Autism is a neurodevelopmental disorder associated with poor social skills, deficits in verbal and non-verbal communication, and frequent engagement in repetitive behaviors. On average, it affects boys more frequently (~5-fold) than girls and signs of the disorder become noticeable in early childhood [between ages 1 and 3]. Estimates suggest that over 21 million individuals throughout the world meet diagnostic criteria for autism spectrum disorder (ASD).
The present-day rate of autism diagnoses is approximated at 1 in every 150 children. To put this in perspective, between the 1970s and 1980s, the rate of autism diagnoses was approximated at 1 in every 2000 children – a staggeringly lower figure. Skyrocketing rates of autism have lead some to hypothesize that aspects of societal modernization may be culpable for causing the disorder, whereas others believe professionals have simply gotten better at making accurate diagnoses.
Though there may be debates as to whether the trend of increased autism rates is associated with societal modernization, superior diagnostic skill of practitioners, or a combination of factors – there’s no disputing that autism affects millions of lives. Not only do those with the condition require lifelong care, but most clinically-recommended interventions such as educational training, cognitive behavioral therapy, and neuropsychiatric drugs – are of questionable efficacy. For this reason, there’s a serious need for the invention of newer, targeted therapies to legitimately improve functional outcomes among individuals with the disorder.
One potentially useful, novel intervention involves modulating bacteria throughout the gastrointestinal tract or “gut.” Gut bacteria modulation could be accomplished via methods such as administering: probiotics, prebiotics, fecal transplants, or helminths (just to name a few). The goal would be to upregulate concentrations of healthy bacteria in the GI tract, decrease pathogenic/opportunistic bacteria, and possibly alter overall bacterial diversity. It is theorized that gut bacteria are implicated in neurological and immune function via the gut-brain axis (GBA), and that strategic modulation may curb symptoms of autism.
The Role of Gut Bacteria in Autism…
Though not all individuals with autism exhibit abnormalities in gut bacteria compared to the neurotypical crowd, it is estimated that around 70% do. Specifically, those with autism exhibit elevated concentrations of pathogenic bacteria (e.g. Clostridium) and reduced concentrations of healthy bacteria (e.g. Bifidobacterium) within the GI tract. Additionally, a subset of patients with autism may have either insufficient or excessive diversity of bacterial species within their gastrointestinal tract.
Why are gut bacteria amiss among individuals with autism spectrum disorders compared to neurotypical individuals? As of current, there are no clear answers – only a few theories. One prominent explanation purports that certain mothers [of individuals with autism] may have contracted an infection during pregnancy (e.g. viral, bacterial, etc.). In response to this infection, the immune system of the mother activates in attempt to stave off any pathogens.
An aspect of the immune response involves the release of proinflammatory cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), and interferon-gamma (IFN-g). These proinflammatory cytokines affect the gastrointestinal tract of the pregnant mother, allowing concentrations of opportunistic, pathogenic bacteria to proliferate while simultaneously compromising the intestinal barrier. Furthermore, the proinflammatory cytokines and the opportunistic bacterial pathogens undergo transfer from the mother to the fetus whereby they interfere with critical stages of development.
When considering that GI dysfunction and autoimmunity often occur among those with autism, it is reasonable to speculate that the mother-to-fetus transfer of pathogenic microbes and proinflammatory cytokines may be to blame for a subset of cases. It is unknown as to whether the amounts (quantities) and specific types of proinflammatory cytokines and/or pathogenic bacteria transferred to the fetus are predictive of the specific alterations incurred by the fetus, however, autism is likely one of the many possible neurodevelopmental outcomes resulting from maternal infection and corresponding immune response.
Researchers have tested this theory in animal models, ultimately confirming that maternal immune activation during pregnancy yields autism-like behaviors in offspring. Furthermore, higher rates of infection during pregnancy have been observed among human mothers of autistic children. Certain studies, such as that by Chaidez, Hansen, and Hertz-Picciotto (2014) discovered that individuals with autism exhibit greater gastrointestinal dysfunction compared to neurotypical children, and that the severity of their GI issues correlates directly with severity of autism symptoms.
This has lead researchers to investigate the implications gut bacteria (also called microflora, flora, microbes, etc.) in autism. Research suggests that individuals with autism exhibit heightened concentrations of pathogenic gut bacteria and altered microbial diversity. Since it is understood that the gut and brain [plus immune system] interact with each other through the gut-brain axis (GBA), it is thought that pathogenic bacteria and altered microbial diversity detrimentally affect neurological function. For this reason, it is suspected that introducing strains of healthy bacteria could favorably modulate signaling via the gut-brain axis (GBA) to improve aspects of autism spectrum disorder including: behavior, cognitive function, and mood.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24193577
- Source: http://www.ncbi.nlm.nih.gov/pubmed/14990420
- Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307601/
Gut Bacteria in Autism Spectrum Disorder (ASD) vs. Neurotypical
As was already discussed, research has sought to elucidate differences in colonization of gut bacteria among individuals with autism compared to neurotypical counterparts. A bulk of the research indicates that elevations in concentrations of pathogenic bacteria species (e.g. those within the Clostridium genus) appear among those with autism spectrum disorder (ASD). In addition to the upregulated quantities of pathogenic bacteria, deficits in healthy bacterial species (e.g. those within the Bifidobacterium genus) are seen.
