Gut Microbiota and Autism

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Introduction


By Bailey Fitzgerald

Figure 1: Diagram of the gut-brain axis and its influence in autism spectrum disorder. Photo credit: Chidambaram et al., https://link.springer.com/chapter/10.1007/978-3-030-30402-7_21.

A healthy adult human intestine harbors billions of bacteria of over 1000 different species.[1][2] These bacteria play a large role in human health through digestion and aiding in immune system development.[2] However, these bacteria can also have a direct influence on their human host’s behavior. Gut microbes have the ability to bidirectionally communicate with the central nervous system and influence both emotional and cognitive centers of the brain.[3] This makes maintenance of the gut microbiome especially important in people with a variety of neurological conditions, including autism spectrum disorder (ASD).

Autism spectrum disorder is a neurological and developmental disorder characterized by deficits in social communication and social interaction, repetitive patterns of behavior or activities, and restricted interests.[4] The CDC estimates that approximately 1 in every 54 children in the United States is affected by autism spectrum disorder.[5] ASD can range in severity from very high-functioning (formerly known as Asperger’s syndrome) in which the individual is able to go about daily life with little to no assistance to low-functioning individuals that need assistance with basic care and needs, or anywhere in between. It is also common to have other diseases and conditions along with autism spectrum disorder. These comorbidities can include sleep disorders, seizure disorders, gastrointestinal disorders, metabolic disorders, and hormonal dysfunction.[6]

Gastrointestinal (GI) issues, such as frequent abdominal pain, gaseousness, diarrhea, constipation or pain on stooling, are a very common comorbidity in ASD patients.[7][8] Studies have found that 23% to 70% of people with ASD suffer from gastrointestinal dysfunction, with the wide range attributed to variances in survey methods.[8] Additionally, the prevalence of more gastrointestinal symptoms was strongly correlated with the severity of autism in patients.[9] These gastrointestinal issues can be attributed to a disturbance in normal gut flora composition.[9] Although the cause of the abnormal gut microbiome in patients with ASD is not certain, researchers hypothesize that it could be due to atypical eating habits.[10] Thus, therapies targeting the gut microbiome could have potential in treating and managing autism spectrum disorders. Because the exact causes of ASD and the mechanisms behind the disorder are difficult to identify, there are very few effective therapies available.[11] This makes the potential of microbiome treatments for ASD even more promising and hopeful for managing the disorder.

Composition of the ASD Microbiome

Figure 2: Composition of gut microbiome in healthy children (HC), children with developmental disorders (PDD-NOS), and children with ASD (AD). Red signifies more prevalent bacterial species while green denotes less prevalence. Samples are grouped using double dendrogram representation (left side) to identify similarities in composition. Photo credit: De Angelis et al., https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076993#pone-0076993-g003.

The microbiome of individuals with autism spectrum disorder differs from that of the average person. Firstly, the intestinal environment itself is abnormal in patients with ASD compared to the typical person. Approximately one third of patients with ASD displayed a higher percentage of abnormal permeability in their intestines compared to the approximately 5% of abnormal permeability in the control population.[12] This increased intestinal permeability causes an increased antigenic load from the GI tract. This allows more chemical signals originating from the GI tract to enter the circulation and then cross over the blood-brain barrier to deliver these chemical signals to the brain where they induce immune responses.[7] Therefore, the microbiota of ASD patients may have even more influence through the gut-brain axis than in the average person.

Patients with ASD have different species of bacteria prevalent in their gut microbiome. The maternal immune activation (MIA) mouse model is an ideal model for studying ASD as it displays many features of the disorder. One study found that offspring of mothers with MIA had more Porphyromonadaceae, Prevotellaceae, unclassified Bacteroidales, and Lachnospiraceae bacterias, whereas control offspring had more Ruminococcaceae, Erysipelotrichaceae, and Alcaligenaceae bacterias.[13] Another model system for studying ASD can be created by inducing autistic-like behaviors in offspring of mice through the administration of valproic acid in pregnant mice. In all offspring of the VPA treated mice, Bacteroidetes and Desulfovibrionales increased in prevalence while Firmicutes decreased. Additionally, male VPA offspring possessed more Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis bacteria compared to their female siblings.[14]

