Mechanisms of enteric disease caused by
rotavirus and Brachyspira ­hyodysenteriae
Adam J. Moeser, DVM, ­PhD
North Carolina State University College of Veterinary Medicine, Raleigh, North C
Introduction
Rotavirus and Brachyspira hyodysen-
teriae are among the most important
causes of diarrheal disease in swine.
Each of these pathogens has distinct
mechanisms by which it causes intes-
tinal disease; however, the common
end point is intestinal epithelial
dysfunction and diarrhea. This paper
will focus on the mechanisms by
which rotavirus and B hyodysenteriae
disrupt intestinal epithelial function
leading to inflammation, malabsorp-
tion, diarrhea, and associated pro-
duction ­losses.
Pathogenic mechanisms
of ­rotavirus
Rotavirus attaches to mature entero-
cytes on the upper third of the villus.
Once bound to the receptor on the
enterocyte (thought to involve sialic
acid-dependent and independent
mechanisms), rotavirus enters the
enterocyte via Ca2+-dependant endo-
cytosis, where it replicates within the
cytoplasm. Rotavirus infection re-
sults in marked changes in histologi-
cal features of the intestine, including
stunted villi and a change from co-
lumnar to cuboidal epithelium within
24 hours of infection. These effects
are most pronounced in the proximal
portion of the small intestine. In addi-
tion to histological damage, rotavirus
can disrupt the normal functioning of
the intestinal epithelium by altering
absorptive and secretory pathways.
Rotavirus has been shown to impair
glucose absorption via 2 mechanisms.
First, rotavirus impairs Na+-glucose
co-transport by inhibiting SGLT-1.1
Second, intestinal disaccharidases
American Association of Swine Veterinarians
(sucrase, maltase, and lactase), re-
sponsible for cleaving monosaccha-
rides for Na+-glucose co-transport
located on the brush border mem-
brane of enterocytes are markedly
attenuated in rotaviral enteritis.2 De-
spite substantial impairment of Na+-
glucose co-transport, glucose-based
oral rehydration solutions have been
effective in replacing fluid losses dur-
ing rotaviral diarrhea, which suggests
that some SGLT-1 transport mecha-
nisms remain intact. The principal
mechanisms associated with rotaviral
diarrhea have long been thought
to be malabsorption and osmosis.
However, there are several lines of
evidence that place the importance
of these mechanisms in question. For
instance, rotavirus-induced diarrhea
develops prior to extensive histologi-
cal evidence of damage to the absorp-
tive intestinal epithelium. Infection
of neonatal pigs with porcine rotavi-
rus results in watery diarrhea 8 hours
after infection, whereas histological
damage to the jejunum is not evi-
dent until 48 hours after infection.3
Furthermore, in a study of the effect
of nutritional status on rotavirus-
induced diarrhea, 9 days after infec-
tion, intestinal structural damage was
similar between nourished and mal-
nourished piglets but the duration of
the diarrheal period was significantly
longer in malnourished piglets.4
With regard to the latter finding,
greater indices of intestinal inflam-
mation were observed in rotavirus-
infected pigs and prolonged in mal-
nourished piglets, which suggests an
important role of nutritional status
and inflammatory responses in ro-
taviral diarrhea.5 These findings can
­ arolina
be explained by emerging evidence
of a novel secretory mechanism as-
sociated with rotavirus infection.
