Gastrointestinal Pathogens Causing Diarrhea, Dysentery, Enteric Fever, Pseudomembranous Colitis, Food Poisoning and Traveler's Diarrhea
Lecture 32 – Introduction to Gastrointestinal Infections – Rotaviruses and V. cholerae
Reading Assignments: (1) Text Chapters 16, 37, 57, pp. 525-533 and 73 (2) “The Digestive System”, Plates 84-87, In Kapit, W. and L.M. Elson. 1977. The Anatomy Coloring Book, Harper and Row Publishers, New York. (3) Salyers, A.A. and D.D. Whitt. 1994. “Host Defenses Against Bacterial Pathogens- Defenses of Body Surfaces”, In Bacterial Pathogenesis – A Molecular Approach, ASM Press, Washington, D.C. (handed out in Lecture 3), (4) “Infectious Diarrhea”, pp. 230-243; p. 244 and 245 (Viral Causes), In Gates, R. H. 1998. Infectious Disease Secrets, Hanley and Belfus, Inc., Philadelphia, (5) Gilligan, P.H., M. L. Smiley, and D. S. Shapiro. 1997. (Case 25, pp. 115-117), Cases in Medical Microbiology and Infectious Diseases (2nd. Ed.), ASM Press, Washington, D.C. (6) Dold, C. “The Cholera Lesson”, pp. 71-75., Discover (February 1999), (7) Cunha, B.A. 1999. Infectious Disease Pearls (Case 20), Hanley and Belfus, Inc., Philadelphia.
1. ANATOMY AND FUNCTION OF THE SMALL AND LARGE INTESTINES
A. SMALL INTESTINE (See Plate 84, The Anatomy Coloring Book)
1. Regions of the Small Intestine
a. duodenum
b. jejunum
c. ileum
2. A Striking Feature of Small Intestine Anatomy
a. Arrangement of the mucosal cells into finger like-projections called villi. Each
villus contains a network of capillaries and lymphatic vessel (lacteal).
b. The surface of each individual epithelial cell of the villus is divided into
microvilli. These in turn are covered by the glycocalyx –a glycoprotein
matrix with enzymatic activity (see below) Together, the microvilli and the
glycocalyx make up the brush border.
3. A Cross Section Through the Small Intestine
a. Mucosa (with cells arranged in villi)
b. Muscularis mucosa
c. Submucosa 3 muscle layers responsible
d. Circular mucosa for peristalsis
e. Longitudinal muscle
f. Serosa
4. A Close Up of the Small Intestine Mucosa
a. Cells of the Mucous Membrane (held together by tight junctions)
1. Epithelial Cells
a. Enterocytes – absorptive cells – the apical portion of each
enterocyte is covered by microvilli and the glycocalyx.
b. Goblet cells (1/5 of the total cells) – secrete mucus (have
fewer microvilli and no glycocalyx)
2. M cells (part of the GALT) – flat, no microvilli
WHAT IS THE GLYCOCALYX??
The glycocalyx is a glycoprotein matrix with enzymatic activity that is anchored in the plasma membrane and extends into the lumen of the gut. It functions in the final stage of the digestive process. After sugars and proteins have been broken down from large molecules into small molecules by mechanical and enzymatic digestion, enzymes in the glycocalyx break down disaccharides into monosacharides (disaccharidases) and dipeptides into amino acids (dipeptidases). These small molecules are then absorbed by transmembranous proteins into the enterocytes.
WHAT HAPPENS IF THE GLYCOCALYX IS DAMAGED OR DESTROYED BY
A PATHOGEN???
b. Cells of The Crypts
Mucosal cells are born in the crypts, move up the villus surface toward the
lumen, and are released into the lumen as new cells moving up behind
replace them. The average life span of the epithelial cells – 2-5 days; ave.
no. of cells shed/day – 17 billion. The crypts are also the home of the goblet
cells (secrete mucus), endocrine cells (secrete hormones), and Paneth cells
(secrete a variety of substances including lysozyme to control bacteria).