Analyses of the microbiota within humans with ASD have been mostly consistent with the findings of these animal models. The microbiome of children with autism spectrum disorder has been shown to be less diverse overall and contains lower levels of Bifidobacterium and Firmicutes while the prevalence of Lactobacillus, Clostridium, Bacteroidetes, Desulfovibrio, Caloramator, and Sarcina bacterias are higher.[15][16][9][17][18][7] Autistic children specifically with GI symptoms had lower prevalence of Prevotella, Coprococcus, and unclassified Veillonellaceae bacteria. Given that these bacteria are versatile carbohydrate-degrading and/or fermenting bacteria, it would suggest that these differences could be attributed to atypical diet and feeding behaviors associated with ASD; however, the study showed no correlation between diet patterns and microbial diversity or abundance.[19]

The increased abundance of Clostridium bacteria in the gut microbiome of individuals with ASD is cause for concern. Clostridium bacteria are known to be toxin-producers, their products of which include neurotoxins that could be harmful to individuals with ASD through the gut-brain axis.[20] Additionally, this bacteria may contribute to gut dysfunction and GI symptoms.[21] Given that increased GI symptoms and ASD severity show positive correlation, Clostridium bacteria may be associated with the development of certain autistic characteristics.[9][21]

Development of the Gut Microbiota and ASD

Figure 3: Antibodies from mothers of children with autism and mothers of neurotypical children reacted with rat prenatal (PN18) brain proteins on 15% SDS–PAGE. Mothers of autistic children and autistic children displayed patterns (A) or (B). Mothers of neurotypical children, neurotypical children, and siblings of autistic children displayed pattern (C). Photo credit: Zimmerman et al., https://www.sciencedirect.com/science/article/pii/S0889159106002947?casa_token=4Of3Dg72tJkAAAAA:xYOYLuKkgkFaK7qXmq4kmazS3iXDrILtzAbjIYNzvxromDMpqUNFWWnBpnXxexqyA9Fuq_omS10#bib24.

Autism spectrum disorder has been observed to have both genetic and environmental factors to its development.[22] Environmental factors specifically affecting the composition and development of the gut microbiome may have an effect on the development of autism spectrum disorder. The most crucial environment in ASD development is the prenatal conditions within their mother’s womb. This is largely determined by maternal health.

Several studies have found a significant connection between maternal obesity, gestational diabetes (GDM), and pregestational diabetes (PGDM) in increased risk of ASD.[23][24][25] Having just one of these conditions during pregnancy is associated with a 1.5 to 2 times increased risk factor for ASD. Whereas when obesity and GDM or obesity and PGDM were both present in mothers, ASD risk showed approximately 2 to 4 times increase.[23][25]

The maternal immune system and responses can also play a factor in ASD development. Mothers of children with ASD have been shown to possess different antibodies than mothers of neurotypical children.[26] When reacted with rat prenatal (PN18) brain proteins, mothers of children with ASD and children with ASD showed one of two patterns while control mothers and their neurotypical children typically showed no reactivity (Figure 3). This suggests these antibodies are pathogenic to fetal brains in autism.[26] Maternal antibodies have also been shown to react with lymphocytes in children with ASD which further suggests reactivity with other tissues in the developing embryo.[27]

A mother’s own microbiota can play a crucial role in fetal development. If the microbiome becomes imbalanced and pathogenic microbes are able to dominate, it can mean more than just illness for an expecting mother. Viral infections during the first trimester and bacterial infections during the second trimester have been associated with greater risk of ASD.[28] Additionally, delivery method can shape the microbiome of newborn babies. Infants delivered vaginally possess gut bacteria very similar to their mother’s vaginal microbiota, mostly composed of Lactobacillus, Prevotella, and Sneathis spp.; infants delivered via Cesarean section have a gut microbiome similar to the composition of their mother’s skin microbiota, mainly consisting of Staphylococcus, Corynebacterium, and Propionibacterium spp.[29] Autism spectrum disorder risk for infants delivered through Cesarean section has been found to be higher than in infants delivered vaginally.[30] Additionally, antibiotics can restructure the composition of the gut microbiome. In children with ASD, the use of antibiotics is much more common than in their neurotypical counterparts.[7] This leads to further imbalance to their already abnormal microbiome composition.

