Pathophysiology of the gastrointestinal tract

1. Pathophysiology
of the gastrointestinal tract

2. Gastrointestinal tract
• Organs of oral cavity
• Esophagus
• Stomach
• Small and large intestine
• Secretory function of
salivary glands, liver,
pancreas
Neurohormonal regulation

3. Major processes in GIT
nutrition
digestion, absorption
movement
Salivary glands
absorption
Vena cava
rectum
stomach
esophagus
Colon
intestine
secretion
digestion
motility

4. Physiology of the stomach
Esophagus
Fundus
Pyloric sphincter
Duodenum
Antrum
(secretion of
mucus,
pepsinogen,
gastrin)
isthmus
Parietal cells
Smooth muscle
cells
G-cells
Chief cells
cells
Body
(secretion of mucus,
pepsinogen, HCl)

5. Regulation of gastric secretion

6. Phases of gastric secretion and their regulation

7. Mechanisms of gastric
hypersecretion
• Stimulation:
neurogenic (vagotonia),
hormonal (gastrin, histamine, ↑Ca2+ in
hyperparathyroidism…)
• Failure of inhibitory mechanisms (antral,
duodenal)
• Hyperplasia of the gastric glands

8. Gastrinoma (Zollinger-Ellison syndrome)
• Marked gastric hypersecretion
• Diarrhea
• Abdominal pain
• Peptic ulcer(s) of upper GI tract
• Gastro-esophageal reflux
• Gastrin-secreting tumor of the duodenum
(75%), pancreas (24%), stomach, liver,
ovary (1%).

10. Pathogenic consequences of
gastric hypersecretion
• Disorders of gastric motility (hypercontraction)
• Disorders of digestion
• Hyperkinesia
• Disorders of water-electrolyte and acid-base balance
Development of acid-dependent diseases
Erosion Acute ulcer Chronic ulcer
mucosa
Submucous layer
Muscle layer
Serous

11. mucus
bicarbonate
PG Е2
Adequate blood flow
HCl
pepsin
Bile acids
Helicobacter рylori
agressive
Aggressive and protective factors of
gastric juice
amylin
protective

12. Helicobacter pylori

13. The role of Helicobacter pylori
Helicobacter pylori
urease
urea
ammonia
Increase of pH
in antrum
Gastrin production
Hyperproduction of
НСl
Increase of
IFN , TNF
apoptosis, slowing
of regeneration and
reparation
Antral gastritis B, ulcer
Risk of cancer
Cytiotoxic
effect
cytotoxines
(Vac A, Cag A…)
Injury of
epithelium
Infiltration with
neutrophils

14. Hypersecretion
↑ Н+ ↑ pepsin
• H2 receptor blockers
• Proton pump inhibitors
H. pylori
Oral vaccine
Eradication therapy:
proton pump
inhibitor plus two
antibiotics
Nonsteroidal anti-
inflammatory drugs
Potentiation
↑ cytokines (IL-1,6, TNFα)
↑ heat shock proteins
↑ chemokines (IL-8)
Virulence factors:
CagA, VacA, urease,
OipA, BabA
Inflammatory cascade
(cytokines, neutrophils,
lymphocytes)
Injury to the mucosa,
mucosal defect and ulcer
formation
↓ prostaglandin
synthesis
Local and systemic
effects
• Prostaglandin
analogues
• Bismuth salts
↓ mucus production
↓ blood flow
↓ bicarbonate
↓ regeneration
↑ neutrophils
Pathogenesis of peptic ulcer and therapeutic targets

15. Pathogenesis of gastro-esophageal
reflux disease (GERD)
Motor dysfunction of the
lower esophageal sphincter
Gastro-esophageal
reflux
Decreased
mucosal
resistance
Increase in
intragastric
pressure
Decreased esophageal clearance
Gravity Esophageal
peristaltics
Saliva
Renewal of the
epithelium

16. Achalasia (cardiospasm)
https://www.roshreview.com/blog/rapid-review-achalasia/

17. Esophageal motor innervation by the vagus nerve
Ates & Vaezi. Gut Liver. 2015;9(4):449-63.

18. Degeneration of inhibitory neurons of the myenteric
plexus results in CCK-OP-mediated constriction
Ates & Vaezi. Gut Liver. 2015;9(4):449-63.