There are also cells in the crypts which can absorb and secrete electrolytes.
c. Lamina Propria
1. Lacteals – lymphatic vessels
2. Arteries and veins
3. The GALT
5. Function of the Small Intestine
a. Most important site of nutrient digestion and absorption. Partially digested
food (chyme) is broken down by mechanical and enzymatic digestion
(secretions from the pancreas, and liver (via the gall bladder)). Final digestion
by the glycocalyx.
b. Peristalsis ensures mixing and efficient absorption of nutrients, and
reabsorption of bile salts and iron.
c. 9 liters of fluid input (2 liters of oral intake and 7 liters of secretions: 1.5 liters
saliva, 2.5 liters gastric juice, 0.5 liters bile, 1.5 liters pancreatic juice, 1 liter
intestinal secretions). The small intestine absorbs 7-8 liters, leaving 1-2 liters
to be absorbed by the colon.
B. ANATOMY AND FUNCTION OF THE LARGE INTESTINE (See Plate 85, Anatomy Coloring
Book)
1. Regions of the Large Intestine
a. caecum (with veriform appendix)
b. ascending, transverse, descending, and sigmoid colons c. rectum, anal canal, and anus
2. A Cross Section Through the Large Intestine (the surface is flat without villi or
folds)
a. Mucosa
1. Epithelial cells
a. enterocytes
b. goblet cells
2. M cells
3. Lamina propria
4. Muscularis mucosae
b. Submucosa
c. Circular muscle
d. Longitudinal muscle
e. Serosa
3. Function of the Large Intestine
a. The only digestion that occurs is from the resident microflora
b. Site of absorption for fluids and electrolytes (absorbs up to 5 liters of
water/day) creating feces. Volume of water left in feces – 100 ml. The rest of
the water is recycled!
2. THE NONSPECIFIC AND SPECIFIC DEFENSES OF THE GASTROINTESTINAL TRACT (Know
these and the way these defenses can be compromised!) (See pp. 519-21 and Reading Assignment
(3), above.)
3. THE NORMAL FLORA OF THE GASTROINTESTINAL TRACT
In the gastrointestinal tract, the density of microorganisms increases from the stomach to the large
intestine.
A. The stomach harbors only transient organisms – predominately acid-tolerant lactobacilli
B. Upper Small Intestine (duodenum) – lightly colonized (104 organisms/g)
C. Middle Small Intestine (jejunum) – (105 – 108/g).
D. Population increases dramatically in the ileum – (108 – 109/g)
E. Bacterial numbers very high in the colon (estimated at 1011/g)- majority are anaerobic
Bacteroides spp.
4. GASTROINTESTINAL TRACT INFECTIONS
A. TERMS USED TO DESCRIBE GI TRACT INFECTIONS
1. Gastroenteritis- inflammation of the mucous membranes of both the stomach and
intestine; characterized by symptoms of nausea, vomiting, diarrhea, and abdominal
discomfort.
2. Enteritis – inflammation of the mucosa of the small intestine
3. Enterocolitis- inflammation of the mucosa of both the small and intestine.
4. Colitis – inflammation of the mucosa of the colon.
5. Hemorrhagic Colitis – inflammation of the colon characterized by hemorrhagic
breakdown of the intestinal mucosa with inflammatory cell infiltration.
6. Hemolytic Uremic Syndrome – a complication of hemorrhagic colitis consisting of
three symptoms- anemia, thrombocytopenia, and renal failure.
7. Pseudomembranous Colitis – a severe ulcerating disease of the colon
characterized by ulcers overlaid with yellow plaques (pseudomembrane) composed of
fibrin, bacteria, cellular debris, and white and red blood cells. This is a life-threatening
condition that can be complicated by perforation and toxic megacolon.
8. Diarrhea – abnormal fecal discharge characterized by frequent and /or fluid stool
a. May be “secretory” (watery) diarrhea – caused by the loss of water and
electrolytes from the enterocytes of the small intestines:
1. the result of bacterial toxins production that cause water and
electrolytes to leave the enterocytes (V. cholerae) or
2. the result of the destruction of the glycocalyx with osmotic loss of
water from the enterocytes
b. May be bloody (inflammatory) diarrhea – caused by the invasion of the
pathogen and an inflammatory process occurring in the ileum or colon.
9. Dysentery – an inflammatory disorder of the colon characterized by (1) cramps, (2)
painful straining to pass stools (tenesmus), and (3) frequent, small-volume bloody,
mucoid diarrhea. Usually resulting from invasive infection of the large intestine
(Shigella spp.and enteroinvasive E. coli ). Diarrhea results from the failure to reabsorb
water from the small intestine.
