Does keto diet help autism

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder that is characterized by stereotyped behavior and deficits in communication and social interaction. Autism spectrum disorder affects 3.4–6.7 per 1,000 children. Boys are four times more likely than girls to have Autism spectrum disorder. The core features of Autism spectrum disorder patients are social communication deficits and repetitive sensory–motor behaviors. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), patients who are diagnosed with Autism spectrum disorder must have persistent deficits in social communication and repetitive and unusual sensory–motor behaviors. Comorbidities in Autism spectrum disorder are common and include epilepsy, sleep disorders, gastrointestinal (GI) symptoms, and psychopathologies such as anxiety, depression, attention deficit hyperactivity disorder, and intellectual disability. Sleep disturbances occur in 50–80% Autism spectrum disorder children, and sleep disorder is associated with behavioral dysregulation. Epilepsy is also one of the most common comorbidities in Autism spectrum disorder children, and the average prevalence reaches 26%. Autism spectrum disorder individuals who have epilepsy are likely to exhibit more severe autism-related symptoms. GI symptoms, which range from 23 to 70% in ASD children, are related to the severity of Autism spectrum disorder. Approximately 31% of children with Autism spectrum disorder have intelligence quotient scores below 70. The cost of raising a child with Autism spectrum disorder is 1.4–3.6 million dollars according to the level of intellectual disability, and the largest expenses are special education costs and the loss of parental productivity. When children grow up, supportive living accommodations and the loss of individual productivity become the highest costs. Therefore, Autism spectrum disorder places a large burden on society and the affected families. There are no effective drugs for Autism spectrum disorder. Several interventions, such as special education and behavioral interventions, provide some benefits, but these interventions do not improve all core symptoms of Autism spectrum disorder and have less effects on comorbidities, including epilepsy. Therefore, new therapies are urgently needed to broaden the management options and improve the prognosis of these patients. Lower levels of disaccharidases and hexose transporters were found in Autism spectrum disorder patients with GI symptoms, which suggests carbohydrate digestion disorders as a physiopathological mechanism in Autism spectrum disorder patients. Therefore, a low-carbohydrate diet, such as a ketogenic diet (KD), is likely suitable for Autism spectrum disorder patients.

A ketogenic diet is a high-fat, appropriate-protein, and low-carbohydrate diet that has a positive effect on energy metabolism. For example, a ketogenic diet increases the levels of adenosine triphosphate (ATP) and enzymes associated with mitochondrial metabolic pathways and enhances mitochondrial biogenesis. Acetyl-CoA is converted to ketone bodies under the effects of d-β-hydroxybutyrate dehydrogenase, acetoacetate succinyl-CoA transferase, and acetoacetyl-CoA-thiolase. Ketone bodies, including β-hydroxybutyrate, acetoacetate, and acetone, function as fuels under fasting or starvation conditions and cross the blood–brain barrier (BBB) to feed the brain. These molecules also prevent mitochondrial permeability transition and attenuate reactive oxygen species (ROS). Therefore, ketone bodies have neuroprotective effects in the central nervous system (CNS). A ketogenic diet is a significantly effective treatment for epilepsy. Refractory epilepsy patients aged 1–18 years treated with a ketogenic diet for 4 months had a 56% reduction in mean seizure frequency. A ketogenic diet may also improve some core autistic features and comorbidities of Autism spectrum disorder, but data of clinical studies of a ketogenic diet as a treatment for Autism spectrum disorder are very limited. The present review examined the role of a ketogenic diet in Autism spectrum disorder treatment and discussed the underlying mechanisms.

A ketogenic diet is a dietary intervention therapy in neurological disorders such as epilepsy and Autism spectrum disorder. A ketogenic diet may be an effective therapy for ASD because it might improve Autism spectrum disorder core symptoms and could benefit its comorbidities, including seizures. The efficiency of a ketogenic diet must be monitored using urinary ketones and serum beta-hydroxybutyrate (BHB). Some evidence showed that a ketogenic diet improved the core features of Autism spectrum disorder patients (Table 1). El-Rashidy et al. showed that a ketogenic diet improved autistic manifestations, which was demonstrated as improved scores on the Autism Treatment Evaluation Test (ATEC) scales and the Childhood Autism Rating Scale (CARS), especially sociability improvement. Lee et al. also reported that a modified ketogenic gluten-free diet with supplemental medium-chain triglycerides (MCTs) improved the social affect subdomain and total autism diagnostic observation schedule, 2nd edition (ADOS-2) scores, but it did not affect the restricted and repetitive behavior scores. A ketogenic diet improved social exploration and social interactions in an animal model of Autism spectrum disorder. It also ameliorates the comorbidities of Autism spectrum disorder more efficiently than the core symptoms of Autism spectrum disorder. A ketogenic diet improved the social communication of one of six Autism spectrum disorder patients, but it reduced the comorbidities of all six Autism spectrum disorder patients, including attention deficit hyperactivity disorder (ADHD), compulsive behavior, preoccupation with parts of objects, and abnormal sleep. It also decreased the frequency of seizures. A case report of an Autism spectrum disorder child found that a ketogenic diet improved the electroencephalogram results and increased the child's intelligence quotient. Although a ketogenic diet-induced decrease in seizures will lead to a better quality of life in patients with epilepsy, including Autism spectrum disorder, it is not associated with improvements in behaviors in Autism spectrum disorder patients. Antiepileptic drugs do not have a large effect on the behavioral symptoms in Autism spectrum disorder.

