Many caregivers know all too well the feeling of helplessness that arises from seeing a loved one with autism spectrum disorder (ASD) suffering from anxiety, particularly if the source of that anxiety remains elusive. Even in patients who are highly independent, episodes of anxiety can quickly cause functionality to deteriorate, and all patients may experience a drastic reduction in quality of life. Unfortunately, anxiety can be difficult to treat, especially when paired with symptoms like social withdrawal, deficits of speech, and obsessive behaviors that are often present in people who have autism. Soothing techniques such as time spent with a therapeutic animal, massage, or talking through fears may not be suitable for some people with autism, and caregivers may hesitate to reach for medications like benzodiazepines and SSRIs due to their potential side effects. Meanwhile, psychotherapeutic approaches like cognitive behavioral therapy may be difficult to implement effectively with patients with ASD and it can take time to see results.
Now, a growing body of research suggests that there may be another way to address anxiety for patients with autism: by targeting the gut-brain axis. It is widely recognized that anxiety can contribute to the gastrointestinal (GI) disturbances associated with autism, which are notoriously detrimental to the well-being of patients. Indeed, most people are familiar to some extent with the influence of anxiety on the gut, whether it manifests as “butterflies in the stomach” or severe gastrointestinal distress. However, the gut can also be a source of anxiety in and of itself due to the complex, bidirectional relationship between the gastrointestinal tract and the central nervous system. This relationship is the gut-brain axis.
The major nerve of the gut-brain axis is the vagus nerve, which refers information regarding the position and comfort of the viscera to the brain. Importantly, the gut-brain axis also relates information regarding satiety and immunological threats in the gut via innervation of the vagus nerve. To refer information regarding these immunological threats, the vagus nerve becomes innervated by inflammation in the gut. This means that excessive inflammation in the gut leads to repeated activation of the vagus nerve, leading to a corresponding activation of the recipient regions in the brain. In cases of chronic gut inflammation, the chronic activation of the vagus nerve may subsequently lead to anxiety as the excessive activation is referred to other areas of the brain. Those with ASD may be particularly vulnerable to this phenomenon, as the excess propionic acid build-up experienced by many patients can cause significant disruptions in the gut microbiome and ongoing inflammation.
In patients with ASD, symptoms deriving from the gut-brain axis can be difficult to recognize, and bouts of anxiety caused by gastrointestinal symptoms may, therefore, seem to be without cause. But research reveals that patients with gastrointestinal problems were 7% more likely to experience social problems and 20% more likely to experience affective issues like anxiety. Thus, GI symptoms have the potential to significantly aggravate a patient’s anxiety and reduce overall quality of life. As such, controlling the impact on of anxiety on the gut and vice versa is critical for patients and caregivers who want their loved ones to be as comfortable as possible. A growing number of patients are now turning to nutritional supplements that seek to address anxiety by supporting gut health. But while there are several such supplements on the market, only butyric acid may provide truly comprehensive support.
Choosing the Right Supplement to Treat Anxiety in ASD Patientsmanipulating the gut-brain axis via nutritional supplementation opens up exciting new paths to wellness for all patients who struggle with anxiety symptoms. However, supplements which are intended for the general public are not always suitable for patients with ASD and it is important to recognize the unique challenges this population group often faces. For example, patients with ASD are often intolerant of the flavors and textures of supplements, and herb-derived supplements may be particularly unappetizing. While caregivers and patients can sometimes get around unpalatable flavors by including supplements or medications in food, adding food may negatively impact bioavailability and compromise therapeutic efficacy. Selecting a well-tolerated supplement that is easily integrated into a patient’s diet without compromising efficacy is, therefore, essential.
Furthermore, most supplements are formulated for use by a patient with typical physiology. For patients with normal metabolisms and normal gastrointestinal tracts, supplements that present absorption challenges can still be therapeutically beneficial provided that they take a large enough dose. Though most of the supplement may be inactivated by the host’s metabolism before reaching the place in the body where it is bioactive, the excess can often be excreted harmlessly. For patients with ASD, however, impaired intestinal permeability can lead to excess supplement material accumulating in the gut, causing constipation or, alternatively, diarrhea, as well as other unwanted side-effects. Patients and caregivers should look for supplements that are formulated to optimize bioavailability and support healthy absorption to avoid these complications.
More dangerously, while researchers are confident that ASD leads to impaired intestinal function, they remain uncertain whether ASD is associated with reduced or increased permeability of the intestines. This means that supplements may be absorbed much faster or slower than in a healthy person, leading to unpredictable onset and uncertain therapeutic impact. For patients seeking relief from anxiety, this it can severely compromise efficacy; supplements that take too long to work may prolong agitation, whereas those which work very quickly but are poorly persistent within the patient’s system won’t provide relief for long enough for anxiety to fully fade. Thus, the most effective supplements for anxiety in patients with autism augment the body’s natural anxiolytic systems or use long-acting physiological mechanisms to trigger a reduction in anxiety.