19. Mechanisms of gastric hyposecretion
• Disorders of regulation:
- neurogenic
- hormonal
• Atrophy of mucosa:
- autoimmune gastritis
- multifocal atrophic gastritis
• Resection of the stomach

20. Sydney classification of chronic gastritis (1996)
Name Non-atrophic Atrophic autoimmune Multifocal atrophic
Synonyms Type B gastritis Type A gastritis Mixed type (A+B)
Etiology H. pylori Autoimmunity (Т-cells) H. рylori, diet disorders
Localization Antral part Corpus and fundus All gastric mucosa
Additional information Severe inflammation, focal
intestinal metaplasia,
hypersecretion
Hypoacidity and
hypochlorhydria, pernicious
anemia
Secondary atrophy, low-grade
inflammation, hyposecretion
Normal

21. Pathogenesis of autoimmune gastritis
Lenti MV et al. Autoimmune gastritis. Nat Rev Dis Primers. 2020; 6(1): 56

22. Multifocal atrophic gastritis Autoimmune gastritis
Localization Initially – colonization of pyloric part, with
time – spreading to the corpus
Only corpus of the stomach
Clinical signs • Peptic ulcer
• Lymphoma
• Iron-deficiency anemia
• Metaplasia, dysplasia,
adenocarcinoma
• В12-deficiency anemia
• Achlorhydria
• Hyperplasia of ECL cells/carcinoid
• Autoimmune polyendocrine syndrome
• Metaplasia, dysplasia
Antibodies • Anti–H. pylori IgG
• Rarely - autoantobodies
• Autoantibodies against proton pump subunits
and/or intrinsic factor
• Sometimes – anti-H. pylori IgG
Cells if the
infiltrate
• Т-helpers 1 and 17, В-cells
• Neutrophils, macrophages, dendritic
cells, eosinophils
• Т-helpers 1 and 17, В-cells
• Macrophages, dendritic cells, eosinophils
Treatment and
monitoring
• Эрадикационная терапия
• Эндоскопический скрининг
• Vitamin В12
• Endoscopic screening
Comparison of multifocal atrophic and autoimmune gastritis

23. Complications of gastric hyposecretion
• Disorders of protein digestion
• Hypokinesia of the stomach
• Disorders in barrier function
• Disorders of iron and vitamin В12 absorption
• Disorders of intestinal secretion and digestion

24. Correa’s cascade – progressive morphological changes in
gastric mucosa leading to adenocarcinoma
Pelayo Correa (born 1927)
He J et al. Cancer Lett. 2022; 542: 215764

25. Increased gastric motility
(gastric hyperkinesia)
• Neurogenic
• Increased production of НСl, gastrin,
motilin …
• Hypercalcemia
• Pylorostenosis
Complications:
• Decrease volume adaptation
• Increase in intragastric pressure
• Increased tone of the stomach
• Dyspepsia

26. Decrease of gastric motility
• Neurogenic:
- reflex gastroparesis
- authonomic neuropathy (diabetes, alcoholism)
- vagotomia
• Humoral:
- hyposecretion of НCl
- increased production of CCК, GIP, amylin…
• Disorders of smooth muscle cell metabolism:
- anorexia
- chronic intoxication
- hypokalemia
- ischemia

27. The passage of chyme through GI tract in normal conditions
(A) and after resection of stomach (B)
A B

28. The consequences of stomach resection
• Disorders in reservoir function of the stomach
• Decreased number of secretory cells (achlorhydria)
• Vitamin B12 deficiency → anemia
• Disturbance of fractional influx of chyme into the duodenum
• Disturbances in the regulation of secretory function of
pancreas and liver
• Accelerated passage of chyme through the small intestine

