A complex neurodevelopmental condition, Autism Spectrum Disorder (ASD) is rising globally, indicating an urgent need to understand its causes. Decades of research have identified genetics and environmental factors as contributors. Whereas the definitive causes of ASD are unclear, genetic anomalies, nutritional deficiencies, toxins, and infections are strongly implicated.
More recently, evidence links gut microbial dysbiosis to ASD, with crucial functions like brain development, psychological balance, and gut health potentially impacted.
This blog will explore the association and explore the possibilities for gut microbiota modification through probiotic and prebiotic use in improving outcomes.
Autism, in brief
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by behaviors that include impaired language development, resistance to change, repetitive behaviors, and social difficulties. ASD commonly coexists with clinical symptoms such as gastrointestinal problems, motor deficits, epilepsy, sleep issues, and intellectual disability.
A 2022 review of prevalence found that ASD is diagnosed in 1 in 100 children worldwide. In the United States, the prevalence of ASD rose from 1 in 150 children in 2000 to 1 in 36 in 2020. ASD was four times more likely in boys than in girls.
ASD is recognized as a condition involving intricate interactions between genetics and the environment. More than 100 genes may be involved —but no one specific gene is responsible—and epigenetic factors may also have a role in ASD onset. Environmental factors such as drugs, toxic exposures, parental age, nutrition, prenatal, natal, and postnatal environments, and many others may contribute up to half of ASD etiology.
The imprecise cause of autism has prompted scientists to investigate alternative triggers, including the environmental risk factors that impact the gut microbiota.
Gut microbiota and ASD
Intestinal distress—constipation, abdominal pain, flatulence, and diarrhea— is common in ASD, and at a higher rate than in neurotypical individuals. In addition, irritable behaviors like social anxiety and withdrawal have been reported to be more frequent in those with intestinal distress.
Numerous studies suggest that such gastrointestinal dysfunctions are of particular relevance in ASD, underscored by several abnormalities along the nerve pathways between the gut and the central nervous system.
Perhaps most notably, patients with ASD host different microbiota than neurotypical children. A recent systematic review and meta-analysis reported increased levels of potentially harmful microbes with reductions in beneficial microbes in patients with ASD. Bacteroides, Parabacteroides, Faecalibacterium, and Clostridium were increased; Coprococcus and Bifidobacterium levels were decreased.
An abundance of potentially harmful bacteria and the low presence of beneficial bacteria microbiota could trigger GI as well as neurological symptoms in ASD. For example, an abundance of Clostridium bacteria with their related inflammatory toxins and metabolites have been linked with repetitive behaviors and GI problems in ASD. In contrast, beneficial Bifidobacterium can produce the main inhibitory neurotransmitter named gamma-aminobutyric acid (GABA), so when the Bifidobacterium is depleted in ASD, GABA is also depleted. Recent research in animals reports that a probiotic strain of Bifidobacterium was effective at restoring depleted GABA and increasing the expression of genes related to GABA receptors.
A summary of research linking microbiota composition to ASD gives a fuller picture of the levels of different microbes in ASD and the effects of variations in autistic patients based on numerous studies.
Dysbiosis in ASD, reported in numerous studies, may lead to compromised gut permeability, production of toxins, impaired immune response, and metabolic abnormalities. An underlying dysbiosis may influence emotional behaviors and brain neurotransmitter systems via the gut-brain axis. It is known that the gut microbiota can alter the brain physiology through neuroendocrine, neuroimmune, and autonomic nervous system pathways, and through its metabolites.
Compromised gut integrity (leaky gut) seen in ASD patients can lead to the production and spread of proinflammatory endotoxins such as lipopolysaccharides (LPS). Potent stimulators of the innate immune system, LPS can damage the blood-brain barrier by activating inflammatory pathways, inducing oxidative stress, altering tight junction proteins, and increasing permeability. The disruption can cause neuroinflammation and brain damage, which may be involved in ASD pathogenesis.