Among supplements intended to treat anxiety in ASD by supporting the gut, several are notable for being tried and tested:
Many people take magnesium as a dietary supplement due to its mild yet consistent anxiolytic effects. In normal quantities, magnesium carries few side effects and can provide up to 12 hours of relief from anxiety. Typically, magnesium is absorbed in the GI tract over the course of an hour after ingestion. However, magnesium is processed less efficiently in people with ASD, which means that they may require higher doses of magnesium supplementation and onset may be slower.
The compromised ability of people with ASD to process magnesium has significant consequences for the microbiome and anxiety levels. Most importantly, magnesium deficiency can prevent the immune system from regulating the microbiome effectively. One study performed on mice indicates that during magnesium deficiency the white blood cells of the gut cause more inflammation than usual. This inflammation activates the gut-brain axis, prompting a mirrored inflammatory response in the brain to the point where higher concentrations of inflammatory signaling molecules were found in the hippocampi of the mice. Restoring the magnesium satiety of the deficient mice restored their brains and microbiomes to healthy norms. For patients with ASD, this study has profound implications because of their altered gastrointestinal absorption characteristics.
Because magnesium isn’t processed or absorbed as efficiently, patients with ASD are at higher risk of being magnesium deficient than neurotypical people, which can affect neurological function; because neurons use magnesium to generate electrochemical signals, lower concentrations of magnesium can result in weaker activity by regulatory tracts of neurons. When these regulatory tracts can’t inhibit other areas of the brain with their signals, these other areas remain more excitable than they would be otherwise, causing anxiety or potentially seizures.
While magnesium supplementation may seem to be an obvious solution, research suggests that it is unlikely to fully relieve anxiety. A review of 11 high-quality clinical trials found that magnesium supplements are helpful in reducing anxiety for roughly 50% of individuals with ASD. A further 7 trials of lower quality documented similar results. All the trials documented reductions in anxiety, aggression, seizure frequency, and constipation concomitant with magnesium supplementation, but the degree of symptom remission varied substantially. The trials of lower quality tended to document higher magnitudes of symptom relief, with at least one claiming full remission of anxiety. Higher quality trials are more conservative, indicating that magnesium may be a useful adjunct treatment for anxiety but unsuitable as a monotherapy for most patients with ASD.
In terms of tolerability, the body of evidence indicates that palatability of magnesium supplements is rarely a problem, and dosing equivalents specifically for ASD patients are well-characterized. Nonetheless, magnesium is a potent laxative, potentially threatening more than one problem area for ASD patients.
Probiotics may be another way that patients with ASD can reduce their level of anxiety. These supplements composed of living microbiota that patients can consume orally with the intention of seeding the organisms within their gastrointestinal tract. By providing the gut with more helpful bacteria, probiotics can prevent harmful bacteria from settling into the gut while also reducing the inflammation associated with their presence.
In patients with ASD, probiotics have the potential to be especially effective because their microbiomes are composed of different proportions of bacteria than in healthy people, leading to excessive inflammation. Because inflammation of the gut causes excitation of the gut-brain axis via the vagus nerve, reducing inflammation of the gut with a probiotic might be a way to diminish the overall level of excitability in the brain and thereby reduce anxiety. This means that the therapeutic implications of a healthier microbiome can be potentially massive for patients with ASD who struggle with anxiety.
Probiotics could also help to reduce gastrointestinal disturbances which may be related to microbiome dysfunction. These disturbances include symptoms like pain, which innervates the vagus nerve directly and subsequently causes anxiety. While high-quality human data is lacking, probiotics remain promising due to studies in mice where symptoms of anxiety caused by an aberrant microbiome were abated by probiotic supplementation. In one mouse study, ASD-model mice exhibited microbiomes which were on average 8% deviant from that of healthy mice. The 8% of their microbiomes which were deviant were dysbiotic, meaning that they dislodged beneficial gut bacteria while also harming their hosts by secreting toxins. After administration of a Bacteroides fragilis probiotic—a beneficial bacteria of the human microbiome—the mice exhibited the anxiety and socializing behaviors of normal, non-ASD model mice. While this effect wore off after a couple of days, the researchers had successfully proven that probiotics could treat anxiety and socializing symptoms in ASD.
In humans, probiotics tend to be well-tolerated, and few patients experience any side effects aside from transient mild nausea after consuming too much at once. The proper dosing of probiotics is a subject of much debate, but there do not appear to be any differences between the way that patients with ASD incorporate the microbiota into their gut and the way that healthy people do. Most probiotics are palatable because they are embedded in foods like yogurts or encapsulated as a pill, though the preferred modality of administration may vary from patient to patient.