SUMMARY: HOW CAN DIARRHEA OR DYSENTERY COME ABOUT???
(1) BY EXCESS SECRETION OF FLUID (SMALL INTESTINE)
(2) BY FAILURE TO ABSORB FLUID (COLON)
10. Food poisoning – a group of acute illnesses caused by the ingestion of
contaminated food, characterized by vomiting, diarrhea, enteritis, and prostration. It
may result from (1) ingestion of preformed toxins, or (2) by food that acts as a vehicle
for the pathogen (food-associated infection). (See Text Chapter 73)
11. Traveler's Diarrhea – diarrhea or dysentery in a traveler who goes from a highly
developed country to a developing country. (See Reading Assignment (4), pp. 241-
242).
12. Cholecystitis – inflammation of the gall bladder (see Lecture 29)
B. EPIDEMIOLOGY OF GASTROINTESTINAL INFECTIONS
1. Transmission – fecal-oral route (4 F's: Food, Fingers, Feces, and Flies) Read: “Why
It Is Hard To Stay Well”.
a. ingestion of pathogens in food or water contaminated with human or animal
feces.
b. Person-to person spread – children put their hands in each other's mouths or
handle toys that have been mouthed by other children. (Outbreaks of
Hepatitis A virus and Shigella spp. in Day Care Centers)
2. The Infectious Dose of diarrheal pathogens varies greatly:
a. Salmonella spp. and V. cholerae – 105 to 107
b. Shigella spp. – less than 10 organisms
C. TREATMENT OF GASTROINTESTINAL INFECTIONS
The major pathophysiologic effect of diarrhea is dehydration due to fluid and electrolyte loss so the most important therapy is oral rehydration therapy (See Text p. 533). Simple solution of glucose, salts, and water given orally are highly effective in treating patients with even severe diarrhea. This therapy, applied in the developing countries, has saved millions of lives of young children.
With certain invasive pathogens, antibiotics are also given.
D. SELECTED PATHOGENS THAT CAUSE GASTROINTESTINAL INFECTIONS (IN ORDER
OF INCRESING INVASIVENESS) (Not covered in this course - other viral, protozoan, and
parasitic causes of GI disease
1. Vibrio cholerae and Enterotoxigenic E. coli (ETEC) (watery diarrhea)
2. Enteroaggregative E. coli (EAEC) (watery diarrhea, persistent diarrhea)
3. Enteropathogenic E. coli (EPEC) (watery diarrhea)
4. Rotaviruses (watery diarrhea)
5. Enterohemorrhagic E. coli (EHEC) (hemorrhagic colitis and hemolytic
uremic syndrome)
6. Shigella spp. and Enteroinvasive E. coli (EIEC) (dysentery and
sometimes hemolytic uremic syndrome)
7. Campylobacter jejuni, Yersinia enterocolitica, and Salmonella spp.
(bloody watery diarrhea)
8. Salmonell typhi and S. paratyphi (enteric fevers)
OTHER INFECTIONS:
9. Clostridium difficile (antibiotic associated pseudomenbranous colitis)
10. Agents of food poisoning:
a. Ingestion of pre-formed toxins – S. aureus, C. botulinum,
B. cereus
b. Food-borne infections – V. cholerae, V. parahemolyticus, C.
perfringens, Campylobacter jejuni, Salmonella spp., Yersinia
enterocolitica, Listeria monocytogenes.
E. ROTAVIRUSES ARE THE MOST COMMON CAUSE OF DIARRHEA IN
CHILDREN IN THE UNITED STATES (Read Chapter 37 (including Case
Study p. 345, and Case 25 in Reading Assignment (5) )
1. Rotaviruses
a. Genome- double stranded segmented RNA
b. Seasonal distribution (See Text p. 346)
c. The pathogenesis of rotaviruses is an example of a localized
viral infection of the mucous membranes (Review Lecture 5
and 6; See Text p. 348.) (Be able to explain the pathogenesis of
this diarrheal pathogen.)
d. A Vaccine Recalled: BONUS QUESTION #1 – EXAM 3
After many years of basic research and vaccine
development, Rotashield, the first vaccine against rotavirus,
was licensed for production by the FDA on August 31, 1998.
One year later, the vaccine was withdrawn from the market.
What did this vaccine consist of, what type of immune
response did it elicit, and why was it withdrawn?