In short, it appears as though varying degrees of dysbiosis are implicated in autism spectrum disorders. Below are some additional details regarding the phyla, family, genus, and species of bacteria that may be implicated in symptomatic exacerbation (and possibly the cause) of autism spectrum disorders.
Clostridium is a form of Gram-positive bacteria that inhabit soils, as well as gastrointestinal tracts of animals and humans. In women, Clostridium is considered normal bacterial component of the lower reproductive tract. However, it appears as though several specific Clostridium species are pathogenic to humans, eliciting toxic effects and inducing dysbiosis. Among individuals with autism, it appears as though various Clostridium species are elevated within the GI tract including: C. Bolteae, C. histolyticum, and C. perfringens.
- Clostridium bolteae
- Clostridium histolyticum
- Clostridium perfringens
- Clostridium tetani
Stool samples from children with autism reveal significant elevations in the concentration of Clostridium species bacteria [compared to non-autistic children]. For reference, a study by Finegold et al. (2002) analyzed gut bacteria among individuals with late-onset autism and discovered significantly greater quantities of Clostridium species among children with autism compared to a control group. Specifically, 9 distinct species of Clostridium were inhabiting the fecal samples of children with autism, yet were absent from the fecal samples of controls.
Interestingly, the study also revealed that there were 25 total Clostridium species in the stool samples of children with autism. Another study conducted by Song, Liu, and Finegold (2004) utilized real-time PCR quantification to identify and quantify all Clostridium bacteria in stool samples of children with autism. Results indicated that children with autism exhibited significantly greater counts of C. Bolteae (between 3-fold and 46-fold) than neurotypical children.
More Clostridium abnormalities were discovered in research by Parracho et al. (2005), in which stool samples of children with autism, siblings of children with autism, and non-autistic children were simultaneously compared. Using a culture-independent assessment technique, it was discovered that all patients with autism exhibited higher concentrations of Clostridium histolyticum compared to the unrelated neurotypical children. Additionally, though higher levels of Clostridium histolyticum were observed among children with autism than their neurotypical siblings, the differences were not statistically significant.
A subsequent study by Martirosian et al. (2011) examined species of Clostridium present in the stools of children with autism. They failed to find toxins from Clostridium difficile species, however, they discovered that Clostridium perfringens appeared more frequently in the stools of children with autism than those without the condition. It should be mentioned that Clostridium perfringens is associated with food poisoning and is a sign of diseased states.
Earlier research postulated that Clostridium tetani, another Clostridium species, may play a role in autism. In 1998, Bolte proposed that significant antibiotic usage during critical developmental years may deplete healthy microflora, leading to upregulation in populations of devious pathogens – one of which may be Clostridium tetani. If Clostridium tetani colonizes within a person’s intestinal wall, it is likely to generate highly toxic metabolites.
These toxic metabolites, referred to as tetanus neurotoxin (TeNT) get shuttled to the CNS through the vagal nerve. Upon entering the brain, it is suspected that TeNT induces a chemical imbalance by cleaving synaptic vesicle membrane proteins. As a result, neurotransmitters are not properly released, brain cells are killed, and neurodevelopment is compromised – leading to onset of disorders, one of which might be autism. Though Clostridium tetani hasn’t been noted as elevated in most autism research, it is possible that it remains undetected and/or could be upregulated in a subset of patients.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12173102/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15528506/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/16157555/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21167951/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/9881820/
Bifidobacterium is a form of Gram-positive anaerobic bacteria that inhibits the mouth, GI tract, and vagina of humans and other mammals. Many species of Bifidobacterium are considered conductive to gastrointestinal health and are thus administered as probiotics. Some evidence suggests that Bifidobacterium can be administered for the management of IBS (irritable bowel syndrome) without any adverse effects.
Among children with autism, it appears as though Bifidobacterium populations are often reduced. A study by Adams et al. (2011) compared the intestinal flora of children with autism to those without the condition. Results from this study indicated that Bifidobacterium species were significantly lower among children with autism (p = 0.002) compared to neurotypical children.
