In the United States, millions of patients and caregivers struggle relentlessly with the multidimensional impact of autism spectrum disorder (ASD). With diverse symptoms like social withdrawal, repetitive behavior, self-injury, stereotyped gestures, and gastrointestinal distress, therapies for ASD must affect a vast number of neurobiological mechanisms to provide relief to patients. Due to the broad spectrum of dysfunction in patients with ASD, therapies that purport to address multiple symptoms simultaneously are attractive for researchers, patients, and caregivers alike.
For many, gamma-aminobutyric acid (GABA) is one such therapy. GABA is one of the brain’s core neurotransmitters responsible for inhibiting neuronal transmissions. When neurons are inhibited, they can’t transmit their electrochemical signals to other neurons as readily as they typically would. Most people are familiar with the subjective effects of GABA in their brains owing to the sedating effect of ethanol consumption; ethanol molecules bind to GABA receptors, precipitating an inhibitory effect across the brain. As more receptors are bound, this inhibitory effect increases, leading to sluggishness, sedation, relaxed muscles, uncoordinated movements, and weakening of impulse inhibition. Cognitive ability drops, and memory consolidation is hampered. While normal levels of GABA don’t cause these effects, they’re still responsible for helping the brain to regulate its level of arousal in multiple ways.
The relaxing effect of GABA emission is only one half of the story, however. People deficient in GABA are prone to neurological issues of over-excitability: seizures, agitation, irritability, and anxiety. All of these issues are common in ASD patients. The rationale for using GABA supplements to treat autism is simple: because ASD presents the same symptoms as systemically overly-excitable neurons, some believe that ASD patients cannot produce enough GABA to regulate neuronal activity. However, the link between GABA and patients with ASD may not necessarily be one of insufficient GABA, as these patients may not have enough of the cellular machinery necessary to utilize GABA normally. Caregivers who are looking for a new therapy to reduce agitated or anxious behavior in patients with ASD must thus be careful when evaluating GABA as a treatment option and may want to explore butyric acid as a more promising alternative.
The Questionable Efficacy of GABA for Autism
Patients with ASD are known to have fewer instances of several GABA receptor subtypes on the neurons in the prefrontal cortex. Similar aberrations are likely present in other parts of the brain. While the cause of this phenomenon is unclear, the effect is that the neurons of ASD patients are less inhibited by GABA than those of a neurotypical person. This means that even if they have enough GABA, their neurons would have a much lower limit on the amount of inhibition which they could bring to bear when they encounter GABA. The downstream result is that regions of the brain like the prefrontal cortex are habitually overstimulated, causing effects ranging from depression to stereotyped behavior. Adding GABA wouldn’t make up for having fewer GABA receptors.
Furthermore, researchers believe that patients with ASD have malformations in the neuronal pathways which utilize GABA to inhibit other tracts of neurons. As such, even if there is a sufficient quantity of GABA ready for use and a sufficient number of receptors ready to accept the molecules, ASD patients may not have the neurotypical neuronal connections which allow it to be used effectively. This would lead to a weaker than expected effect of GABA. Adding more GABA won’t change the structure of neuronal tracts, but it might cause systemic inhibition and cause intense sedation as a side effect.
Even without side effects, there are other issues with GABA supplements. Canonically, GABA cannot cross the blood-brain-barrier. This means that it would not be capable of treating neurological issues by operating directly on neurons. Even when delivered to the brain directly via injection (which is not done outside experimental contexts), neuronal mechanisms like the GABA reuptake protein ensure that it is rapidly eliminated. Dietary supplements claiming to offer therapeutic effects owing to their GABA content have nonetheless shown minor beneficial effects in a small pilot study; in the study, patients who consumed GABA supplements experienced reduced levels of anxiety. As noted by the authors, these findings indicate that GABA may be able to cross the blood-brain-barrier in small quantities, but further research is needed to draw firm conclusions. At present, there are no studies examining the efficacy of GABA supplements on ASD symptoms; this study, like others investigating GABA supplementation, was limited to neurotypical participants examined during performance of anxiogenic tasks like mental arithmetic. The study also found that the participants’ immune systems showed signs of suppression in the form of reduced immunoglobulin secretion—a problematic side effect which would leave people at a higher risk of illness.
The gaps in the research and lingering engineering challenges regarding bioavailability mean that GABA supplements still have a ways to go before they will start to help ASD patients. This shouldn’t dissuade patients from investigating an alternative compound which may seem superficially similar, however. Indeed, patients and caregivers who are interested in a natural yet effective ASD therapy may be better served by butyric acid, a compound which has the potential to treat multiple dimensions of autism at the same time but lacks the major drawbacks of GABA.
The Possibilities of Treating ASD with Butyric Acid
While GABA is an organic acid, other organic acids may be more effective therapies for ASD. Butyric acid is one such alternative. While laymen may believe that butyric acid is similar to gamma-aminobutyric acid owing to its name, butyric acid is a distinct chemical from GABA, and its physiological role is entirely different. Produced in the gut, butyric acid is used by the body to feed helpful gut microbiota and signal white blood cells. Butyric acid may also be considered a neurotransmitter, though its capacity in this role requires further research. Interestingly, in the capacity of immune cell signaling, GABA and butyric acid share similar purposes; both inhibit the ability of white blood cells to cause inflammation by reducing their ability to secrete proinflammatory molecules. Butyric acid has more to offer ASD patients than the suppression of inflammation alone, however.