Rotavirus secretes an enterotoxin
called NSP4, which induces entero-
cyte secretion by inducing increases
in intracellular Ca2+. On the basis of
known ion transport mechanisms,
these increases in Ca2+ would be
expected to induce secretion via ef-
fects on basolateral K+ channels, with
resultant increases in Cl- secretion via
the CFTR. However, NSP4 induces
secretion of Cl- to a similar extent
in cystic fibrosis tissues in which the
CFTR is essentially non-functional.6
These findings suggest a novel CaCC
on the apical membrane. In addi-
tion, there is evidence to indicate
that NSP4 interferes with NaCl
and solute absorption. For example,
NSP4 directly damages or interferes
with the function of the apical Na+-
glucose transporter SGLT, further
exacerbating diarrhea.7 NSP4 also
inhibits Na+/K+ ATPase function,
thus impairing both NaCl and Na+-
linked nutrient transport. Interest-
ingly, NSP4 toxin has little effect in
adult animals, possibly because of
age-dependant decreases in CaCC
expression.8 It should be noted that
the mechanistic studies on NSP4
have been performed almost ex-
clusively in laboratory rodents and
rabbits. However a specific NSP4
antibody response has been detected
in gnotobiotic pigs infected with hu-
man ­rotavirus.9
Rotavirus-induced fluid secretory
responses are greatly reduced (by >
60%) in the presence of enteric neu-
ral blockers such as tetrodotoxin and
429
2012 AASV Annual Meeting: Integrating Science, Welfare, and Economics in Practice
lidocaine, suggesting that activation
of the enteric nervous system is a
major component of rotaviral diar-
rhea.10 However, the exact mecha-
nisms by which rotavirus/NSP4
activates the ENS remain unclear,
although recently, 5HT and VIP
have been determined to be the ma-
jor neurotransmitters involved in ro-
taviral secretory responses suggesting
activation of neural secretory reflex
arcs.11 Villus ischemia and enhanced
tight junction permeability have also
been detected in rotavirus-infected
animals and may also contribute to
d­ iarrhea.12
Pathogenic mechanisms
of Brachyspira
­hyodysenteriae
There are 2 major spirochetal organ-
isms known to cause predominantly
malabsorptive diarrhea and de-
creased weight gain in grower and
finisher pigs. Brachyspira (Serpulina)
hyodysenteriae causes swine dysen-
tery and Brachyspira (Serpulina)
pilosicoli causes porcine intestinal
spirochetosis. B hyodysenteriae causes
severe catarrhal and hemorrhagic
colitis thought to be predominantly
malabsorptive in nature. Severely
impaired Na+ and water absorptive
capabilities have been detected in B
hyodysenteriae-infected colonic epi-
thelium.13 B hyodysenteriae infection
is not associated with increases in the
second messengers cAMP or cGMP
or enhanced responsiveness to the
cAMP secretagogue, theophylline 14
suggesting that diarrhea is predomi-
nantly attributable to malabsorption
rather than activation of intestinal
secretory processes. Large intestinal
diarrhea predominates in B hyodysen-
teriae infection whereas the small
intestine is largely unaffected. In fact,
glucose-dependant stimulation of
solute and water absorption is unal-
tered in infected jejunum suggesting
that ORS would be beneficial in
430 American Association of Swine Veterinarians
restoring extracellular fluid losses as-
sociated with this disease.15 The role
of the 2 toxins of B hyodysenteriae,
hemolysin and lipopolysaccharide,
in the pathogenesis of diarrhea is
unclear. Injection of hemolysin toxin
into ligated ileal and colonic loops
of gnotobiotic pigs results in marked
epithelial sloughing at the villus
tips and subsequent villus contrac-
tion; however, no fluid accumula-
tion, hemorrhage, or inflammation
is evident.16,17 Whipp et al infused
colonic loops of commercial-bred
pigs with known pathogenic isolates
of B hyodysenteriae and observed
histopathologic lesions in addition
to fluid accumulation, hemorrhage,
and inflammation.18 Results of these
studies may suggest that although he-
molysin may be important in epithe-
lial destruction, other mechanisms,
toxins, or both are likely required for
development of diarrhea in pigs. Like
Rotavirus, B hyodysenteriae diarrhea
may involve activation of the enteric
nervous system. A recent study by
Kalecyc et al (2010) demonstrated
increased levels of galanin, substance
P, and increased galanin-positive
n
­ eurons.19
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