The degree to which various species and subspecies of the Bifidobacterium genus are deficient in autism remains unclear. Further research may reveal the specific species of Bifidobacterium with greatest deficits in autism. Nonetheless, it is suspected that there’s an inverse relationship between Clostridium and Bifidobacterium such as when Clostridium is elevated, Bifidobacterium is reduced and vice-versa. It should also be noted that various Bifidobacterium are among the best probiotics for depression and anxiety; depletion of this species may negatively impact emotion and/or stress response of those with autism.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21410934/
Other bacterial abnormalities in autism spectrum disorders
In addition to elevated Clostridium and deficient Bifidobacterium, individuals with autism may exhibit a myriad of bacterial irregularities. These irregularities appear to involve phyla such as Bacteroidetes and Firmicutes; genus’ such as Desulfovibrio, Lactobacillus, and Sutterella; and species such as Ruminococcus torques and Bacteroides vulgatus. Keep in mind that more research needs to be done to determine which of the irregularities listed below are likely to be most pronounced among those with autism.
Actinobacteria: This is a phylum of Gram-positive bacteria that carries high cytosine and guanine within their DNA. Various species of Actinobacteria such as Streptomyces are therapeutically useful as antibacterial, antifungal, and antiviral agents. In any regard, humans with autism appear to exhibit abnormalities in concentrations of Actinobacteria in the GI tract, particularly deficits in the genus Bifidobacterium.
Aeromonas: This is a genus of rod-shaped, anaerobic, Gram-negative bacteria within the appears elevated in persons with autism spectrum disorders. The finding of elevated Aeromonas is congruent with the finding that bacteria of the phylum under which it is categorized (Proteobacteria) is also inflated among people with ASD. Most species of Aeromonas are pathogenic to humans and are understood to: generate endotoxins, compromise immune function, induce diarrhea, infect wounds, and play a role in gastroenteritis.
Akkermansia: This is a genus of bacteria within the Verrucomicrobia phylum with only one known species, Akkermansia muciniphila. Individuals with autism spectrum disorder (ASD) appear to have significantly low concentrations of Akkermansia. It is understood that Akkermansia muciniphila is capable of populating within the human gastrointestinal tract and is hypothesized to exert a favorable effect on metabolism. It may also restore intestinal integrity, reverse obesity, reduce inflammation, and modulate blood sugar.
Alcaligenaceae: This is a family of bacteria including members that have adapted to inhabit water, soil, animals, and humans. Certain species within the Alcaligenaceae family are regarded as pathogenic to humans (as well as animals), causing things like: diseased states, coughing, and inflammation. According to some research, quantities of Alcaligenaceae bacteria may be abnormally high in persons with autism.
Alistipes: This is a genus of bacteria within the Bacteroidetes phylum. Individuals with autism spectrum disorders (ASDs) and pervasive developmental disorder (PDD) appear to have significantly higher levels of Alistipes than neurotypical persons. When considering that all bacteria within phylum of Bacteroidetes tends to be high in cases of autism, it’s no surprise that the Alistipes genus is also elevated. Other research suggests that high concentrations of Alistipes is associated with mood disorders such as major depression.
Bacteroidetes: This is a phylum characterized by Gram-negative, non-spore forming, rod-shaped bacteria. Bacteroidetes are found throughout the environment in soil/sediment and water, but are also present within the human intestinal tract. Research indicates that bacteroidetes are elevated in the gut of individuals with autism compared to those with neurotypical development. It is suspected that excessive quantities of certain species within the bacteroides genus could exert pathogenic effects.
Bacteroides vulgatus: This is a pathogenic bacterial species within the bacteroidetes phylum. Elevations in Bacteroides vulgatus are associated with bowel disease and gastrointestinal dysfunction. Stool sample analyses indicate that Bacteroides vulgatus is significantly elevated among children with severe autism compared to neurotypical children.
Caloramator: This is a genus of bacteria within the Firmicutes phylum. A subset of studies indicate that bacteria within Firmicutes appear lower among those with ASD compared to neurotypical persons. That said, Caloramator is a genus within the Firmicutes phylum that’s actually elevated among those with ASD compared to neurotypical individuals. More intriguing is the fact that Caloramator levels are also significantly greater among persons with ASD compared to those with PDD-NOS (pervasive developmental disorder). Based on these findings, it is reasonable to speculate that Caloramator species may play a direct role in autism-specific symptoms.
Coprococcus: This is a genus of anaerobic bacteria found within the fecal flora of humans. It is from the Lachnospiraceae family of bacteria, populous within the gut microbiome. Bacterial genus within the Lachnospiraceae family are associated with the onset of obesity, but may offer some protection against colon cancer as a result of producing butyric acid. Among individuals with autism, it appears as though quantities of Coprococcus are reduced. When considering that bacteria from the Firmicutes phylum are often deficient among those with autism, and that Coprococcus falls within the Firmicutes phylum, it makes sense that Coprococcus levels may be suboptimal among persons with autism.