After ketogenic diet treatment, some blood parameters changed, such as an upregulation of beta-hydroxybutyrate, high-density lipoprotein (HDL), low-density lipoprotein, and cholesterol and a downregulation of eosinophils. Only the HDL increase, eosinophil percentage, and white blood cell count decrease predicted the effects of a modified ketogenic diet treatment in Autism spectrum disorder patients. Why the effects of ketogenic diet vary so much from patient to patient in Autism spectrum disorder is not clear. The pro-inflammatory condition at baseline was associated with an effective ketogenic diet treatment, which was demonstrated by a reduction in eosinophils.

A ketogenic diet seems effective in Autism spectrum disorder patients, but all of these clinical studies had small sample sizes, which is likely due to the difficulty of setting up randomized trials in Autism spectrum disorder children. Autism spectrum disorder patients also eat a narrower range of foods and exhibit more feeding problems. They refuse some food because of the presentation or the need for certain utensils. Therefore, it is difficult to introduce the ketogenic diet to Autism spectrum disorder children. The duration of these studies was 3–16 months, which is not sufficient to assess the side effects of ketogenic diet. In summary, more studies are needed to verify the precise role of ketogenic diet in Autism spectrum disorder patients.

The Neuroprotective Role of a ketogenic diet in the Central Nervous System

A ketogenic diet contains abundant fat and induces the generation of acetyl-CoA in the mitochondria of the liver via fatty acid oxidation. Therefore, abundant acetyl-CoA is shunted to the formation of ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) in the liver. These ketone bodies enter into the circulation and are used to produce energy. One of the main ketones is acetone, which increases the seizure threshold and potentiates the anticonvulsant activity of some antiepileptic drugs. Therefore, fatty acids and ketone bodies exert neuroprotective effects in the brain. For example, ketone bodies improve the energy metabolism by enhancing ATP production and normalizing mitochondrial function via the stimulation of mitochondrial biogenesis and the reduction of oxidative stress, which reduces neuronal death. Ketone bodies regulate neurotransmitters, increase γ-aminobutyric acid (GABA) levels, and inhibit the activation of the mammalian target of rapamycin (mTOR) signaling pathway. However, the exact neuroprotective mechanisms of a ketogenic diet are not fully understood.

The Improvement of Energy Metabolism in the Central Nervous System

Autism spectrum disorder individuals have impaired mitochondrial energy production due to the presence of abnormal mitochondrial markers in their plasma, such as elevated levels of lactic acid and pyruvate. Weissman et al. showed that Autism spectrum disorder patients had mitochondrial electron transport chain dysfunction, including complex I and complex III deficiencies. A ketogenic diet provides fuel sources in the human body, and the ketone bodies, including β-hydroxybutyrate, cross the blood-brain barrier and replace glucose as fuel for the brain. This molecule crosses the blood-brain barrier via proton symporters and a sodium-dependent monocarboxylate transporter, which is located in the blood-brain barrier, neurons, and astrocytes. Ketone bodies enhance adenosine triphosphate (ATP) production via the Krebs cycle to generate energy and balance metabolism. A ketogenic diet reduced seizures by enhancing brain metabolism via the regulation of transcripts encoding energy metabolism enzymes or mitochondrial proteins in rats with seizures.

Anti-inflammatory Activity and Antioxidative Stress

One of the risk factors for Autism spectrum disorder in children is abnormal maternal immune activation. For example, pregnant mice were injected with double-stranded RNA (dsRNA) poly (I: C) to mimic a viral infection, and the offspring of these mice had Autism spectrum disorder-like behaviors. Autism spectrum disorder patients also experience aberrant inflammation. Some cytokines and chemokines, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and monocyte chemotactic protein-1, are found at abnormal levels in brain samples and cerebrospinal fluid in Autism spectrum disorder patients. These cytokines activate the immune response via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Young and colleagues found that the NF-κB protein was hyper-expressed in mature microglia in brain samples in Autism spectrum disorder patients, which indicates that immunity is activated in the brains of Autism spectrum disorder patients. Autism spectrum disorder patients also had higher levels of eight cytokines in plasma compared to control individuals. Autism spectrum disorder individuals also have associated oxidative stress level upregulation and antioxidant ability downregulation. Evidence showed that antioxidant enzymes, including superoxide dismutase and glutathione peroxidase, are altered in Autism spectrum disorder patients, which increases inflammation. In summary, there is a consensus that Autism spectrum disorder individuals have immune dysfunction.