Researchers have found that ASD patients typically have markedly lower concentrations of butyric acid in their intestines than is found in healthy patients. This may be a contributing factor to ASD patients’ consistent gastrointestinal inflammation. But the benefits of butyric acid aren’t limited to gastrointestinal health; researchers believe that butyric acid could be effective at simultaneously treating inflammation of the GI tract and addressing behavioral symptoms in patients with ASD. The rationale is that by inhibiting the gastrointestinal white blood cells which are causing excessive inflammation, the patient’s gut-brain axis will be less overstimulated, resulting in a concomitant drop in overstimulation of the patient’s brain.
Controlling the level of stimulation in the gut-brain axis is critical. The gut-brain axis is the primary conduit of nerves connecting the viscera to the brain’s sensory cortices. In short, when patients experience nausea, inflammation, or discomfort in their intestines, it’s the gut-brain axis which relays that information to the brain and links it to initiating compensatory behavior. Too much actuation of the gut-brain axis will lead to over-stimulation of the areas of the brain which process the sensory input. Patients could thus experience agitation, self-injurious behavior, and anxiety. Butyric acid therapy thus keeps the gut-brain axis from causing problems elsewhere.
There is another major reason butyric acid is an appealing therapy: unlike GABA, butyric acid can reliably cross the blood-brain-barrier. While butyric acid administered orally would begin to act on the gastrointestinal tract, once the butyric acid was distributed through the patient’s bloodstream it would eventually infiltrate the brain. Once in the brain, butyric acid’s effects could include better orientation of attention, inhibition of motor tics, and improved emotional regulation—all areas in which patients with ASD struggle. These benefits are the result of butyric acid reducing the propensity for inflammation in white blood cells that it contacts.
Patients with ASD are thought to have high levels of inflammation in their brains, which in part contribute to their cognitive and behavioral symptoms. When inflammation in the brain increases, general brain function decreases. The deficits of brain function that are the most noticeable in terms of patient symptoms occur in the frontal lobe and include symptoms like difficulty concentrating and regulating emotions. Reducing inflammation in the brain is therefore a pathway to treating a handful of different ASD symptoms. Treatment with butyric acid weakens the ability of white blood cells to cause inflammation by inhibiting their ability to retransmit chemical signals which tell them to secrete proinflammatory molecules. The systemic impact is that the brain’s total level of inflammation drops. For the moment, measuring the concentration of proinflammatory molecules in the brain isn’t possible with living patients.
Choosing Evidence-Based TreatmentExciting new research is in the process of establishing a definitive account of butyric acid’s impact on ASD, but the initial evidence is more than enough to make a comparison with GABA. While GABA suffers from a number of immutable physiological barriers to being an effective ASD treatment, butyric acid takes advantage of a variety of different mechanisms to treat the disorder more effectively. Furthermore, while the GABA supplements on the market are unreliable and unproven in the scientific literature, butyric acid is already produced to a high standard of quality and is supported by a growing body of literature.
Butyric acid is known to be effective in treating gastrointestinal inflammation in multiple contexts. As shown by a 2011 study published in the Cellular Metabolism journal, butyric acid prevents autoimmune activation in the event of compromised colon cells. When colon cells are compromised by excessive inflammation or malnutrition—both of which are more likely to occur in ASD patients —they begin a process known as autophagy where the cells on the inside of the colon wall are broken down and consumed for energy. As shown in the study, adding butyric acid to the colonocytes prevents them from their cannibalistic behavior. Inflammation is suppressed as a result, and negative externalities like intestinal pain or constipation are ameliorated. These benefits carry over directly to ASD patients who struggle with these symptoms.
Mouse studies have also reliably linked the beneficial effects of butyric acid to improvements in behavioral ASD symptoms. In one such mouse study, a group of mice was artificially induced to have symptoms which mimicked ASD. Then, the mice were split into several groups and given either placebo or compounds containing butyric acid and similar chemicals. The researchers subsequently introduced the mice to neurotypical mice who they had not met before. The neurotypical mice in the control group interacted with the new neurotypical mice for an average of 300 seconds, whereas the ASD model mice who had received the placebo interacted with the neurotypical mice for 20% less time than the normal mice. When the researchers tested the ASD model mice which had received the butyric acid-containing compound, the mice were able to socialize with the others for just under 290 seconds—an improvement of roughly 50 seconds when compared to the mice which didn’t receive the treatment. With the help of the treatment, the mice were able to socialize at around 95% as long as neurotypical mice.
While the effects in the mouse models don’t necessarily carry over to human patients, the results show that the upshot of successful treatment is massive. Clinical trials in humans are ongoing, and soon researchers should be able to show similar data in human patients. If patients and caregivers are eager to start treatment before the clinical data is available, they can easily and safely do so. Caregivers questioning which therapy to try with their patient should evaluate the evidence for themselves and plan their treatment strategy accordingly.
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