The gut connection to autism
The takeaway:
Besides genetics, several factors contribute to autism spectrum disorder (ASD), including gut microbial imbalances, immune dysfunction and diet.
ASD patients tend to suffer from more gastrointestinal symptoms and also have imbalances in their gut microbiota.
Interventions to treat ASD aim to heal the gut and restore the balance of bacteria, including probiotics, fecal microbiota transplantation and specific diets.
Read on for more!
“Autism spectrum disorder is a neurodevelopmental disorder that is characterized by social and communication impairment and is often accompanied by behavioral symptoms, repetitive behaviors, GI disturbance, and immune dysfunction” [1].
The incidence of ASD has increased dramatically, with diagnoses rising from 1 in 150 children to 1 in the year 2000 to 1 in 59 children in 2014 [2]. Although ASD has a clear genetic component, the significant increase in cases suggests that other factors are at play, including immune dysregulation, inflammation and gut microbiota [3].
Patients with ASD are more likely to have increased intestinal permeability and to experience GI symptoms such as diarrhea or constipation, abdominal pain and gastric reflux [4, 5]. These symptoms can contribute to behavioral issues such as social withdrawal, irritability and hyperactivity [6, 7]. They also point to a potential link between the gut and ASD.
Evidence from several other studies further indicates a gut-brain link in ASD. These studies show that germ-free rodents exhibit decreased sociability and are less likely to interact with new rodents compared to familiar ones [8, 9, 10]. However, colonizing the germ-free mice with gut microbiota of normal mice corrects some of the social impairments [11].
Gut microbial imbalances
Other studies in mice and humans have shown that ASD is associated with altered microbial composition and function [3, 6]. Comparison of the gut microbiota of ASD patients to healthy people has revealed several differences, which are summarized below [3, 6, 12, 13].
Higher abundance of Clostridium, Lactobacillus, Desulfovibrio, Sutterella and Candida
Decreased Bacteroidetes/Firmicutes ratio
Decreased Bifidobacterium, Prevotella, Coprococcus, Veilonellaceae (bacteria that ferment carbohydrates)
Less microbial diversity
Unfortunately, no signature microbiota or specific microbial disturbance has been identified in all ASD cases. The differences noted above are not necessarily consistent across studies, thus additional research is needed to determine if there is a specific gut microbiome associated with ASD. Rather than identifying which microbes are present or absent Exploring gut microbiome function by measuring gene activity and metabolites, like short chain fatty acids and neurotransmitters, will expand our understanding of the ASD gut.
The influence of the immune system
As we learned in my last post the immune system provides a link between gut microbiota and the brain. One stark example of this is how maternal immune activation and gut microbiota can increase the risk of ASD in offspring, which I wrote about previously In pregnant mice, maternal infection with a virus can cause an inflammatory immune reaction, which is exacerbated by certain gut bacteria. The immune response can cause lesions in the brain of the mouse fetus, leading to ASD-like symptoms in the offspring [14, 15]. However, treatment of the offspring with the human gut bacterium Bacteroides fragilis corrected the ASD-like symptoms, as well as reducing gut permeability and altering the microbial community [16].
Stress or infection can impair intestinal barrier, allowing bacteria to pass through, which can activate the immune system. Immune system activation causes elevated inflammatory signaling molecules called cytokines and stimulation of the vagus nerve, which in turn, regulates the central nervous system [17]. One study found that cytokine-induced vagal system stimulation induced behavioral depression [18].
Additionally, gut permeability allows endotoxin, a bacterial component that causes inflammation, to enter the bloodstream. Endotoxin activates the immune system, the enteric nervous system, and the central nervous system [19]. In mice, the effect of endotoxin in the bloodstream included reduced social communication and increased repetitive behavior [3].
Modulation of gut bacteria to treat ASD
Probiotics are one of the many options that have been explored to treat ASD. Several studies have shown promising results with probiotic supplementation in children with ASD. These trials tested various combinations of standard probiotic bacteria, including different species of Lactobacillus, Bifidobacterium, and Streptococcus. The trials lasted from 4 weeks to 6 months and all used different doses of probiotic bacteria. The probiotics helped balance the microbiota of ASD patients, relieved GI symptoms, and improved ASD-like symptoms, such as improved social behavior like following directions, reduced stress response, and decreased anxiety- and depression-related behavior [3, 12].
