smoking, microbiota changes, and development of IBD.
Prof.Anna Vašků60
Summary
̶ there is some evidence to suggest that environmental factors,
such as early antibiotic use, enteric infections, breast-feeding, diet,
and cigarette smoking, affect the gut microbiota and drive immune
activation in subjects genetically susceptible to the development of
IBD.
Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory
bowel disease. J Allergy Clin Immunol. 2020;145(1):16–27.
doi:10.1016/j.jaci.2019.11.003
Relations between inflammation and cancer
Prof.Anna Vašků61
Prof.Anna Vašků62
Cancer
̶ IBD patients are at a greater risk of developing colorectal cancer, small bowel
cancer, and some extra-intestinal cancers compared to the general
population. The cause is considered to be multifactorial, and potential drivers
of the carcinogenesis are assumed to be inflammation and
immunosuppression:
̶ Colorectal cancer
̶ Small bowel cancer
̶ Extraintestinal cancer (the risk of developing cancer in the upper GI tract,
bladder, skin (squamous cell), and lungs was significantly increased in CD.
UC patients on the contrary had increased risk for developing hepatic and
biliary cancer, as well as leukemia but a decreased risk of lung cancer
compared to the general population). Weimers P, Munkholm P. The Natural History of IBD: Lessons Learned. Curr
Treat Options Gastroenterol. 2018;16(1):101–111. doi:10.1007/s11938-018-0173-3
Relations between inflammation and cancer
macrophage migration inhibitory factor
Prof.Anna Vašků63
Pathophysiological mechanisms connecting obesity and
gastrointestinal tract
John BJ, 2006
Prof.Anna Vašků64
Thank you for your attention
Prof.Anna Vašků65