However, probiotic research is still in its infancy, however. Patients seeking anxiety relief might consider probiotics to be a second-line supplemental therapy or perhaps a useful adjunct to other therapies supporting the health of the microbiome. Significantly, because probiotics contribute relatively small quantities of bacteria when compared to the entire microbiome, they can take several days to become established enough for therapeutic effects to begin, though this varies widely with the species or mixture of bacteria used in the probiotic. As such, probiotics will not provide rapid relief. Once established, however, patients may experience longer lasting effects than with magnesium.
Butyric acid is another therapy which supports the health of the microbiome, but it differs substantially from probiotics in several important ways. Researchers have observed that people with ASD have lower levels of butyric acid than healthy individuals, which carries significant implications for both physiological and psychological well-being.
The body naturally produces butyric acid for the purpose of nourishing the microbiome and regulating the white blood cells that cultivate it. Gut biota consume butyric acid directly as chemical energy and help the gut to digest nutrients and absorb water in return; the microbiota don’t have enough butyric acid, they can’t help the gut with digestion. Under ideal conditions, these gut biotas have sufficient butyric acid for their needs, and they subsequently exert a beneficial effect on the brain, promoting the synthesis of critical neurotransmitters like serotonin. These neurotransmitters subsequently help to regulate anxiety when they are used by inhibitory tracts of neurons. This is one of the bases of the therapeutic effect that butyric acid exerts: the inhibitory neurotransmitters promoted by butyric acid are associated with reduced anxiety, somnolence, and fewer seizures. Critically, the fact that butyric acid prompts synthesis of new neurotransmitters contributes to its longer period of therapeutic action, especially when compared to supplements like magnesium which don’t.
However, the primary benefit of butyric acid may not be derived from its direct impact on the brain or the gut microbiome, but rather its effect on the immune cells of the gut which are responsible for regulating the microbiome. Patients with ASD often struggle with high levels of gastrointestinal inflammation. The cause of this is unknown, but researchers suspect that it is a result of the aberrant microbiomes, including divergent bacterial colonies and proportions, which may be caused in part by excess propionic acid. Because some of these bacteria may secrete toxins, the immune system attempts to remove them, resulting in high levels of inflammation and subsequent patient discomfort. Butyric acid balances excessive propionic acid and attenuates this response, preventing the white blood cells of the gut from causing inflammation except in cases of acutely noxious bacteria. When white blood cells in the gut encounter butyric acid, it behaves as an inhibitory cellular signaling molecule, causing them to generate less inflammation. But the natural butyric acid deficiency experienced by many patients with ASD causes high levels of gut inflammation owing to the body’s inability to inhibit the white blood cells there as effectively as it should be able to.
In ASD patients, butyric acid deficiency is likely a central cause of elevated inflammation of the gastrointestinal tract, but there may be additional contributing factors. Thus, supplementing the gut with additional butyric acid helps it to make up for any native shortages while also reducing the level of inflammation created by other causes associated with ASD. More importantly, when the gut has less inflammation as a result of butyric acid-mediated signaling in ASD, the brain also has less inflammation. In mouse models of ASD, reduced neuroinflammation prompted by butyric acid was correlated to increased sociability and reduced anxiety. These results were later replicated by other researchers, indicating that butyric acid can be a powerful multimodal therapeutic option. When taken in summary, providing butyric acid to the gut could thus have a bevy of beneficial anxiolytic effects in patients with ASD.
Modern Butyric Acid Supplements Offer Effective, Well-Tolerated TreatmentProButyrate and AuRx from Tesseract Medical Research are optimized for bioavailability and have an onset of under an hour, proving fast relief from anxiety. Whereas other butyric acid supplements are produced using butyrate salts, Tesseract’s supplements deliver butyric acid in its most concentrated form, significantly enhancing efficacy, They are also tasteless, overcoming butyric acid’s notorious palatability issues to enhance patient adherence. Most importantly, these supplements have the potential to get to the root—or rather, the gut—of one of the major drivers of anxiety in patients with ASD, allowing patients to experience safe and effective symptom remission without worrying about severe side effects or invisible damage.
While human clinical trials investigating the utility of butyric acid in addressing anxiety in ASD remain forthcoming, researchers are optimistic that butyric acid supplementation can be a safe and powerful therapy based on extensive animal and clinical trials examining the effects of butyric acid on other ASD symptoms. When patients use butyric acid supplements, they’ll be correcting any deficiencies which may have resulted from ASD while also providing their gut’s immune system with the ability to cut down on inflammation. With less inflammation of the gut and less innervation of the gut-brain axis, patients will experience rapid and durable reduction of their anxiety as well as their gastrointestinal symptoms—a uniquely powerful result.
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