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Introduction

Clinical findings in autism and relevance of dysfunctional calcium signalling in
:

    Brain Development
     Neurotransmitters
     Hormones
     Motor/Sensory Disturbances
     Blood Brain Barrier
     Epilepsy/Seizures
     Immunity and Inflammation
     Gastrointestinal Issues
     Membrane Metabolism
     Oxidative Stress
     Mitochondrial Dysfunction
     Gender Differences

Dysregulating Factors:
     Genetic Factors
     Hypoxia/Ischemia
     Toxins
     Infectious Agents
     Other

Conclusion

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Summary of abnormal biomedical findings in autism






Gastrointestinal issues



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.

A recent 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, 20048084).

The most frequent complaints are chronic constipation and/or diarrhea (frequently accompanied by indigested or partially digested food in stools), gaseousness, and abdominal discomfort and distension [14523189]. 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, 12010627, 1176974].

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, 15741748, 11007230, 15622451, 20068312]. 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, 15031638] (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 [10547242].

There are also reports of prominent epithelium damage [11241044], 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 [1552850, 12173102, 16157555].

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, 4072828]. Calcium influx through the plasma membrane as controlled by VGCC is also involved in fluid secretion by the enteric nervous system [9338518].

Gut motility, especially during inflammation, also seems to be mediated by calcium flux [10973625] [11498505]. In one study verapamil, a calcium channel blocker, was able to inhibit giant migrating contractions and diarrhea during small intestinal inflammation [9357819]. 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, 11159888]. Inflammation of the colon results in changes in ion channel activity of smooth muscle cells [10964716].

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 [12457627] (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 [8578176]. 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 [15253703] (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 [16908541]. In addition, pancreatic fluid and enzyme secretion is dependent on extracellular calcium and its entry through plasma membrane [6257554, 6121340]. Inappropriate regulation of beta-cell CaV channels causes beta-cell dysfunction. Glucose-stimulated insulin secretion depends on calcium influx through voltage gated channels [17148757] 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 [16868246]. 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 [2424631].

Dysregulating factors

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 [7585886]. 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 [12557143].

In 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 [12904279, 10795755]. Calcium-blocking agents, such as magnesium and tetrandrine, have shown protective effects against damage to acinar cells induced by such calcium overload [16524508, 11259384].

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 digestion [12438636, 11044126, 7637021].

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 space [11413111, 2838520, 7900810].

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, 2803034]. 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 [10482428]. 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 disorders [9094690]. In one study a reactivation of latent herpesviruses was identified in several children with active inflammatory bowel disease [2298361]. 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 [10644841]. 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 [10872268] (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 [10980963]. 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 [16567208].

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 [7321919].

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 [15655777].

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 [11950955].


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, 11872088].

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 [11875005].

(see Infectious_Agents)

In additon to infectious agents, various toxins are known to affect functioning of GI tract [9181600, 8699562] (see Toxins).


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