A ketogenic diet has powerful anti-inflammatory activity and antioxidative stress effects in the brain. Jeong et al. found that a ketogenic diet reduced neuroinflammation via the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) and protected against excitotoxicity-induced neuronal cell death. Fatty acids activate PPARs and are critical regulators of lipid metabolism. Greco et al. found that ketone bodies decreased oxidative stress and improved the mitochondrial respiratory complex activity in a traumatic brain injury animal model. A ketogenic diet likely normalizes mitochondrial function by stimulating mitochondrial biogenesis, decreasing oxidative stress and the levels of pro-apoptotic factors, preventing changes in mitochondrial permeability, and decreasing the mitochondrial ROS production in neocortical neurons. Mirza et al. showed that rats treated with propionic acid exhibited social impairment and repetitive behavior. The cerebellum, brainstem, and prefrontal cortex of these rats had high levels of oxidative stress and inflammation, with increased IL-6 and TNF-α levels and decreased IL-10 levels. They also found that decreased levels of oxidative stress and inflammation improved neurobehavioral disorders in rats.

The Regulation of Neurotransmitters in the Brain

GABA is the main inhibitory neurotransmitter in the brain, and it originates from glutamate decarboxylation. Glutamate is the primary excitatory neurotransmitter in the Central Nervous System. Patients with autism exhibited abnormal levels of proteins and messenger RNAs (mRNAs) associated with the glutamate system in the cerebellum. The medium-chain fatty acids that are present during the consumption of a ketogenic diet directly inhibit glutamate receptors and reduce seizures. Other studies found that beta-hydroxybutyrate, which is produced from a ketogenic diet, inhibited GABA degradation in astrocytes. One study showed that children with Autism spectrum disorder had reduced GABA levels in sensorimotor function, and this phenomenon was associated with poor tactile performance compared to healthy children. Autism spectrum disorder patients had significantly lower GABA concentrations in the auditory cortex. Patients with Autism spectrum disorder also had abnormal maturation of the neuronal circuitry on magnetoencephalography (MEG) and edited magnetic resonance spectroscopy (MRS). In summary, a ketogenic diet may ameliorate Autism spectrum disorder behaviors via the modulation of neurotransmitters, such as increasing GABA levels.

Modulation of the Gut Microbiota

gastrointestinal symptoms, including constipation and diarrhea, are common in Autism spectrum disorder individuals and are associated with the severity of Autism spectrum disorder symptoms. Gorrindo et al. reported that constipation was associated with increased social impairment and language disorders. Patients with Autism spectrum disorder have different gut microbiome components and metabolic products. The gut microbiota communicates with the brain via the neuroendocrine, neuroimmune, and autonomic nervous systems, which is the so-called microbiota–gut-brain axis. Porphyromonadaceae, Prevotellaceae, Bacteroidales, and Lachnospiraceae were more abundant in the Autism spectrum disorder animal model. An increasing number of studies showed that gut microbiota disturbances were associated with Autism spectrum disorder patients, and modulation of the gut microbiota improved symptoms in Autism spectrum disorder patients.

A ketogenic diet restored gut microbial composition and improved Autism spectrum disorder core features, including social communication and repetitive behaviors, in an Autism spectrum disorder animal model. A ketogenic diet increased the levels of Akkermansia, Parabacteroides, Bacteroides, and Desulfovibrio spp. in animal models of seizure, glucose transporter 1 deficiency syndrome, and Autism spectrum disorder. A ketogenic diet did not change locomotor activity, anxiety-related behaviors, recognition memory, or sociability in young male rats, which suggests that a ketogenic diet may be more effective in females in some cases. As mentioned above, a ketogenic diet likely modifies the composition of the gut microbiota in different animal disease models, including Autism spectrum disorder. However, there are few studies on alterations of the gut microbiota in humans treated with a ketogenic diet. In summary, modulation of the gut microbiota may be a new target for therapy in Autism spectrum disorder patients.

The Side Effects of a Ketogenic Diet

Autism spectrum disorder children have feeding problems because most of them are selective eaters. Therefore, it is difficult to apply a Ketogenic Diet to children with Autism spectrum disorder. There are also some side effects of the long-term implementation of a Ketogenic Diet in children. The main side effects of Ketogenic Diet treatment in children are constipation, vomiting, lack of energy, and hunger. Late-onset adverse effects include hyperuricemia, hyperlipidemia, and kidney stones. One serious side effect of a Ketogenic Diet in children is the suppression of physical development. Long-term Ketogenic Diet administration decreased growth, as indicated by height z-scores but growth, as indicated by weight z-scores, did not change. A Ketogenic Diet may cause height deceleration. However, these side effects do not occur often, and a Ketogenic Diet has been widely used in children with refractory epilepsy. In summary, although studies with larger samples of Autism spectrum disorder patients are lacking, Ketogenic Diet is a safe and effective treatment in people with Autism spectrum disorder.