Desulfovibrio: This is a genus of Gram-negative, sulfate-reducing bacteria commonly found near watery regions. Research by Finegold et al. (2010) indicated that children with autism excreted significantly greater amounts of Desulfovibrio in stool samples than neurotypical children. The impact of high Desulfovibrio on neurological function and/or autism symptoms remains unclear. Further research may be helpful to identify the particularly problematic species of Desulfovibrio.
Enterobacteria: The family of Enterobacteriaceae falls under the taxonomic categorization of the Proteobacteria phylum. The Enterobacteria family is large and encompasses a mix of healthy, harmless, and pathogenic bacteria. Examples of pathogenic bacteria within this family include: Salmonella and Escherichia coli. Individuals with autism spectrum disorders appear to have elevated concentrations of Enterobacteria (likely pathogenic species) compared to those with normative neurological status.
Eubacteriaceae: This is a Gram-positive family of anaerobic bacteria identified under the Firmicutes phylum and Clostridia class. Research suggests that Eubacteriaceae are commonly seen in fecal samples of healthy controls compared to those with autism spectrum disorders. Not only are Eubacteriaceae concentrations lower among those with autism, deficits are seen among those with IBS (irritable bowel syndrome) and Type-1 diabetes. Reversing deficiencies in Eubacteriaceae is understood to promote healthier GI function, and may prove therapeutic for those with autism.
Faecalibacterium: This is a genus of bacteria with just one species that’s been identified, Faecalibacterium prausnitzii. It is regarded as a health-promoting bacteria within the human gastrointestinal tract and functions by synthesizing butyrate and manufacturing a variety of short-chain fatty acids (SCFAs) via fermentation of fiber. Findings suggest that Faecalibacterium species are significantly lower among persons with autism compared to people of neurotypical status. It may be that lack of Faecalibacterium results in deficiencies in butyrate (and other helpful SCFAs), leading to symptomatic exacerbation.
Firmicutes: This is a phylum characterized by rounded or rod-like, spore-yielding, Gram-positive bacteria. Though some bacteria species within the firmicutes phyla are pathogenic, others are conducive to health. Firmicutes bacteria are the single most populous bacterial phyla within the human gastrointestinal tract. Children with autism appear to have lower levels of firmicutes bacteria than healthy non-autistic counterparts.
Lactobacillus: This is a genus of Gram-positive, anaerobic, non-spore forming bacteria associated with lactic acid. Lactobacillus bacteria is present within humans throughout many regions of the body. Nonetheless, research by Adams et al. (2011) documents significantly elevated Lactobacillus within the intestinal flora of children with autism [compared to healthy controls].
Paenibacillus: Until 1993, Paenibacillus was considered to fall under the genus Bacillus. It is now understood to be its own genus of endospore-forming, anaerobic bacteria and was appropriately dubbed Paenibacillus (derived from the Latin term “paene” translating to “nearly bacilli”). Bacteria within the Paenibacillus genus are observed in a multitude of niches including: soil, water, vegetables, larvae, and humans. Persons with autism may exhibit elevations in this genus compared to the general population.
Porphyromonas: This is a genus of small Gram-negative, anaerobic bacteria with short rods that generate colonies of greyish-black pigmentation. Species within the Porphyromonas are considered part of the normal intestinal, vaginal, pharyngeal, and mucosal flora in humans. Though some Porphyromonas bacteria is normal, individuals with autism may have too much. Stool samples of those with autism harbor significantly more Porphyromonas than healthy controls.
Prevotella: This is a genus of Gram-negative bacteria of the Bacteroidetes phylum. Members of the Prevotella genus inhabit the oral and vaginal flora. Populations of Prevotella are thought to vary based on a person’s dietary intake. Dietary studies suggest that individuals consuming greater quantities of fibrous carbohydrates tend to have greater levels of Prevotella than those who don’t, likely because Prevotella bacteria are implicated in the degradation of carbohydrates. Research by Kang et al. (2013) documented lower levels of Prevotella in the gastrointestinal microbiota of individuals with autism compared to neurotypical children.
Proteobacteria: This is a phylum of Gram-negative bacteria encompassing pathogenic bacterial strains such as Escherichia, Helicobacter, and Salmonella. Multiple studies have noted elevations in Proteobacteria among individuals with autism when compared to controls. Though the evidence of Proteobacteria abnormalities in autism is less convincing than evidence of other phyla abnormalities (e.g. Bacteroidetes and Firmicutes), it is possible that high Proteobacteria exacerbates certain symptoms.
Pseudomonas: This is a genus of aerobic, rod-shaped, Gram-negative bacteria of the Pseudomonadaceae family. Pseudomonas are capable of colonizing in a variety of environments including: seeds, soils, water, and the human intestinal tract. It is understood that certain species of pseudomonas (e.g. P. aeruginosa) are pathogenic to humans. Individuals with autism appear to excrete significantly greater quantities of Pseudomonas than neurotypical persons, suggesting that they are likely elevated within the GI tract of those with ASD.