Dysbiosis in autism also leads to immune system dysregulation, altering neuropeptide synthesis and normal brain activity. Patients with autism often exhibit systemic changes, ranging from inflammation in the brain to disruptions in both innate and adaptive immune responses in the periphery. As illustration, levels of the neuropeptide oxytocin —involved in a range of physiological and behavioral functions, including social bonding, maternal behaviors, and stress response—may be altered via immune-endocrine-brain signaling networks. Research has shown that the oxytocin level correlates with gut microbiome dysbiosis in children with ASD.
A key function of gut microbiota is the production of metabolites such as short-chain fatty acids (SCFAs) and compounds that act as neurotransmitters.
When it comes to SCFA levels in autistic children, research indicates conflicting findings. Individuals with ASD exhibit an upregulation of acetate and propionate, while there is a notable decrease in butyrate levels. One study demonstrated the potential impact: rats treated with propionic acid displayed hyperactivity, stereotypy, and repetitive movements, changes similar to those seen in ASD patients. In addition, a decrease in butyrate levels may be significant as it has a beneficial effect on social and repetitive behaviors in an ASD-like mouse model.
Regarding the levels of microbe-produced neurotransmitters, both serotonin and GABA are altered in ASD, suggesting a pathway by which dysbiosis of the gut microbiota impacts brain activity across the gut-brain axis.
Modifying gut microbiota in ASD
The evidence linking dysbiosis to ASD has led researchers to test strategies for altering the gut microbiota in search of effective therapies. Mounting evidence suggests that gut microbial-targeting therapy may be a safe and beneficial approach for treating ASD.
Probiotics
Evidence exists that probiotics may modulate GI dysfunction and behavioral symptoms in ASD. In mouse models of ASD, probiotics have shown positive effects. A 2020 review paper provides a comparison of results from probiotic supplementation across various pre-clinical studies.
For example, mouse models of ASD treated with Bacteroides fragilis showed ameliorationof dysbiosis and improvement in ASD-like behaviors. In another study, a combination of three strains of probiotics along with prebiotics administered orally to pregnant mice prevented the ASD-like behaviors induced by maternal immune activation in their offspring.
In humans, studies have shown some — albeit limited— promise for probiotics.
In a 2018 study, 30 children with ASD were supplemented with a combination of three strains of probiotics for three months. Compared to the baseline at the start, fecal Bifidobacteria and Lactobacilli levels increased, and significant improvements in the severity of autism (assessed by the Autism Treatment Evaluation Checklist or ATEC), and gastrointestinal symptoms were observed.
In a 2020 study, 63 preschoolers with ASD were randomly assigned to a multi-strain probiotic (eight strains) or placebo for six months. Though significant changes in ASD symptoms were not seen in the overall sample, significant improvements in core ASD symptoms were observed in children without gastrointestinal symptoms. According to reviewers, more research is needed to validate the use of probiotics in ASD patients.
Prebiotics
Fermentation of prebiotics produces SCFAs, which may confer a health benefit in ASD. In an in vitro study on a gut model, the analysis of feces samples from children with ASD and non-autistic children showed that the prebiotic galacto-oligosaccharide raised the abundance of Bifidobacterium spp. However, the effect on ASD remains to be seen, as studies are limited.
Additional therapies
As for other therapies, some studies show the benefits of antibiotics, ketogenic, gluten-free, and casein-free diets, omega-3 supplementation, fecal microbiota transplantation (FMT), and microbiota transfer therapy (MTT), in benefiting ASD patients. Their examination is beyond the scope of this blog.
Takeaway
The rising incidence of ASD underscores the need to uncover its causes and mechanisms. In recent years, a growing body of evidence suggests a strong connection between dysbiosis and ASD, leading scientists to explore interventions targeting the gut microbiota as potential therapies. Probiotics have shown promise in mitigating dysbiosis and improving ASD-like behaviors in mouse models. Human trials, while showing some degree of promise, indicate that probiotics may offer benefits, emphasizing the need for further research to validate their use in ASD patients.