After birth, diet plays a critical role in shaping and maintaining the human gut microbiome. Risk of ASD has been observed to increase for infants that are not breastfed and decreases with longer periods of breastfeeding.[31] However, complications in breastfeeding infants with ASD, such as difficulty with the child’s engagement in the feeding process and temperamental or behavioral issues associated with ASD, may also be to blame for this correlation.[10] Later in life, feeding issues associated with ASD may contribute to an imbalanced gut microbiome. 90% of children with ASD display feeding related concerns, the most common of which is food selectivity.[32][10] This selectivity and imbalanced diet leads to many health concerns such as nutritional deficiencies and GI conditions.[10]

Microbiome Treatments for ASD

Antibiotics

Antibiotics may be a viable option for treating neurological conditions, like autism spectrum disorder. The use of antibiotic treatment in mice was shown to have impacts on anxiety and cognitive behaviors through the alteration of gut-brain communication neuromodulators.[33] Desbonnet et al. administered treatment that restructured the gut microbiome and reduced the richness of bacterial species (Figure 4). This restructured microbiome resulted in altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the brain; changes in these neurochemical levels showed association with reduction of anxiety, non-spatial memory, and performance in the social transmission of food preference.[33] Overall, this study shows evidence of interactions between antibiotic treatments and neurological processes, solidifying antibiotics as a possible therapy for neurological disorders.

Antibiotic treatment has been shown to be beneficial in treating ASD patients that also suffer from GI symptoms. After a short course of oral vancomycin treatment, children with ASD exhibited both reduced diarrhea and improved behavior and communication.[34] These results suggest the treatment caused a reduction of pathogenic bacteria in the gut microbiome and provides further evidence of interactions between the gut-brain axis in ASD severity. However, the improvements seen in the behavior and communication of ASD patients showed regression at a later follow-up, suggesting only a temporary benefit to antibiotic treatments.[34]

A later study also supports beneficial outcomes of antibiotic treatments for ASD. Geier et al.,[35] administered levocarnitine treatment over a three month period to individuals diagnosed with autism spectrum disorder in a randomized, double-blind clinical trial. This treatment showed significant improvement in ASD symptoms as well as physical improvement in the loss of fat mass and gain of muscle mass.[35] Although the results of this study are promising, later follow-up on the subjects was not conducted, so it is unclear whether these improvements are only temporary like what was found by Sandler et al. in Vancomycin treatment. Nonetheless, antibiotic treatments remain a viable option for ASD treatment but should be considered in combination with other forms of therapy.

Microbiota Transplantation and Transfer

Two other options for microbiota treatment in autism spectrum disorder are fecal microbiota transplantation (FMT) and microbiota transfer therapy (MTT). In FMT, filtrate stool from a healthy donor is injected into a patient to restore their own gut microbiome to a healthy state.[36] FMT has been used to treat various GI issues, such as food poisoning and severe diarrhea, Clostridium difficile infections, and irritable bowel syndrome (IBS).[37][38] Given the commonality of GI issues in individuals with ASD and the correlation between GI symptoms and ASD severity, FMT has promising potential as a method of therapy in treating ASD. However, the safety of FMT and possible adverse effects, such as diarrhea, abdominal cramps, belching in the short term, mild abdominal discomfort/bloating, and transient low-grade fever, need to be considered in its application to ASD.[7][39]

Due to the concerns of FMT safety in treating ASD, very few studies have been conducted on it. One researcher, T. Borody, reports improvement in ASD symptoms for two children as a result of FMT treatment but there is no published study on these results.[40] One small clinical trial of FMT treatment for ASD was conducted in Beijing, China through 2016 and 2017. This study found that those given the FMT showed 10.8% improvement in ASD symptoms after the first transplant and maintained this improvement after a second transplant. Additionally only mild adverse effects were reported with the treatment.[41] These reports suggest FMT does have high potential for ASD treatment, but more research is required before it can be a widely accepted form of therapy.