INFECTIONS IN CHILDREN AND ADULTS
1. Enterobacteriaceae
a. E. coli
b. Salmonella spp.
c. Shigella spp.
d. Yersinia spp.
Common characteristics: Gram negative rods; nonmotile or motile with peritrichous
flagella; share a common antigenic structure.
Antigenic Structure:
a. O antigens – LPS
b. K antigens (or Vi antigens for Salmonella typhi– capsular
polysaccharides (external to the O antigen.
c. H antigens – a heat-labile antigen carried on the flagella
Antigenic Classification indicates the presence of each antigen,
e.g. E. coli O55:K5:H21
2. Vibrionaceae
a. Vibrio cholerae
b. Vibrio parahemolyticus
Common characteristics: Gram negative – curved shaped bacteria with polar
flagella. Members of a species are subdivided based on their O antigens (139
described to date). For example, V. cholerae O1 and O 139 cause epidemic or
pandemic outbreaks of classic cholera.
3. Campylobacter jejuni- changing classification- currently classified as
members of superfamily VI of Gram negative bacilli
Common characteristics: Gram negative -curved (gull-wing or S
shaped) with polar flagella; microaerophilic
G. COMMON THEMES IN THE PATHOGENESIS OF GASTROINTESTINAL PATHOGENS
1. Entry into the host by ingestion.
2. Survival of the nonspecific defenses of the host and successful arrival at the mucous
membrane.
3. Attachment to and colonization of the mucous membrane (on the
surface of the enterocytes) or invasion across the mucous membrane.
4. Evasion of the nonspecific host defenses (inflammation, phagocytosis, complement)
and the specific host defenses.
5. Multiplication on the mucous membrane and/or spread into deeper tissues.
6. Damage to the host by:
a. colonization of the surface of the enterocyte with production of an exotoxin (s)
(enterotoxin) that acts locally (V. cholerae and ETEC)
b. colonization of the surface of the enterocyte with damage to the enterocyte
(EPEC and EAEC (+ cytoxin))
c. colonization of the surface of the enterocyte with damage to the enterocyte
and production of a exotoxin (cytotoxin) that acts locally in the GI tract and
systemically in the kidneys (EHEC)
d. invasion across the mucosal membrane via the M cells (triggering an
inflammatory response in the lamina propria), followed by invasion into
enterocyte with intracellular multiplication and spread. (Shigella spp. and
EIEC) (Rare strains elaborate a toxin that acts systemically like (c)).
e. invasion across the mucosal membrane (intracellularly or via the M cells),
multiplication in the lamina propria (triggering an inflammatory response),
spread to the Peyer's Patches and mesenteric lymph nodes (rare bacteremia)
– C. jejuni and Salmonella spp. )
f. invasion across the mucosal membrane via the M cells, systemic spread to
Peyer's Patches, mesenteric lymph nodes and bloodstream, and
dissemination throughout the body; late infection of the intestines via bile (S.
typhi and S. paratyphi)
H. GENETICS OF BACTERIAL PATHOGENS- THE ROLE OF MOBILE GENETIC ELEMENTS
IN VIRULENCE
Mobile genetic elements (including phages, plasmids, and pathogenicity islands)
contribute to the virulence of bacterial gastrointestinal pathogens! Think of pathogens as
having a baseline genome to which is added virulence genes. Individual virulence genes
(or blocks of genes) can be carried on extrachromosomal plasmids or on the chromosome –as lysogenized phages or pathogenicity islands. (See Stanley Falkow – What is a Pathogen? and Text p. 50). The virulence gene(s) that the pathogen carries determines the type of disease the pathogen causes.
Some examples:
1. C. diphtheriae and V. cholerae are lysogenized with phages that carry genes for A-B
exotoxins. It is the exotoxins that cause the characteristic symptoms of disease.
2. Enterotoxigenic E. coli strains carry plasmids that encode for adhesins that allow
colonization and heat-labile and heat-stable enterotoxins that cause watery diarrhea.
3. E. coli strains associated with urinary tract infections carry pathogenicity islands that
carry the genes encoding P pili (important for the adherence of E. coli to the urinary
tract epithelium) and a hemolysin (which contributes to the damage and inflammation
associated with urinary tract infections.)
4. Enterohemorrhagic E. coli strains carry genes for toxins (encoded on bacteriophages
integrated into the chromosome), and for adhesins and hemolysins found on a
plasmid.