Image by Gerd Altmann from Pixabay
Key references
Abdellatif, Basma et al. “The Promising Role of Probiotics in Managing the Altered Gut in Autism Spectrum Disorders.” International journal of molecular sciences vol. 21,11 4159. 10 Jun. 2020, doi:10.3390/ijms21114159
Alharthi, Amani et al. “The Human Gut Microbiome as a Potential Factor in Autism Spectrum Disorder.” International journal of molecular sciences vol. 23,3 1363. 25 Jan. 2022, doi:10.3390/ijms23031363
Argou-Cardozo, Isadora, and Fares Zeidán-Chuliá. “Clostridium Bacteria and Autism Spectrum Conditions: A Systematic Review and Hypothetical Contribution of Environmental Glyphosate Levels.” Medical sciences (Basel, Switzerland) vol. 6,2 29. 4 Apr. 2018, doi:10.3390/medsci6020029
Banks, William A et al. “Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit.” Journal of neuroinflammation vol. 12 223. 25 Nov. 2015, doi:10.1186/s12974-015-0434-1
Chaste, Pauline, and Marion Leboyer. “Autism risk factors: genes, environment, and gene-environment interactions.” Dialogues in clinical neuroscience vol. 14,3 (2012): 281-92. doi:10.31887/DCNS.2012.14.3/pchaste
Doenyas, Ceymi. “Gut Microbiota, Inflammation, and Probiotics on Neural Development in Autism Spectrum Disorder.” Neuroscience vol. 374 (2018): 271-286. doi:10.1016/j.neuroscience.2018.01.060
Erdman, S E, and T Poutahidis. “Microbes and Oxytocin: Benefits for Host Physiology and Behavior.” International review of neurobiology vol. 131 (2016): 91-126. doi:10.1016/bs.irn.2016.07.004
Fiorentino, Maria et al. “Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.” Molecular autism vol. 7 49. 29 Nov. 2016, doi:10.1186/s13229-016-0110-z
Garcia-Gutierrez, Enriqueta et al. “Autism Spectrum Disorder Associated With Gut Microbiota at Immune, Metabolomic, and Neuroactive Level.” Frontiers in neuroscience vol. 14 578666. 8 Oct. 2020, doi:10.3389/fnins.2020.578666
Grimaldi, Roberta et al. “In vitro fermentation of B-GOS: impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children.” FEMS microbiology ecology vol. 93,2 (2017): fiw233. doi:10.1093/femsec/fiw233
Gyawali, Shreeya, and Bichitra Nanda Patra. “Trends in concept and nosology of autism spectrum disorder: A review.” Asian journal of psychiatry vol. 40 (2019): 92-99. doi:10.1016/j.ajp.2019.01.021
Haba, Ryota et al. “Lipopolysaccharide affects exploratory behaviors toward novel objects by impairing cognition and/or motivation in mice: Possible role of activation of the central amygdala.” Behavioural brain research vol. 228,2 (2012): 423-31. doi:10.1016/j.bbr.2011.12.027
Hodges, Holly et al. “Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation.” Translational pediatrics vol. 9,Suppl 1 (2020): S55-S65. doi:10.21037/tp.2019.09.09
Holingue, Calliope et al. “Gastrointestinal symptoms in autism spectrum disorder: A review of the literature on ascertainment and prevalence.” Autism research : official journal of the International Society for Autism Research vol. 11,1 (2018): 24-36. doi:10.1002/aur.1854
Hsiao, Elaine Y et al. “Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.” Cell vol. 155,7 (2013): 1451-63. doi:10.1016/j.cell.2013.11.024
Huang, Minshi et al. “Serum Oxytocin Level Correlates With Gut Microbiome Dysbiosis in Children With Autism Spectrum Disorder.” Frontiers in neuroscience vol. 15 721884. 1 Oct. 2021, doi:10.3389/fnins.2021.721884
Kang, Dae-Wook et al. “Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study.” Microbiome vol. 5,1 10. 23 Jan. 2017, doi:10.1186/s40168-016-0225-7
Kastin, Abba J, and Weihong Pan. “Concepts for biologically active peptides.” Current pharmaceutical design vol. 16,30 (2010): 3390-400. doi:10.2174/138161210793563491
Lefter, Radu et al. “A Descriptive Review on the Prevalence of Gastrointestinal Disturbances and Their Multiple Associations in Autism Spectrum Disorder.” Medicina (Kaunas, Lithuania) vol. 56,1 11. 27 Dec. 2019, doi:10.3390/medicina56010011
