Gastrointestinal findings in autism
Individuals with autistic spectrum disorders tend to suffer
from various, sometimes severe gastrointestinal problems. Children
with ASD are suspected to have a higher rate of gastrointestinal
(GI) symptoms when compared with children of either typical
development or another developmental disorder, although large-scale
studies are yet to be carried out and the significance of the
association between many gastrointestinal pathologies and autism
is yet to be confirmed.
concensus report on evaluation, diagnosis, and treatment of
gastrointestinal disorders in individuals with autism concluded
that care providers should be aware that problem behavior
in patients with ASDs may be the primary or sole symptom of
the underlying medical condition, including gastrointestinal
disorders, and guideliness have been issued on evaluation
and treatment of common gastrointestinal problems in children
with ASDs, such as abdominal pain, chronic constipation, and
gastroesophageal reflux disease (20048083,
frequent complaints are chronic constipation and/or
diarrhea (frequently accompanied by indigested or partially
digested food in stools), gaseousness, and abdominal discomfort
and distension .
Decreased sulfation capacity of the liver,
pathologic intestinal permeability, increased secretory response
to intravenous secretin injection, and decreased digestive enzyme
activities were reported in many children with autism. Treatment
of digestive problems is reported to have positive effects on
autistic behavior in some individuals [8888921,
Defects of innate immune responses in ASD children with GI problems
have been detected, and intestinal pathology,
including ileocolonic lymphoid nodular hyperplasia
(LNH) and mucosal inflammation, with enhanced
pro-inflammatory cytokine production, has been characterised
in varous studies. A majority of the children were shown to
have chronic swelling of the lymphoid tissue
lining the intestines, particularly near where the small and
large intestines meet, and chronic inflammation of the
large intestine. Secondary eosinophilic colitis has
also been observed in autism. There is a consistent profile
of CD3+ lymphocyte cytokines in the small and large intestinal
mucosa of these ASD children, involving increased pro-inflammatory
and decreased regulatory activities [16494951,
The mucosal immunopathology in children with autism is reported
to be suggestive of autoimmune lesion and is apparently distinct
from other inflammatory bowel diseases [11986981,
(see also Immune/Inflammation).
One study examining histologic findings in children with autism
revealed high incidence of grade I or II reflux esophagitis,
chronic gastritis and chronic duodenitis.
The number of Paneth cells in the duodenal crypts was significantly
elevated in autistic children compared to controls. Low intestinal
carbohydrate digestive enzyme activity was
reported in over half of the children with autism, although
there was no abnormality found in pancreatic function. Seventy-five
percent of the autistic children had an increased pancreatico-biliary
fluid output after intravenous secretin administration, suggesting
an upregulation of secretin receptors in the
pancreas and liver .
There are also reports of prominent epithelium damage
and of significant alterations in the upper and lower intestinal
flora of children with autism. One striking finding
was complete absence of non-spore-forming anaerobes and microaerophilic
bacteria from control children and significant numbers of such
bacteria from children with autism. The faecal flora of ASD
patients was found to contain a higher incidence of the Clostridium
histolyticum group of bacteria than that of healthy children
On the other
hand a low-grade edotoxemia has recently been observed in autism.
Compared with healthy subjects, serum levels of bacterial endotoxin
were significantly higher in autistic patients and inversely
and independently correlated with the severity of autism symptoms,
noting the need for further studies to establish whether increased
endotoxin may contribute to the pathophysiology of inflammation
and behavioural and social impairments in autism (20097267).
Presence in blood of endotoxins produced by gastrointestinal
pathogens is indicative of impaired gastrointestinal permeability
and present in chronic infectious and inflammatory conditions
– a good example is the association of HIV-infection with
increased gut permeability and microbial translocation, evidenced
by increased circulating lipopolysaccharide (LPS) levels, mirroring
the above-mentioned findings in autism (17720995).
Some aspects of calcium signalling in GI tract
Gastric acid is one of the main secretions
of the stomach – if its production is insuffucient the
risk of gastrointestinal infections and of developing gastroenteritis
is greatly increased, while on the other hand excessive production,
which can sometimes be caused by hypercalcemia, can cause gastric
ulcers. Voltage gated calcium channels are thought to be involved
in the regulation of gastric acid secretion. Calcium channel
blocker nifedipine was shown to significantly reduce gastric
acid secretion, and verapamil, diltiazem, cinnarizine, nifedipine
and hydralazine showed similar effects [7721557,
Calcium influx through the plasma membrane as controlled by
VGCC is also involved in fluid secretion by the enteric nervous
Gut motility, especially during inflammation,
also seems to be mediated by calcium flux 
In one study verapamil, a calcium channel blocker, was able
to inhibit giant migrating contractions and diarrhea during
small intestinal inflammation .
Abnormalities in muscle contraction and digestion in inflammatory
bowel disease, such as ulcerative colitis or Crohn's disease,
are associated with disturbances of calcium homeostasis in the
inflamed muscle cells [10492128,
Inflammation of the colon results in changes in ion channel
activity of smooth muscle cells .
