Recent studies estimate that between one in 88 and one in 110 children in the United States has Autism Spectrum Disorder (ASD). Currently, there are no medications to treat the core symptoms, largely due to a lack of understanding about the fundamental causes of ASD. There is undoubtedly a strong genetic component: about 90% of monozygotic (identical) twins are concordant for broadly defined ASD.However, genetics cannot be the sole cause of the disorder: in some cases, one twin may have severe ASD and the other twin may be neurotypical (an average child).

Many researchers believe that inflammation within the brain may cause ASD. Activation of microglia (a type of immune cell in the brain) also seems to play an important part. Post-mortem studies of ASD brains have shown marked microglial activation and increased microglial density in several brain areas that have been implicated in ASD pathology. Furthermore, cerebrospinal fluid (fluid that surrounds the brain and spinal cord) taken from individuals living with ASD showed increased levels of proinflammatory chemicals.

Microglial activation and proinflammatory chemicals can have many deleterious effects on the brain, particularly during development. Moreover, higher levels of markers for microglial activation were correlated with greater severity of social impairments in ASD and greater levels of inflammatory chemicals were correlated with greater cognitive impairment in ASD.

The root cause of this inflammation is disputed. However, several studies have suggested that this inflammation (and ASD pathology itself) are linked to abnormalities in the gut. There are several possible candidate gut abnormalities, including improper balance of gut bacteria, deficient sulfur metabolism, and reduced elimination of heavy metals. Although it is highly probable that these abnormalities are involved in ASD pathology, it seems that the most convincing evidence supports the theory that “leaky gut” syndrome, or increased intestinal permeability (IPT) is the major component in ASD pathology. Increased IPT occurs when the epithelial barrier function of the small and/or large intestine is compromised, allowing greater numbers and types of molecules to pass from the gut into the blood.

In a 2010 study, researchers gave participants an oral dose of inert sugars and measured their excretion in the urine. The greater the intestinal permeability, the more of certain sugars would be able to pass into the blood and from there into the urine. They found that individuals with ASD (and to a lesser extent their first degree relatives) had significantly increased IPT compared to controls.

Although it is, as usual, difficult to determine causation in humans, it has been shown that in many instances, gluten and casein may increase intestinal permeability.After eliminating these two proteins from the diet of ASD children, parents reported a significant improvement in both behavioral and intestinal symptoms.This indicates that altered IPT may play an important role in ASD behaviors.

The best causational evidence comes from a rodent study that made use of propionic acid (PPA). PPA is a short chain fatty acid that is naturally found in the gut. When PPA remains in the gut, it produces no ill effects. However, in cases of increased IPT, PPA may leave the gut and enter the circulatory system. Once in the bloodstream, it readily crosses the blood-brain barrier where it has significant detrimental effects on both behavior and markers of neural inflammation.

Experimenters injected PPA directly into the brains of rats and studied the effects. They found that rats injected with PPA displayed impaired social behaviors and poorer learning. PPA injected rats also showed a trend toward increased microglial activation.

The intestinal permeability theory is consistent with current ASD research in that IPT is affected by both genes and environmental factors. Although the exact relationship between genes and increased IPT is unknown, many diseases that involve abnormal IPT (irritable bowel syndrome, ulcerative colitis, celiac disease, etc.) have a significant genetic component, indicating that susceptibility to altered IPT is likely to be related to genetics. However, increased IPT is also affected by the environment, especially certain toxins and dietary proteins like gluten.

Although it is unknown whether increased IPT is more common in males than females, there is preliminary research that suggests males are more sensitive than females to immune challenges early in life. For example, male rats exposed to small amounts of the bacteria E. coli shortly after birth will have altered immune cell activation and impaired learning that persists throughout adulthood, an effect not seen in female rats.Mechanisms for this are uncertain, although it has been suggested that it is due to the immunomodulatory effects of sex steroid hormones like estrogen and testosterone. Thus, although IPT may not be more common in males, males may have a stronger immune response to the abnormal molecules allowed to pass into the blood. They would thus have more inflammation and more severely affected behavior.

Clearly, enormous amounts of research remain to be done. Yet diet-based and pharmacological interventions targeted at reducing intestinal permeability and neuroinflammation in infants and children at risk for autism seems to hold great promise in the management of this notoriously difficult to treat disease.

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