Bertrand, Paul P.

Linden, David R.

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Paul P. Bertrand

David R. Linden

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Frontiers in Neuroscience

Getting a Handle on Cholera and the Circuits Controlling Intestinal Motility

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www.frontiersin.org November 2010 | Volume 4 | Article 197 | 1
General Commentary
published: 25 November 2010
doi: 10.3389/fnins.2010.00197
Getting a handle on cholera and the circuits controlling 
intestinal motility
Paul P. Bertrand1* and David R. Linden2
1 Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
2 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
*Correspondence: dr.p.bertrand@gmail.com
A commentary on
Luminal cholera toxin alters motility in 
isolated guinea-pig jejunum via a pathway 
independent of 5-HT
3
 receptors.
by Fung, C., Ellis, M., and Bornstein, J. C. 
(2010). Front. Neurosci. 4:162 doi: 10.3389/
fnins.2010.00162. 
Diarrheal diseases, which are typically bac-
terial in nature, are a major global health 
problem (Zuckerman et al., 2007). The 
majority of diarrheal episodes are asso-
ciated with Escherichia coli, or Shigella, 
Campylobacter or Samonella spp., however, 
infection with the bacterium Vibrio cholerae 
is perhaps the most renowned because it 
produces diarrhea that can lead to severe 
dehydration and death, sometimes within 
hours of the first symptoms, and outbreaks 
reach epidemic proportions prior to the dis-
covery of the contaminated source. Forced 
rehydration is the current treatment modal-
ity for cholera and while prevention is typi-
cally sought by bolstering infrastructure to 
provide clean water, vaccine development 
is the most active and controversial front in 
therapeutic advancement (Chaignat, 2008). 
Cholera has traditionally been considered 
to act by increasing cAMP levels in epithe-
lial cells to evoke secretion (Vanden Broeck 
et al., 2007), but newer lines of evidence point 
to enteroendocrine-mediated initiation of 
secretory reflexes within the enteric nervous 
system (ENS) as a primary cause (Farthing, 
2002), the most compelling data of which 
is that tetrodotoxin, and 5-hydroxytryp-
tamine (5-HT)
3
 receptor antagonists block 
cholera toxin-induced secretory diarrhea 
(Beubler et al., 1989; Jodal, 1990).
The ENS, a network of neurons 
present within the wall of the alimen-
tary canal, coordinates the complex and 
varied functions of the gastrointestinal 
(GI) tract (Furness, 2006). One class 
of enteric  neuron are the secretomotor 
neurons which, when paired with dila-
tion of intestinal blood vessels, can cause 
the secretion of vast amounts of fluid. 
Cholera toxin, perhaps by direct activa-
tion, or perhaps indirectly through the 
release of 5-HT and activation of intrin-
sic afferent neurons, increases the firing 
rate of these secretomotor neurons (Jiang 
et al., 1993; Gwynne et al., 2009). Intrinsic 
afferent neurons and secretomotor neu-
rons form a recurrent network which is 
likely to explain the uncontrolled firing of 
secretory motorneurons following cholera 
toxin exposure (Chambers et al., 2005).
While the mechanisms by which chol-
era toxin enhances secretion are becom-
ing clear, it’s effects on GI motor function 
remain murky. On one hand, an early 
study found an increase in transit in suck-
ling rabbits infected with whole V. cholerae 
(Finkelstein et al., 1964) while on the other 
hand, a marker perfusion study failed to 
identify changes in GI transit in patients 
with cholera (Banwell et al., 1970; Brigham 
et al., 1970). Similarly, Banwell and Sherr 
(1973) observed that a small intestinal loop 
exposed to V. cholerae became flaccid but a 
later myoelectrical analysis of infected open 
loops of rabbit intestine revealed increases 
in migrating action potential complexes 
4 h post-inoculation with cholera toxin 
(Mathias et al., 1976; Mathias et al., 1977). 
Reduced motility has also been seen using 
strain gages in awake, fed dogs (Cowles and 
Sarna, 1990a,b) while Kordasti et al. (2006), 
saw little effect of cholera toxin on the fre-
quency or amplitude of contractions in rats 
in vivo. Interestingly, when the 5-HT
3
 recep-
tor antagonist, granisetron, was adminis-