Another aspect of the inflammation of the intestine is that
it may be a subject to oxidative stress. Treatment of isolated
segments from the rabbit jejunum and from the guinea pig ileum
with free radicals resulted in dysfunctions of contractility.
This effect was reversed by Bay-K 8644, which activates LTCC,
suggesting that oxidative stress might have a direct effect
on calcium entry through these channels 
(see Oxidative Stress).
It has been suggested that oxygen free radicals and calcium
influx may play a role in the development of endothelial
barrier injury, possibly leading to intestinal hyperpermeability
Under certain conditions intestinal epithelial cells may become
a source of proinflammatory cytokines, which actively contribute
to ongoing inflammation through autocrine disruption of epithelial
barrier function In gastrointestinal tract, mucosal hypoxia
is closely associated with chronic inflammation, and these events
are dependent on alterations in the expression and function
of CREB, an event regulated mainly through influx of calcium
via VGCC 
(see also Hypoxia and Brain).
In addition to endothelial cells, calcium homeostasis plays
a central role in the maintenance tight junctions,
which represent the major barrier between intestinal cells and
whose disruption can also lead or contribute to intestinal hyperpermeability,
or "leaky gut" (see BBB).
Calcium flux through plasma membrane plays a crucial role in
secretory functions of pancreas. It is the
main mechanism for release of insulin and regulation
of insulin synthesis – significant increases of calcium
levels in the cells causes release of previously synthesised
insulin, which has previously been stored in secretory vesicles.
The calcium level also regulates expression of the insulin gene
via the calcium responsive element binding protein (CREB), which
is central in beta-cell gene expression and function .
In addition, pancreatic fluid and enzyme secretion
is dependent on extracellular calcium and its entry through
plasma membrane [6257554,
Inappropriate regulation of beta-cell CaV channels causes beta-cell
dysfunction. Glucose-stimulated insulin secretion depends
on calcium influx through voltage gated channels 
and a mutation in the human CaV1.2 gene results in excessive
insulin secretion. Trinucleotide expansion in the human CaV1.3
and CaV2.1 gene is revealed in a subgroup of patients with type
2 diabetes .
It is of interest to note the role of glutathione: in pancreatic
islets insulin secretion in response to a variety of stimulators
is sensitive to the redox state of extracellular and intracellular
thiols. One major localization of critical thiols appears to
be related to the influx of calcium through VGCC .
Several infectious agents have been shown to
have direct dysregulary effects on calcium homeostasis in the
gastrointestinal tract. HIV-1, one of the the most widely studied
viruses, may directly alter ion secretion in the intestine,
which is suggested to be the mechanism behind the watery diarrhea
associated with HIV-1 infection .
The HIV-1 transactivating factor protein (Tat) induces ion secretion
in Caco-2 cells and in human colonic mucosa similar to that
induced by bacterial enterotoxins. It also significantly prevents
enterocyte proliferation. Increase in intracellular calcium
concentration and the antiproliferative effects of Tat are mediated
by l-type calcium channels .
pancreatic acinar cells calcium overload is an early event in
the pathogenesis of cell damage and dysregulation of calcium
homeostasis is be one of the main causes or mediators of pancreatic
acinar cell damage induced by bacterial lipopolysaccharides
Calcium-blocking agents, such as magnesium and tetrandrine,
have shown protective effects against damage to acinar cells
induced by such calcium overload [16524508,
Rotavirus infection induces increases in intracellular calcium
concentration in human intestinal epithelial cells. Rotavirus
protein NSP4 induces increased membrane permeability, calcium
influx and diarrhea when administered to mice, an effect thought
to be age-dependent and mediated through calcium dependent chloride
secretion and calcium-induced impairment of nutrient
Inflammatory effects of Clostridium Difficile toxins in the
intestine may be related to their ability to induce elevation
of cell calcium levels, both by mobilising it from intracellular
stores and by provoking calcium influx from the extracellular
Acute and chronic gastrointestinal diseases are known to be
commonly caused by viral infection of GI tract. The symptoms
are though to be the result of damage to the villi, but there
are also indications of active secretion and motility disturbances.
Rotaviruses are known to cause acute gastroenteritis
- the virus infects enterocytes of the villi of the small intestine,
leading to structural changes of the epithelium and diarrhea,
sometimes followed by vomiting and low-grade fever. Rotaviruses
tend to affect gastrointestinal epithelial cells that are at
the tip of the villus. Their triple protein coats make them
very resistant to the normally prohibitive pH of the stomach,
and also to digestive enzymes (lipases and proteases) in the
GI tract. Temporary lactose intolerance has also been associated
with rotavirus-induced gastroenteritis. [17031143,
Rotavirus was also shown in one study to affect amino acid uptake
in the small intestine. Infected mice showed significant reduction
in their bodyweights and intestinal lengths compared with controls.
Gluthatione uptake was amongst others to be significantly reduced.
Findings showed damage to the villi in the jejunum and prominent
cytoplasmic vacuolation in the ileum of infected animals .