Li, Qinrui et al. “The Gut Microbiota and Autism Spectrum Disorders.” Frontiers in cellular neuroscience vol. 11 120. 28 Apr. 2017, doi:10.3389/fncel.2017.00120
Lin, Chia-Wen et al. “A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.” Molecular psychiatry vol. 27,8 (2022): 3343-3354. doi:10.1038/s41380-022-01566-y
Martin, Clair R et al. “The Brain-Gut-Microbiome Axis.” Cellular and molecular gastroenterology and hepatology vol. 6,2 133-148. 12 Apr. 2018, doi:10.1016/j.jcmgh.2018.04.003
Masini, Elena et al. “An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity.” International journal of molecular sciences vol. 21,21 8290. 5 Nov. 2020, doi:10.3390/ijms21218290
McElhanon, Barbara O et al. “Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis.” Pediatrics vol. 133,5 (2014): 872-83. doi:10.1542/peds.2013-3995
Meeking, Melissa M et al. “Propionic acid induced behavioural effects of relevance to autism spectrum disorder evaluated in the hole board test with rats.” Progress in neuro-psychopharmacology & biological psychiatry vol. 97 (2020): 109794. doi:10.1016/j.pnpbp.2019.109794
Mehra, Anshula et al. “Gut microbiota and Autism Spectrum Disorder: From pathogenesis to potential therapeutic perspectives.” Journal of traditional and complementary medicine vol. 13,2 135-149. 8 Mar. 2022, doi:10.1016/j.jtcme.2022.03.001
Peng, Xiaoyao et al. “Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy.” Frontiers in cellular and infection microbiology vol. 11 768108. 4 Nov. 2021, doi:10.3389/fcimb.2021.768108
Rothschild, Daphna et al. “Environment dominates over host genetics in shaping human gut microbiota.” Nature vol. 555,7695 (2018): 210-215. doi:10.1038/nature25973
Rylaarsdam, Lauren, and Alicia Guemez-Gamboa. “Genetic Causes and Modifiers of Autism Spectrum Disorder.” Frontiers in cellular neuroscience vol. 13 385. 20 Aug. 2019, doi:10.3389/fncel.2019.00385
Santocchi, Elisa et al. “Effects of Probiotic Supplementation on Gastrointestinal, Sensory and Core Symptoms in Autism Spectrum Disorders: A Randomized Controlled Trial.” Frontiers in psychiatry vol. 11 550593. 25 Sep. 2020, doi:10.3389/fpsyt.2020.550593
Shaaban, Sanaa Y et al. “The role of probiotics in children with autism spectrum disorder: A prospective, open-label study.” Nutritional neuroscience vol. 21,9 (2018): 676-681. doi:10.1080/1028415X.2017.1347746
Silva, Ygor Parladore et al. “The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication.” Frontiers in endocrinology vol. 11 25. 31 Jan. 2020, doi:10.3389/fendo.2020.00025
Vuong, Helen E, and Elaine Y Hsiao. “Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder.” Biological psychiatry vol. 81,5 (2017): 411-423. doi:10.1016/j.biopsych.2016.08.024
Wang, Lulu W et al. “The prevalence of gastrointestinal problems in children across the United States with autism spectrum disorders from families with multiple affected members.” Journal of developmental and behavioral pediatrics : JDBP vol. 32,5 (2011): 351-60. doi:10.1097/DBP.0b013e31821bd06a
Wang, Xiao et al. “Oral probiotic administration during pregnancy prevents autism-related behaviors in offspring induced by maternal immune activation via anti-inflammation in mice.” Autism research : official journal of the International Society for Autism Research vol. 12,4 (2019): 576-588. doi:10.1002/aur.2079
Xu, Mingyu et al. “Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.” Frontiers in psychiatry vol. 10 473. 17 Jul. 2019, doi:10.3389/fpsyt.2019.00473
Yunes, R A et al. “GABA production and structure of gadB/gadC genes in Lactobacillus and Bifidobacterium strains from human microbiota.” Anaerobe vol. 42 (2016): 197-204. doi:10.1016/j.anaerobe.2016.10.011
Zeidan, Jinan et al. “Global prevalence of autism: A systematic review update.” Autism research : official journal of the International Society for Autism Research vol. 15,5 (2022): 778-790. doi:10.1002/aur.2696