Ruminococcus: This is a genus of Gram-positive, anaerobic gut bacteria of the Clostridia classification, that are commonly found in the intestinal tract of humans. Some evidence suggests that the species Ruminococcus torques is high among persons with autism compared to non-autistic individuals. That said, other studies suggest that the Ruminococcus species is abnormally low among those with autism compared to neurotypical individuals. Though some may interpret this as a contradictory finding, it could be that other Ruminococcus species (besides Ruminococcus torques) are low and that Ruminococcus torques is an outlier.
Ruminococcus torques: In the already-mentioned study by Wang et al., elevations of the bacteria Ruminococcus torques were recorded. Interestingly, high concentrations of Ruminococcus torques did not appear in all children with autism. Only children with autism plus gastrointestinal symptoms exhibited elevations in Ruminococcus torques. There’s a possibility that Ruminococcus torques could influence autism symptoms, especially considering that GI distress is often correlated with symptomatic severity.
Sarcina: This is a genus of Gram-positive bacteria within the Clostridiaceae family and under the Firmicutes phylum. It is capable of synthesizing cellulose and is located within the GI tract and skin of humans. Similar to the Caloramator genus, Sarcina is a distinct genus within the Firmicutes phylum that’s high among persons with autism spectrum disorder compared to non-autistic individuals.
Sutterella: This is a genus of Gram-negative, anaerobic, non-spore forming bacteria often seen in human feces. Research by Wang et al. (2013) collected stool samples of children with autism and compared bacterial compositions to stool samples from neurotypical controls. Their research documented significantly heightened concentrations of Sutterella species appeared among children with autism – compared to the control group.
Veillonellaceae: This is a family of Gram-negative anaerobic bacteria that falls under the Firmicutes phylum and Negativicutes class. (Some research suggests that Veillonellaceae may more accurately fall within the Clostridia class of bacteria). Veillonellaceae can be found within gastrointestinal tract of humans as well as other vertebrates. Some research suggests that Veillonellaceae populations may be lower in the GI tract among those with autism compared to neurotypical people.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21410934
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24188502/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20603222/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23844187
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21114016
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24130822
Note: Some of the aforestated findings regarding phylum, family, genus, species, and subspecies of bacteria may not reflect everyone diagnosed with autism. Furthermore, some of the findings may contradict with other findings and/or seem contradictory. For example, a particular species of bacteria within a broad phylum may appear elevated, yet as a whole, bacteria within that phylum may appear lower than usual in ASD – leading one to speculate a potential contradiction. Due to possibly underpowered studies (associated with small sample sizes), further research is necessary to validate differences in gut bacteria among those with ASD and without.
How Modifying Gut Bacteria May Treat Autism
There are numerous mechanisms by which modifying gut bacteria might reduce symptoms of autism spectrum disorder. Assuming that a person with autism exhibits dysbiosis, is is reasonable to speculate that crosstalk between the gut and brain via the gut-brain axis (vagal nerve and peripheral immune system) reinforces preexisting aberrant signaling. The strategic, calculated introduction of healthy bacteria and/or simultaneous degradation of pathogenic bacteria may reverse problematic gut-to-brain signaling, favorably affecting neurological function and reducing symptoms of autism.
Identify gut microbiome abnormalities in autism
If attempting to minimize symptoms of autism by modifying the gut, it is necessary to identify specific abnormalities among individuals with autism compared to healthy subjects. As was already discussed above, there appear to be differences in populations of various phyla, families, genus, and species. The goal should be to identify the specific species and/or subspecies that are deficient, as well as those that are overpopulated in the gut of persons with autism.
Taking things one step further, researchers may want to identify gut microbiome abnormalities on an individualized basis [among those with autism]. By conducting individualized gut assays of persons with autism, we may discover correlations between certain species/subspecies of bacteria and specific autism symptoms. Upon pinpointing the bacteria suspected to play a role in autism, we can devise a customized protocol for modulation of gut bacteria.
In some cases, it may be difficult to devise a customized gut modulation protocol. That said, even if specific gut bacteria abnormalities are not identified in an assay, the assay may reveal reduced microbial diversity. This may lead us to hypothesize that increasing diversity in the species of gut microbes could improve symptoms of persons with autism.
Strategic modulation of gut bacteria
In the future, a professional may be able to recommend specific bacterial species for populating the gut of a person with autism. Current strategies for modulating gut bacteria include the usage of: antibiotics, fermented foods, prebiotics, probiotics, and in extreme cases – fecal transplantation. It is also known that altering dietary intake affects populations of gut bacteria, possibly [partially] explaining why certain individuals with autism benefit from restrictive diets.
- Antibiotics: Antibiotics eradicate both the healthy and pathogenic bacteria inhabiting the lining of the gastrointestinal tract. Though the usage of antibiotics is often perceived as unfavorable based on the fact that healthy bacteria will die, the upside is that pathogenic bacteria will also perish. Numerous anecdotes have claimed that administration of antibiotics significantly reduced symptoms of autism. There’s a major possibility that some of the symptomatic reduction is mediated by the gut upon elimination of pathogenic bacteria.