Microbial transfer treatment, an extended version of fecal microbial transplant, has also being explored as a potential treatment option for ASD. In microbial transfer treatment, gut microbes derived from the fecal material of a healthy donor are transplanted to a patient. Fecal microbial transplant is over 90% successful in treating chronic Clostridium dificile infections [20]. A small trial was conducted in 18 children with ASD. The treatment normalized gut microbiota and improved GI symptoms, including constipation, diarrhea, indigestion and abdominal pain, and ASD-related symptoms in ASD patients [13]. These improvements were maintained even 8 weeks after the treatment ended.
Diets to alleviate ASD symptoms
Diets eliminating gluten and/or casein (protein found in dairy) have been heralded by many parents as drastically improving their child’s ASD behaviors, physiological symptoms and social behaviors [21]. In some people, gluten and casein are known to aggravate the intestinal lining and may contribute to gut permeability. Since many ASD children also suffer from GI disorders and symptoms, removing gluten and casein has the potential to alleviate several factors of ASD. However, despite the anecdotal evidence from parents, the scientific literature in support of such diets is lacking. More trials are needed to determine the actual efficacy of a gluten-free casein-free diet and to identify ASD patients that will respond to such an intervention (such as those with severe GI disorders) [22].
In mice models of ASD, a ketogenic diet (which I describe here) lowers total microbial counts, improves sociability and social communication, and reduces repetitive behaviors [3]. The result of lowering total gut microbial counts suggests that bacterial overgrowth may contribute to ASD in some cases. However, a small trial of 15 children on a ketogenic diet supplemented with medium-chain triglycerides showed mixed results. Some children showed significant improvement in ASD core symptoms, but retained repetitive behaviors, whereas some children experienced no improvement [23]. Again, more trials will determine which ASD patients could benefit from a ketogenic diet.
The GAPS (Gut and Psychology Syndrome) diet has received some attention as a way to treat and manage ASD symptoms, among other neurological conditions. The goal of the diet is to heal the intestine and repair leaky gut. It comprises 6 stages which detail a fairly strict, regimented elimination diet, followed by slow and controlled reintroduction of foods. I couldn’t find any trials assessing the GAPS diet.
Do you have experience with ASD? Have you used any of these tools, probiotics or diet, to help manage symptoms? I’d love to hear what has worked and what hasn’t!
References
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Baio, J., et al., Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ, 2018. 67(6): p. 1-23.
Li, Q., et al., The Gut Microbiota and Autism Spectrum Disorders. Front Cell Neurosci, 2017. 11: p. 120.
Emanuele, E., et al., Low-grade endotoxemia in patients with severe autism. Neurosci Lett, 2010. 471(3): p. 162-5.
de Magistris, L., et al., Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr, 2010. 51(4): p. 418-24.
Vuong, H.E. and E.Y. Hsiao, Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder. Biol Psychiatry, 2017. 81(5): p. 411-423.
McElhanon, B.O., et al., Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics, 2014. 133(5): p. 872-83.
Desbonnet, L., et al., Microbiota is essential for social development in the mouse. Mol Psychiatry, 2014. 19(2): p. 146-8.
Arentsen, T., et al., Host microbiota modulates development of social preference in mice. Microb Ecol Health Dis, 2015. 26: p. 29719.
Crumeyrolle-Arias, M., et al., Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology, 2014. 42: p. 207-17.
Clarke, G., et al., The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry, 2013. 18(6): p. 666-73.
Yang, Y., J. Tian, and B. Yang, Targeting gut microbiome: A novel and potential therapy for autism. Life Sci, 2018. 194: p. 111-119.
Kang, D.W., et al., Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome, 2017. 5(1): p. 10.
Wong, H. and C. Hoeffer, Maternal IL-17A in autism. Exp Neurol, 2017.
Shin Yim, Y., et al., Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature, 2017. 549(7673): p. 482-487.
Hsiao, E.Y., et al., Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 2013. 155(7): p. 1451-63.
Yarandi, S.S., et al., Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases. J Neurogastroenterol Motil, 2016. 22(2): p. 201-12.
Konsman, J.P., et al., The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis. Eur J Neurosci, 2000. 12(12): p. 4434-46.
Abreu, M.T., Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol, 2010. 10(2): p. 131-44.
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Elder, J.H., et al., The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord, 2006. 36(3): p. 413-20.
Elder, J.H., et al., A review of gluten- and casein-free diets for treatment of autism: 2005-2015. Nutr Diet Suppl, 2015. 7: p. 87-101.
Lee, R.W.Y., et al., A modified ketogenic gluten-free diet with MCT improves behavior in children with autism spectrum disorder. Physiol Behav, 2018. 188: p. 205-211.
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