tered to these rats to reduce the secretory 
effect of cholera toxin, there was a sig-
nificant increase in contractions (Kordasti 
et al., 2006). It is into this arena that Fung 
et al. (2010) have entered, using a relatively 
new approach for studying GI motility.
High resolution spatio-temporal map-
ping of intestinal diameter allows the posi-
tion and magnitude of contractions or 
dilations to be mapped down to an accu-
racy of less than a millimeter with data 
sampled 30 times a second. This allows the 
experimenter a much greater objectivity 
when distinguishing between propagating 
and segmenting contractions. Using this 
technique, Fung et al. have demonstrated a 
modest but significant increase in the fre-
quency of propulsive contractions following 
cholera toxin administration into the lumen 
of the small intestine, with no change in the 
occurrence of segmenting contractions. In 
contrast, in preparations pre-treated with 
granisetron, cholera toxin caused a dramatic 
increase in propulsive contractions with a 
later switch to segmenting contractions. 
When the lumen of the intestine was per-
fused with the nutrient decanoic acid, chol-
era toxin switched segmenting contractions 
normally associated with decanoic acid, to 
propulsive contractions. The authors con-
cluded that cholera toxin stimulates several 
distinct, and in some cases opposing, neural 
circuits which overall cause an increase in 
the propulsive contractions at the expense 
of nutrient induced segmentation.
This study shows convincingly that chol-
era toxin can induce motility changes in the 
intestine and begins to explain why evidence 
to date has been mixed. Nonetheless, some 
mysteries remain. For example, previous 
studies have found that changes in motil-
ity generally occur later during cholera 
toxin-induced secretion while in the present 
study motility was induced much earlier. 
One drawback of the present study is that 
it used intestinal segments removed from 
the animal. This could increase mucosal 
permeability which may allow cholera toxin 
more direct access to enteric neurons. In 
another study using in vitro guinea pig 
ileum, increases in electrogenic secretion 
were seen within 30–40 min (Carey and 
Cooke, 1986) as opposed to hours when 
studied in vivo (e.g., Mathias et al., 1976). 
Perhaps a study utilizing exteriorized small 
intestine combined with spatio-temporal 
Frontiers in Neuroscience | Autonomic Neuroscience  November 2010 | Volume 4 | Article 197 | 2
Bertrand and Linden Cholera and intestinal motility
mapping (Ferens et al., 2005) would be the 
best way to clarify the time course of action 
for cholera toxin.
 It is unclear whether the results of 
this study will directly improve treat-
ments for cholera infection, though they 
could explain the variable results of 5-HT
3
 
receptor antagonists in treating cholera 
 toxin-induced hypersecretion in humans 
(Hunt et al., 1992, Turvill and Farthing, 
1997) as 5-HT
3
 receptor inhibition in this 
study markedly enhanced the pro-propul-
sive effects of cholera toxin. What is clear 
from the present study is that spatio-tem-
poral mapping provides previously una-
vailable insights in to the multiple enteric 
neural reflexes activated by cholera toxin. 
The results of this study provide an excel-
lent working model to further dissect the 
complex neural circuitry that contributes 
to GI motor activity.
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Received: 09 November 2010; accepted: 11 November 2010; 
published online: 25 November 2010.
Citation: Bertrand PP and Linden DR (2010) Getting 
a handle on cholera and the circuits controlling intes-
tinal motility. Front. Neurosci. 4:197. doi: 10.3389/
fnins.2010.00197
This article was submitted to Frontiers in Autonomic 
Neuroscience, a specialty of Frontiers in Neuroscience.
Copyright © 2010 Bertrand and Linden. This is an open-
access article subject to a non-exclusive license between the 
authors and Frontiers Media SA, which permits use, dis-
tribution and reproduction in other forums, provided the 
original authors and source are credited and other Frontiers 
conditions are complied with.
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