- Fecal transplant: A fecal transplant involves collection of fecal samples from a healthy donor. The fecal samples are then encapsulated and anally injected into GI tract of person with a Clostridium difficile colitis (C. diff) infection. Some individuals with autism may have Clostridium difficile colitis infections, but may also pursue fecal transplantation without a C. diff infection to populate the gut with healthier bacteria. Anecdotal reports suggest that fecal transplantation may yield lasting benefit for a subset of persons with autism.
- Fermented foods: It is well-understood that dietary intake affects the gut microbiome. People who eat more fibrous carbohydrates exhibit different bacterial microbes than those who refrain from fibrous carbs. Similarly, those who consume copious amounts of fat exhibit distinct microbiomes from those who avoid fat consumption. Ingestion of unprocessed foods may have an effect upon the gut microbiome, but fermented foods seem to be the best bet. Examples of fermented foods include: kefir, kimchi, natto, yogurt, et al. Since fermented foods contain many microbes, regular consumption may enhance diversity of the gut microbiome, ultimately improving neurological activity in autism.
- Helminths: Another strategy involves ingestion of helminths (large parasitic worms). The theory is that by ingesting helminths such as pig whipworm (Trichuris suis), the enteric immune system is stimulated and the intestinal microflora of the host is altered. This is thought to modulate gut-brain-immune axis activity to improve symptoms of autism.
- Prebiotics: Prebiotics are comprised of non-digestible food ingredients that, upon ingestion, induce growth of healthy bacteria within the gut. Unlike probiotics, prebiotics do not contain actual species of bacteria – they just induce endogenous bacterial growth. Specifically, prebiotics bypass the small intestine and undergo fermentation, being used with the intent of feeding healthy bacteria. Some claim that prebiotics may reduce symptoms of autism in certain individuals.
- Probiotics: Probiotics are considered any living bacteria that is conducive to healthy function of the gastrointestinal system. Taking specific strains of probiotics can increase concentrations of health-promoting bacteria within the gut. Not only do healthy bacteria facilitate optimal gastrointestinal and brain function, they’re able to overtake opportunistic microbial pathogens. Proof-of-concept animal model studies have documented substantial reduction in autism symptoms following administration of specific probiotic agents.
In theory, it may be possible to use a combination of all of the aforestated interventions for modulation of gut bacteria. For example, Clostridium populations may remain high despite introduction of healthier bacteria via probiotics or fecal content. In this case, a person could first use antibiotics to eliminate Clostridium (and other pathogens) and then repopulate the gut with healthy bacteria using fermented foods, probiotics/prebiotics, or fecal transplants.
Gut-brain axis activity changes
The gut exhibits bidirectional crosstalk with the brain through the gut-brain axis (GBA), comprised of: the central nervous system (CNS) – brain and spinal cord, autonomic nervous system (ANS), enteric nervous system (ENS), and the hypothalamic pituitary adrenal (HPA) axis. The bidirectional relationship between the gut and brain means that when activity is altered in the gut, activity is simultaneously altered in the brain – and vice-versa. As an example, psychological stress will signal to the gut and trigger an upregulation in quantities of various bacteria.
Oppositely, an upregulation of pathogenic gut bacteria can directly induce psychological tress. It may take days, weeks, or months of treatment with antibiotics, prebiotics/probiotics, and/or fecal ingestions to substantially alter bacterial composition of the gut. Assuming an individual with autism attains an increase of healthy bacteria and decrease of pathogenic bacteria within his/her gut, this should favorably modulate the function of his/her brain.
The gut flora is capable of generating neuroactive molecules plus metabolites including: acetylcholine, epinephrine, GABA, histamine, melatonin, norepinephrine, and serotonin – just to name a few. These molecules and molecular byproducts induce vagal innervations to alter brain activity. Though the vagal nerve seems to be the most prominent conduit between the gut and brain, the gut may also signal the brain through spinal, enteric, and peripheral immune pathways.
Strategic modification of gut bacteria could therefore change a person’s: neurochemistry (neurotransmitters, neuropeptides, neurohormones), neuroelectrical activity (i.e. brain waves), neural connectivity, regional activity and blood flow, cytokine levels, and circulating reactive oxygen species (ROS) / reactive nitrogen species (RNS). Additionally, since pathogenic bacteria may generate neurotoxins that get shuttled to the brain, eliminating them should improve neurological health. Moreover, when considering the gut has significant influence over brain activity, it’s not surprising that individuals with autism report symptomatic attenuation from adherence to a probiotic regimen.