29. Mechanisms of jejunal (postgastrectomy,
dumping) syndrome
 Early (~75%)
Dumping of the hyperosmolar chyme into the
intestine
• Influx of water into the lumen
• Stimulation of intestinal peristaltics
• Stimulation of BAS formation (5-HT, VIP, kinins etc.)
 Late (~25%)
Absorption of high amount of carbohydrates
into the blood
• Hyperglycemia  insulin release  hypoglycemia
 activation of sympathetic nervous system 
tachycardia, perspiration

30. chyme
secretion
digestion
absorption
blood
movement
• Digestion (hydrolysis) of
substances
• Absorption of proteins, fats
and carbohydrates
• Absorption of water,
microelements and vitamins
• Absorption of endogenous
and bacterial substances
(bile acids, short chain fatty
acids …)
General processes in intestine

31. Digestion and absorption of
carbohydrates and proteins
Epithelium
Lumen Capillary
Carbohydrates
Proteins
Pancreatic
enzymes
Intestinal
enzymes
Amino acids
Monosaccharides
Diffusion
Active
transport

32. Malabsorption syndrome (complex
of several symptoms: loss of weight,
diarrhea, edema, anemia etc.)
Three groups of causes of malabsorption:
1. Lack of digestion (maldigestion syndrome):
inadequate mixing, lack of enzymes and/or
bile salts
2. Mucosal/mural problems (e. g., autoimmune
enteropathy, systemic sclerosis)
3. Microbial causes (viral, bacterial or protozoal
enteritis)

33. Classification of malabsorption
syndrome
1. Gastrogenic
2. Hepatogenic
3. Pancreatic
4. Enterogenic:
- enterocellular
- postcellular
20% of alcohol
Ca, Mg, Fe
glucose
Water-soluble
vitamins
Fat-soluble
vitamins
Amino acids
fats
80% of alcohol
water
Bile acids
Vit В12
water
Acids, gases
Na, K
Na, K
Stomach
Intestine
Colon
Rectum
1. Primary
2. Secondary

34. Mechanisms of pancreatic
malabsorption: insufficiency
of pancreatic enzymes
Absolute
• Decrease in secretory cells amount (chronic
pancreatitis)
• Disorders of regulation
• Genetic disorders
• Disorders of entrance of pancreatic juice into the
intestine (biliary stones, cystic fibrosis etc.)
Relative
• Lipase inactivation
• Inhibition of activation of pro-enzymes
• Hypekinesia of intestine

35. Consequences of pancreatic
insufficiency
• Maldigestion
• Malabsorption
• Entrance of large volumes of chyme into
the colon
• Autoagressive effect of pancreatic
enzymes

36. Disorders of membrane
digestion
Causes
• Decreased number of enterocytes
• Decreased functional activity of
enterocytes
• Accelerated passage of chyme
Complications
• Enterogenic malabsorption syndrome

37. По T.L. Lentz, Cell Fine Structure. Philadelphia: Saunders, 1971
Enterocyte Goblet cell Enteroendocrine
cell (>15 types)
Paneth cell
Four major types of cells in the enteric mucosa

38. Differences between enterocellular and
postcellular malabsorption
Enterocellular Postcellular
Normal
Lumen

39. Enterocellular type of malabsorption
microvilli
Lactase
• Inherited deficit of enzymes and
transporters of carbohydrates, amino acids …
• Atrophy of intestinal epithelium (chronic
intestinal ischemia, inflammation)
• Surgical resection of intestine
Example - deficiency of lactase
• Lactose – substrate for bacteria
• Osmotic diarrhea, spastic pain……..