MTT is another method of FMT. In MTT, a 2 week course of antibiotics is followed by a bowel cleanse and decreasing daily doses of FMT over 7 to 8 weeks.[42] Kang et al. administered this treatment to children with ASD for very positive outcomes. Patients showed an approximately 80% decrease in GI symptoms and significant improvement in ASD symptoms that persisted for the 8 weeks after treatment in which the patients were followed, suggesting a long-term impact.[42] MTT proves to be the most promising microbiota treatment for ASD as of yet.

Probiotics

Figure 5: Diagram of the influence of probiotics on ASD behavior and symptoms. Photo credit: Chidambaram et al., https://link.springer.com/chapter/10.1007/978-3-030-30402-7_21.

Probiotics are live microbes that provide health benefits to their host when ingested.[43] Probiotics have been shown to be successful in treating many different diseases including obesity, depression, colorectal cancer, and Crohn’s disease.[44][45][46][47] Probiotic treatment is a very accessible treatment as it can be done by simply consuming certain foods and no medical professional is needed. For example, eating a fermented milk product, like yogurt or cheese, that contains Bifidobacterium animalis subsp lactis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis subsp lactis has been shown to alter activity in the regions of the brain that control the processing of emotions and sensations.[48] Given the ability of probiotics to both alter brain chemistry and GI health, it makes the treatment ideal for ASD patients with GI issues.

Probiotics have also been shown to improve intestinal barrier function, a common GI issue in individuals with ASD. Lactobacillus reuteri and Lactobacillus rhamnosus, have been shown to decrease barrier permeability through increased expression of tight junction proteins and improved mucus layer integrity.[49][50] Bacteroides fragilis was shown to both reduce intestinal barrier permeability and improve communicative, sensorimotor, and anxiety-like behaviors in a model mouse system for studying ASD and other neurodevelopmental conditions.[13]

Several other studies have also found probiotics that improve ASD symptoms. Parracho et al.[51] delivered a three week course of probiotic Lactobacillus plantarum to patients with ASD. After treatment, the patients displayed improved ASD symptoms in destructive and antisocial behaviour, anxiety, and communication problems.[51] Another study delivered a 2 month course of probiotic L. acidophilus to ASD patients and found improved ASD symptoms in concentration and abilty to follow directions.[52] In a study examining the effectiveness of combining both antibiotic and probiotic treatment, an 8 week course of vancomycin was followed by a 4 week course of probiotic L. acidophilus, L. bulgaricus and B. bifidum, and individuals exhibited improved ASD symptoms in communication and behavioral patterns after treatment.[34] With such positive outcomes and no apparent adverse effects, probiotic treatments stand as a strong option for ASD treatment.

Diet

ASD-related feeding concerns and selective eating habits are one of the contributors to the abnormal gut microbiome in individuals with autism spectrum disorder. Adjusting diet is a way that the gut microbiota could be adjusted. The introduction of more omega-3 fatty acids to the diet of children with ASD was shown to be one beneficial dietary change. In a 12 week trial, omega-3 fatty acid supplements were associated with significant improvement in social and behavioral ASD symptoms.[53] Several studies have shown that gluten-free and casein-free diets are associated with improved behavior, social, and physiological related ASD symptoms.[54][55][56] A high-fat and low-carbohydrate keto diet has also been shown to increase sociability and communication as well as reduce repetitive behaviors and lower gut microbial abundance.[57][58]

Conclusion

As awareness and understanding of autism spectrum disorder increases, the number of individuals diagnosed with the condition has risen. This has made research and treatments for ASD more relevant and important. GI issues are a common comorbidity in individuals with ASD. With interactions between the central nervous system and gut microbiome in the gut-brain axis, addressing these intestinal issues can help improve the neurological symptoms related to ASD. The composition of the gut microbiome in ASD patients differs from that of the average person. Some of these bacteria that are more abundant within the ASD microbiome are known to release neurotoxins that likely contribute to worsened ASD symptom severity. There are many possible factors that may contribute to the development of ASD and the abnormal gut microbiome associated with the condition, and much more research is needed to pinpoint the exact causes. Nonetheless, treatments and therapies to address the ASD microbiome and GI issues are available. Research has shown successful outcomes in a variety treatments including antibiotics, probiotics, fecal microbiota transplants, and dietary changes. Although these treatments are certainly no cure to the disorder, they can significantly improve the severity of ASD and gastrointestinal problems.

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Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2021, Kenyon College.