Upon deliberately altering the composition of the gut microflora, persons with autism spectrum disorders may experience behavioral, cognitive, and emotional improvements. The degree to which autism symptoms are reduced after microbial therapy is likely subject to individual variation based on preexisting microbe populations in the GI tract. Autistic patients with severe dysbiosis and/or lack of microbial diversity may derive significant benefit from the administration of probiotics.
Conversely, autistic patients without gastrointestinal abnormalities may not benefit much from microbial modification. Nevertheless, since up to 70% of children with autism report gastrointestinal dysfunction, modifying the gut microbiota warrants consideration as an intervention. Not only should the correction of bacterial imbalances reduce gastrointestinal complaints, it is likely to improve core autism symptoms.
It is unclear as to how long an individual with autism may need to administer a probiotic [or antibiotic] to maintain his/her initial symptomatic reduction. In some cases, a single round of a multi-month treatment protocol may be sufficient for long-term, sustainable therapeutic effects without a need for ongoing dosing. In other cases, to maintain therapeutic benefit, it may be necessary to administer probiotics regularly (e.g. daily / weekly) for the rest of a person’s life.
Those who benefit from a single round of probiotics may find that once their gut heals, it is able to maintain healthy function. Unless damaged again, it should be able to sustain healthy function on its own. Persons who require regular lifelong treatment with probiotics may have other neurological and/or immune abnormalities that induce proliferation of pathogenic bacteria, hence requiring regular probiotics to offset reversion to homeostatic dysbiosis.
Benefits of Probiotics for Autism (Possibilities)
The full scope of benefits to be attained from modulating gut bacteria among those with autism remains unknown. It is likely that some individuals will benefit more from the administration of probiotics/prebiotics than others. Arguably the biggest potential benefit is that modulation of gut microbiota would prevent cases of late-onset autism. Other advantages of microbial modulation for autism include: a unique mechanism of action, preliminary efficacy (in animal models), and few unwanted side effects.
- Adjunct: It is possible that administration of probiotics/prebiotics to modulate the gut microflora may be an effective adjunct to behavioral therapy and/or medications (e.g. SSRIs, SNRIs, etc.) utilized in the treatment of autism. Research may show that patients with autism respond better to first-line interventions when probiotic/prebiotic is administered as an adjunct. Modulation of the ENS may complement the effects of CNS-modulation by a neuropsychiatric drug. While further testing is necessary to ensure that gut-microbe modulation doesn’t cause an interaction with centrally-acting medications, most speculate that interactions are unlikely to occur.
- Alternative intervention: Many individuals with autism don’t respond well to first-line behavioral and pharmacological interventions, hence the need for novel alternative interventions such as probiotics/prebiotics. If a person with autism spectrum disorder fails to benefit (or ends up worse) from behavioral therapy and/or neuropsychiatric medications, modulation of gut bacteria may serve as a necessary alternative therapy. When considering that first-line pharmacology for autism consists of antipsychotics (associated with brain volume loss) and antidepressants (associated with possible induction of suicidal thoughts) – it’s clear that alternative interventions are needed.
- Comorbid conditions: Most sources agree that upwards of 70% of all individuals with autism exhibit gastrointestinal comorbidities. Other medical conditions commonly co-occurring with autism include: anxiety, autoimmunity, epilepsy, depression, OCD, and sleep disorders. Interestingly, many of these comorbidities have been shown to derive benefit from modulation of bacteria within the gut. It is possible that administration of probiotics/prebiotics may treat medical comorbidities equally as well as (or possibly better than) symptoms of autism.
- Efficacy: The effectiveness of gut-microbe modulation for the treatment of autism remains unclear, however, animal models of autism appear to respond extremely well to administration of probiotic species. In fact, in maternal immune activation (MIA) models of autism, administration of probiotics completely reversed autism-like symptoms. Though thus far only proof-of-concept animal trials have been conducted, it’s possible that the right probiotics will prove highly efficacious. Persons with severe dysbiosis prior to microbial modulation should be thought to attain greatest benefit from this intervention.
- Onset of action: Some hypothesize that probiotics have an extremely fast onset of therapeutic action. It is estimated that probiotics could significantly reduce symptoms of autism within as quickly as 1-2 days of administration. More realistically, it may take several weeks or months for full benefits to be attained, but this may still prove quicker in effect than antipsychotics and/or antidepressants (which can take 4 to 8 weeks to kick-in).
- Personalized treatment: At this juncture, it seems much easier to attain approximate estimations of bacterial phyla, families, and species within the gut – compared to neurotransmitter levels within the brain. Something as basic as a stool sample reveals a lot of information about microbial activity within the gut. Assuming gut-assay/bacterial sequencing technology continues to improve, it may be easy to assay the gut of each person with autism, then prescribe a personalized bacterial subspecies as treatment based on the assay results. Most people prefer the idea of personalized medicine over rolling the dice with a drug that may OR may not be correcting a neurochemical imbalance.