40. Postcellular type of malabsorption
• Lymphoid hyperplasia
• Intestinal lymphangiectasia
• Amyloidosis of mesentery vessels
Epithelial
cells
Arterioles
Venules
Lymphatic vessels
Mucous-producing
cells

41. Pathogenesis of the main manifestations of
malabsorption syndrome
• Decreased body weight (↓ absorption of fats, carbohydrates,
amino acids)
• Peripheral edema (↓ absorption of amino acids,
hypoproteinemia)
• Osteoporosis (↓ vit. D absorption → Ca2+ deficiency)
• Peripheral neuritis (vit. B deficiency)
• Anemia (deficiency of proteins, vit. B12 and Fe)
• Hemorrhages (vit. K deficiency)

42. Irritable bowel syndrome
• Leading functional disorder of digestion
• Chronic abdominal discomfort
• Abdominal pain (decreasing after defecation)
• Changes in the frequency of defecation:
constipation predominant, diarrhea predominant,
or alternating constipation and diarrhea

43. Intestinal microbiota
• The gut contains 100 trillion bacteria - about three
pounds
• At least 1000 different species of known bacteria
• Small intestine is almost sterile while most of the
microorganisms reside in large intestine
• Main functions of intestinal flora:
– Stimulation of immune system
– Synthesis of vitamins
– Regulation of intestinal motility
– Colonization resistance
– Xenobiotic and drug metabolism

45. Causes of intestinal dysbiosis
• Antibiotics and immunosuppressive drugs
• Resection of the stomach and/or intestine
• Severe gastric hyposecretion
• Unbalanced food with excessive amount of
carbohydrates
• Primary and secondary immune deficiencies
• Malabsorption syndrome
• Intestinal obstruction (tumors, Crohn disease, etc.)
• Impaired passage of chyme through the intestine
(motor dysfunction)

46. Consequences of intestinal dysbiosis
• Altered microbiota profile
• Increased amount of Gram-negative and
anaerobic microorganisms
• Increased permeability of the gut barrier
• Injury to entrocytes (shortening of the villi)
• Impaired luminal and membrane digestion
• Secondary malabsorption

47. Main typical pathological processes which
affect intestinal function
• Infectious inflammation (bacterial, viral, protozoal etc.)
• Non-infectious chronic inflammation
• Immune-mediated injury
• Tumor growth
• Ischemia

48. Pathogenesis of shigellosis

49. Celiac disease (gluten entropathy,
nontropical sprue): immune-mediated
intestinal injury
1. Main manifestations: chronic inflammation
of mucosa, atrophy of the villi,
malabsorption
2. Infiltration of mucosa with T-lymphocytes
3. The process is triggered by intake of
gluten (wheat protein)
4. Genetic background: HLA-DQ2, HLA-DQ8

50. Immunopathogenesis of celiac disease

51. Acute mesenteric ischemia
• Local arterial obstruction
(atherosclerosis, thrombosis, embolism)
• Acute impairment of venous outflow
• Systemic hemodynamic disorder (e. g.,
shock) resulting in severe intestinal
hypoxic injury

52. Anatomical and physiological characteristics
of the villus microcirculation

53. Multifactorial basis of inflammatory bowel disease
Altered composition of
intestinal microbiota
+
increased epithelial
permeability
Loss of tolerance to
commensal bacteria
Environmental factors:
•Western diet
•Smoking
•Stress
•Vitamin D deficiency
•Appendectomy
•Oral contraceptives
•NSAIDs
Activation of innate and adaptive
immunity
Genetic predisposition
(> 230 genes):
•Cytokines
•Chemokines
•Antimicrobial peptides
•Pattern-recognition
receptors (TLR, NOD)
Infiltration of mucosa with leukocytes
Chronic inflammation

54. Inflammatory bowel disease

55. Inflammatory bowel disease

56. Intestinal tumors
• Tumors are much more common in the colon and
rectum than in the small intestine
• Hereditary form – familial adenomatous polyposis
syndrome (AD, multiple tubular adenomas of the
colon, 100% malignization)
• Acquired colorectal cancer (98 % - adenocarcinoma)
has several dietary risk factors:
– Deficiency of non-absorbable fibers in the food
– Increased amount of carbohydrates and fats
– Low amount of vitamins A, C and E

57. Mechanisms of disorders in
intestinal motility
• Activation or inhibition of n. vagus
• Inhibitory effects of adrenergic nerves
• Changes in the activity of the neurons of
intramural plexuses
• Pacemaker activity change
• Ectopic excitation
• Disorders of migratory myoelectrical
complex

