Faisal Basheer

How do bacteria cause disease of the gastrointestinal tract?

Infections of the gastrointestinal tract (GIT) are some of the commonest, affecting all communities
across the world. They are one of the largest causes of morbidity and mortality, and are still highly
prevalent even in the UK, despite the standards of sanitation and education being high.

Structure and natural defences of the GIT

The gastrointestinal tract (GIT) is basically a long tube, open (hence exposed to the environment) at
both ends. Bacteria, along with other microorganisms, are capable of entering the mouth, every time
food or drink is ingested, or utensils are put into the mouth. The local environments in different parts of
the gastrointestinal tract vary widely, and this influences the nature of the local flora, and therefore, of
the pathogens which may invade it.
The stomach has a highly acidic internal environment, and contains variable amounts of air. Few bacteria
are capable of surviving in such an atmosphere for long periods of time, and the majority swiftly pass on
through. Bacteria can be protected from this acidity by passing through inside boluses of food, especially
fats.
The duodenum and upper small intestine have internal alkaline environments and possess highly
vascular mucosa, which attracts adherent parasites. The highly absorptive mucosa of the jejunum and
the ileum provides a possible means of entry for toxins, not only those adapted to adhere to mucosal
cells, but systemic toxins that can cause non-intestinal disease (e.g. botulism).
The terminal ileum and colon have highly anaerobic environments compared to the rest of the bowel.
Thus, they are inhabited by large numbers of anaerobic bacteria, both Gram +ve and –ve. Facultative
organisms are also capable of occupying this environment.
The GIT has many natural defences – gastric acid being a major one. It reduces the numbers of bacteria
that enter the stomach and pass into the intestines. However, bacteria such as Shigella can evade this,
by having protective outer coat proteins, or Helicobacter Pylori, which diminishes the local acidity by
biochemical means. Bile salts of the duodenum inhibit the survival of many organisms. Immune
responses are also protective mechanisms. Bowel mucosa is rich in lymphocytes and contains much
lymphoid tissues, e.g. Peyer’s patches. Cell mediated immunity is provided by lymphocytes sensitised to
antigens of recently active pathogens. Secreted IgA provides humoral immunity. Plasma cells are often
plentiful too. The response of the immune system to disease of the GIT caused by bacteria can largely
underlie the pathology of the disease. However, pathogenic bacteria have evolved many means of
causing disease, and evading the host’s natural defences.

Typical bacterial diseases

Most bacterial infections exhibit a general non-specific pattern of damage to the surface epithelium,
decreased epithelial cell maturation, increased regenerative rate of cells and variable neutrophilic
infiltration into the lamina propria and epithelial layer. Bacterial damage to host tissues depends on their
ability to adhere to host cells, invade cells and tissues, and deliver toxic moieties. These virulence
properties are determined by a multitude of genes and gene products.
Bacteria can cause disease either by food intoxication (via toxins) or by actually infecting the host, either
by being invasive or by colonising the epithelial surface and exerting their effects from there. Disease is
caused by 1) Ingesting preformed toxin, 2) Infection by enteroinvasive organisms, 3) Infection by
toxinogenic organisms (which proliferate in the gut lumen and produce an enterotoxin)

Typical food intoxications can occur from species such as Clostridium botulinum, which causes
botulism. Preformed toxins of the Clostridium botulinum during anaerobic growth in food, enter the GIT,
and are absorbed from the stomach. The toxin cleaves synaptobrevin in presynaptic nerve terminals, and
prevents the release of neurotransmitter, causing a flaccid paralysis, which can be life threatening.
Staphylococcus aureus is able to produce a variety of toxins, among which are enterotoxins A-E. They
are preformed toxins produced during the replication of staphylococci in prepared food. Food poisoning
occurs when an infected individual, contaminates food usually from a skin lesion or nasopharyngeal
secretions. The organism subsequently multiplies and produces toxin, which is absorbed and travels in
the circulation to the ‘vomiting centre’ of the hypothalamus and causes vomiting by a central effect.
Vomiting maybe forceful enough to be described as “projectile vomiting”. It may also cause bowel
irritation leading to mild and transient diarrhoea.
Bacillus cereus, an aerobic Gram +ve rod, forms spores and contaminates cereals and types of bean. It
may also occur in faeces and contaminate meat. Food poisoning serotypes of this bacteria produces
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spores, which are resistant to boiling. Boiled foods may be stored at ambient temperatures for later
rewarming and it is in this period where the spores germinate and highly heat resistant preformed toxins
accumulate in the food. The toxins cause severe vomiting and produce an illness similar to
staphylococcal food poisoning.