Rotavirus pathogenesis and gastrointestinal symptomatology is
though to be age-dependant. In additon, increasing line of evidence
suggests that rotavirus is able to spread to a number of different
organs in the body, including the brain, where it can cause
neurological disturbances, most notably seizures and loss of
language and social interaction (see Infectious_Agents).
Viruses can remain latent in gastrointestinal tissues and produce
disease many years after initial infection. Latent herpes simplex
virus type 1 gene expression is prevalent in human adult nodose
ganglia, suggesting that infection of gastrointestinal sensory
nerves probably occurs commonly and that HSV-1 reactivation
from this site may play a role in recurrent gastrointestinal
In one study a reactivation of latent herpesviruses was identified
in several children with active inflammatory bowel disease .
Murine gammaherpesvirus-68, used to study human EBV and HSV-8
viruses, was shown to induce a systemic lymphocytosis in mice
and to establish a latent infection of lymphocytes .
Two herpesviruses, cytomegalovirus and herpes simplex virus,
can cause ulcerative disease of the gastrointestinal tract.
Acute gastroenteritis occurs in healthy persons
but it is thought to be more common and more severe in immunocompromised
patients. In patients with Acquired Immunodeficiency Syndrome
(AIDS) and immunocompromised hosts, CMV can cause primary, latent
or chronic persistent infection. Primary CMV infection is very
severe in immunocompromised patients as well as among healthy
population. Among patients with AIDS CMV is usually isolated
from patients specimen in association with other pathogens (Pneumocystis
carinii, Candida albicans). There is high prevalence in AIDS
population of serious CMV–related deseases, including
chorioretinitis, gastrointestinal disease, interstitial pneumonia
and central nervous system disease 
(see also Immune/Inflammation).
Epstein-Barr virus, human papilloma virus, and human herpesvirus-8
are implicated in proliferative diseases of
the gastrointestinal tract. Epstein-Barr virus has been associated
with immunoproliferative disease after transplantation and may
also cause small-bowel and colonic lymphoma.
Human papillomaviruses cause anorectal condyloma and anal cancer.
Human herpesvirus-8 causes gastrointestinal Kaposi sarcoma .
Intestinal CMV-infected cells in infants have prevalently been
associated with neonatal necrotizing enterocolitis. A case report
of an infant with congenital or perinatal CMV infection with
gastrointestinal involvement describes inflammation in the GI
tract, development of a colonic stricture and manifested a clinical
picture simulating Hirschsprung's disease (characterised by
bowel obstructions, megacolon, protruding abdomen).
Chorioretinitis was also present .
It has been hypothesized that both chronic gastritis
and ulcerative colitis are induced by viral
infection, and that such chronic infection of the mucosa may
lead to ulceration and occasionally cancer .
A case report on a 12 week old fetus that was aborted following
herpes family varicella-zoster virus (VZV) infection in mother,
viral infection was identified in fetal dorsal root ganglia,
meninges, gastrointestinal tract, pancreas, smooth muscle, liver,
and placental trophoblast inclusions (see Infectious_Agents
and Maternal_Factors), indicating the
presence of a nonproductive, latency-like VZV infection. It
was concluded that widespread nonproductive infection in the
absence of histological clues is an early event in VZV infection
in fetuses. Latency-like infection in nonneural cell types may
potentially reactivate, leading to multifocal necrosis, fibrosis,
and dystrophic calcifications, as observed in advanced congenital
varicella syndrome .
In recent years there have been increasing evidence of the involvement
of measles virus in ileocolonic lymphonodular hyperplasia -
a new form of inflammatory bowel disease that has been described
in a cohort of children with developmental disorders. Seventy
five of 91 patients with a histologically confirmed diagnosis
of ileal lymphonodular hyperplasia and enterocolitis were positive
for measles virus in their intestinal tissue compared with five
of 70 control patients. Measles virus was identified within
the follicular dendritic cells and some lymphocytes in foci
of reactive follicular hyperplasia .
In the light of recent discoveries of critical roles
played by several chemokines and their receptors in lymphoid
development, mucosal immunity, and intestinal inflammation,
possible upregulation of these receptors in autism and downstream
consequences on calcium signalling would merit closer investigation.
Based on the fact that chemokines and their receptors
are crucial mediators of inflammation and tissue injury, it
is now believed that their antagonists could provide novel therapeutic
tools in the treatment of inflammatory bowel disease [11149563,
Several genetic polymorphisms related to chemokine
receptor expression play a role in vulnerability of gastrointestinal
tract to infectious agents. A good example is that genetic deficiency
in the chemokine receptor CCR1 was shown to protects against
acute Clostridium difficile toxin A enteritis in mice - while the
toxin induced in all mice a significant increase in ileal fluid
accumulation, epithelial damage, and neutrophil infiltration,
all parameters were significantly lower in CCR1 and MIP-1alpha
knockout mice .
In additon to infectious agents, various toxins are known
to affect functioning of GI tract [9181600,