58. Complications of intestinal
hyperkinesia
• Relative enzyme insufficiency
• Decreased contact of chyme with
enterocytes
• Colon overload
• Diarrhea

59. Complications of intestinal
hypokinesia
• Stagnation of chyme
• Reflux of bacteria
• Putrefaction, fermentation
• Intestinal endotoxicosis

60. Intestinal obstruction
• Mechanical:
– Obturation
– Strangulation
• Functional (dynamic):
– Spastic
– Paralytic

61. Mechanical intestinal obstruction
Mechanical
Obturation
(lumen is
blocked but the
blood flow and
innervation are
normal)
Intraintestinal obturation:
• Tumors
• Scars
• Biliary stones,
• Foreign bodies
• Worm aggregations
Extraintestinal compression:
• Tumors and cysts of the abdominal
organs
• Infiltrates and abscesses of the
abdominal cavity
Strangulation
(↓ lumen +
compression of
vessels/nerves)
• Volvulus
• Closed-loop obstruction
• Strangulation of hernia
Combined • Intussusception
• Multiple adhesions

62. Water absorption in GI tract
Consumption
2000 ml
Daily volume in duodenum
8000-10000 ml
Consumption 2000 ml
Saliva 1500 ml
Gastric juice 2500 ml
Bile 500 ml
Pancreatic juice 1500 ml
Intestinal secret 1000 ml
Excreted 100 ml
1500 ml

63. Types of diarrhea
• Secretory (stimulation of secretion by microbial toxins,
bioactive substances or hormones)
• Osmotic (decreased absorption, i.e. lactase deficiency)
• Hyperkinetic (increased intestinal motility, e.g., IBS or
dumping syndrome)
• Exudative – severe injury to gut barrier (enteritis, e.g.
salmonella, amoebiasis, etc.)

64. Exogenous
infectious
Enteric bacterial infections (entrotoxigenic E. coli, Shigella spp.,
Salmonella spp., Clostridium perfringens, Clostridium botulinum,
Vibrio cholerae)
Viral diarrhea (Norwalk, Rotavirus)
Exogenous non-
infectious
Use of laxative drugs
Other drugs (diuretics, cholinomimetics, quinidine)
Exogenous intoxications (As, insecticides, ethanol)
Endogenous
infectious
Enterotoxins of normal or opportunistic flora (E. coli,
Staphylococcus aureus, Clostridium difficile)
Endogenous
non-infectious
Hyperproduction of vasoactive intestinal polypeptide
Gastrin-producing tumor (ZES)
Medullary carcinoma of the thyroid (increased production of
calcitonin and prostaglandins)
Mastocytoma (increased production of histamin)
Increased level of bile acids and short-chain fatty acids in the colon
Main causes of secretory diarrhea

65. Cholera: a secretory diarrhea
Lumen
Enterocyte
V. cholera
Cholera
toxin
Adenylate
cyclase
↑ cAMP ↑
Cl- Cl-
+
Na+
H+
Cl-
HCO3
-
-

66. Other factors contributing to
pathogenesis of diarrhea
• Motility changes (increased or decreased
transit time)
• Release of inflammatory mediators
(histamine, serotonin, prostaglandins etc.)
• Increased permeability of the intestinal
barrier (weakening of tight junctions)
• Epithelial dynamics

67. Mechanisms of constipation
• Insufficiency of neurogenic
regulation
• Disorders of humoral
regulation
• Deficiency of bile acids
• Insufficient mechanical
stimulation of the colon
• Congenital lack of ganglionic
cells in the colonic submucosa

68. Classification of bariatric surgery types
Bariatric surgeries
Restrictive Combined
(malabsorption + restriction)
Intragastric balloon
Adjustable
gastric band
Sleeve gastrectomy
Gastric bypass
Biliopancreatic
diversion

69. Mechanisms of weight reduction after bariatric surgery
Pucci A, Batterham RL. J Endocrinol Invest. 2019; 42(2):117-128