Invasive Bacteria such as Salmonella, Shigella and enteroinvasive E. Coli (EIEC), invade and destroy
mucosa of the large intestines, passing through tissue planes, and may even reach the blood supply.
Both EIEC and Shigella possess a large virulence plasmid conferring the capacity for epithelial cell
invasion. Bacterial invasion is followed by proliferation intracellularly, cell lysis, and spreading from cell to
cell.
Salmonella are flagellated, Gram -ve bacteria, causing a food-borne and water-borne gastroenteritis.
Salmonella enteriditis causes typical Salmonella food poisoning, by infecting the gut epithelium. However
it does not pass beyond the basement membrane. The salmonellae first digest the mucosal glycocalyx,
and then invade the mucosa. This is followed by induction of cytoskeletal rearrangement and
phagocytosis by the endothelial cells. This is via the ‘trigger’ mechanism, where the bacterium injects
invasion proteins that induce the cytoskeletal rearrangement around it, and are endocytosed into a
vacuole. The phagocytotic vacuole is used as a means of traversing the cell and passing into the
subepithelial space, where they multiply and cause intense local acute inflammation. This is what causes
the effects of disease. Salmonella typhimurium adapted for the human host causes systemic typhoid
fever. It has the capacity to spread from the submucosa, and multiply in various organs, e.g. liver,
spleen, lymph nodes etc. It is capable of passing through the basement membrane and spreading via
the bloodstream. Typhoid fever is a protracted disease associated with bacteraemia, fever and chills
during the first week, rash, abdominal pain, and ulceration of Peyer’s patches with intestinal bleeding
and shock during the 3rd week or so.
Shigella bacteria cause bacillary dysentery, which is characterised by diarrhoea with abdominal
cramping, and tenesmus in which faeces contain blood and pus. Shigellae are enteroinvasive, passing
through the intestinal mucosal cells, but remain outside the lamina propria. The disease is caused when
the bacteria escape the epithelial phagolysosome, multiply within the cytoplasm, and destroy host cells.
They also cause apoptosis of macrophages in the region. Shigellae also produce Shiga toxin which, via
blocking protein synthesis by cleaving rRNA, causes haemorrhagic colitis and possibly haemolytic uremic
syndrome, by damaging endothelial cells in the colon and glomerulus respectively. In the latter case,
renal failure can occur as a result.
Listeria invades and traverses the intestinal mucosa too and can enter macrophages. However, it can
spread systemically, and also invade hepatocytes where it multiplies and spreads.

Colonising bacteria tend to colonise the epithelial surface and tend not to invade the cell layer, but
exert their effects from there. To produce disease, these organisms must adhere to the mucosa;
otherwise they are swept away by the fluid stream.
Vibrio cholera do not invade epithelium, but instead remain in the lumen and secret enterotoxin which is
encoded by a virulence phage. Adherence of such an enterotoxinogenic organism is mediated by
plasmid-coded adhesins. These proteins are expressed on the surface of the organism in the form of
fimbriae or pili. V. Cholera causes disease by releasing cholera toxin, composed of five binding peptides
‘B’ and one ‘A’. A is the active subunit, and enters the epithelial cells via B forming a pore in their
membranes, and causes ADP-ribosylation of the subunit of a G s G-protein. This generates excess cAMP,
which causes intestinal epithelial cells to secrete isosmotic fluid, resulting in copious amounts of ‘rice-
water’ diarrhoea and loss of water and electrolytes. This can lead to shock and collapse, and cardiac
failure.
Helicobacter pylori is another good example of a colonising bacteria. It is Gram –ve, and causes gastritis.
It elaborates urease – producing ammonia from urea endogenously, and buffers gastric acid in its
immediate vicinity. It is extremely motile, and binds to gastric epithelial cells via a bacterial adhesin. As a
result, it colonises the mucin layer near gastric mucosal cells. It causes intense inflammation and leads
to ulceration, and progression of the ulcer is accompanied by more inflammation and more tissue
destruction.

Bacteria however, tend not to cause disease by solely one of these general methods and some species
use a mixture of them, for example Escherichia Coli. It uses a range of virulence factors to cause disease
in the host. E. Coli can be divided into 4 types by their varying functions and means of pathogenicity.
However, all are Gram –ve bacteria. Enterotoxinogenic E. Coli (ETEC) colonises the lumen via adhesins
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and produces cholera like Labile toxin, that exerts similar effects to the cholera toxin and is related to it
biologically and immunologically. However, E. Coli can also be enterohaemorrhagic (EHEC), producing a
Shiga like toxin, inducing the release of cytokines and causing intense inflammation. This destroys
epithelial cells and leads to vascular damage and renal failure. Enteropathogenic E. Coli however, will
only attach to the surface of epithelial cells (forming ‘pedestals’ by cytoskeletal rearrangement). E. Coli
also has an invasive form Enteroinvasive E. Coli, which invades the cell layers and spreads, causing
similar effects to EHEC and Shigella.

In general, have developed many individual complex mechanisms of causing disease of the
Gastrointestinal tract, but these can be grouped into more general categories, by their inherent
similarities in terms of overall mode of function.