- Prevention: There’s a theory that some cases of late-onset autism may result (in part) from the proliferation of opportunistic pathogens within the gut after birth. A newborn may initially appear normal, but may take a turn for the worse after pathogenic bacteria/metabolites and cytokines disrupt neurodevelopment. To prevent bacterial-induced late-onset autism, early modulation of gut bacteria may be helpful. Even if something like probiotics wouldn’t fully prevent cases of gut-mediated late-onset autism, they may act as a buffer against more extreme neurodevelopmental abnormalities.
- Side effects: Compared to most medications, probiotics (in proper amounts) aren’t associated with severe deleterious side effects. Unlike many neuropsychiatric drugs which may exacerbate anxiety, depression, irritability, and cause weight gain – probiotics tend to be well-tolerated. The tolerability of probiotics is likely related to the fact that healthy bacteria are overtaking pathogenic species. In the event that some side effects occur, they are unlikely to be long-lasting or serious.
- Sustained efficacy: It is possible that gut-bacteria modulation (such as with probiotics) may yield a sustained therapeutic effect over a long-term. In other words, a person may never develop a tolerance to their probiotic supplement and find that it remains effective for curbing autism symptoms for an extended term – or possibly throughout their entire lifetime. This may differ from administration of neuropsychiatric drugs which are associated with an onset of tolerance over an extended duration as a result of CNS adaptation.
- Unique mechanism of action: Administration of probiotics to treat autism specifically involves acting upon the enteric nervous system (ENS). The enteric nervous system signals to the autonomic nervous system (ANS), which in turn signals to the brain (mostly via the vagal nerve) to alter neurological function. Compared to currently-recommended medications used to treat autism, probiotics differ in that they do not act directly upon the CNS.
Drawbacks of Probiotics for Autism (Possibilities)
Though benefits may be attained from gut microbiota modulation as a treatment for autism, potential drawbacks warrant equal consideration. The most prominent drawback is that administration of species-specific probiotic supplements may prove ineffective for symptomatic reduction, failing to live up to the current hype. Other drawbacks that necessitate contemplation include: cost of therapy, inferiority to other interventions, unwanted side effects, and onset of tolerance.
- Brain development: Autism is generally recognized by age 2, but ability for earlier detection and/or diagnosis of the condition may improve in forthcoming years. Some parents may be informed that their child is at risk for late-onset autism. Others parents may realize that their young child has autism and put forth effort into treating it by altering gut bacteria. It is possible that administration of probiotic treatments, especially at high doses, could adversely affect the child’s brain development.
- Cost: Pharmaceutical companies are looking into patenting and marketing strain-specific probiotics for the treatment of autism (and many other conditions). If a novel probiotic therapy is to ever hit the market for the management of autism symptoms, it is unlikely to be cheap. In fact, many persons without sufficient insurance may skip treatment with a pharmaceutical-grade probiotic altogether due to the high costs. Most new medications cost between $200 and $300 per 30 pills.
- Inefficacy: Despite favorable results from preliminary proof-of-concept trials of probiotics in animal models, it’s possible that probiotics may never work well for humans with autism. Clinical trials may reveal that species-specific probiotics are no more effective than a placebo for the reduction of autism symptoms. Furthermore, even if probiotics turn out to be effective for some patients, they are unlikely to be an effective intervention for all cases of autism. It may turn out that only a small percentage of autistic patients benefit from gut-bacteria alteration.
- Inferiority: Even if randomized controlled trials (RCTs) were to suggest that a probiotic is effective in reducing certain symptoms of autism, it may turn out to be less effective than other new treatments. With an array of new autism medications in the developmental pipeline, it is possible that new pharmaceutical CNS-acting medications are significantly more effective than a hypothetically-approved probiotic. Modulation of gut bacteria may be a second-rate or poor option for persons devoid of gastrointestinal abnormalities and/or dysbiosis. It may also be that the gut microbiota is a poor, suboptimal, and/or inefficient biological target for symptomatic improvement.
- Interference: It is possible that administration of a probiotic may interfere with the action of an already-effective neuropsychiatric drug. In other words, a conventional medication may alter neurotransmitters to improve a specific set of autism symptoms, however, an adjunct probiotic may induce vagal-to-brain innervations to interfere with the medication’s effect upon the CNS. Though noticeable interference effects are unlikely, people should consider that probiotics/prebiotics may compromise the therapeutic capacity of other pharmacological interventions.
- Regular administration: If probiotics are effective for certain individuals with autism, they may require ongoing administration – similar to most medications. Some patients may need to take their probiotic treatment (at low doses) on a daily basis for the rest of their lives in order to attain significant benefit. While most may expect that probiotics would linger in the GI tract – eliminating the need for ongoing administration, it’s necessary to consider the effect of the brain, immune system, and genes on the gut. Even if the gut is altered temporarily with a probiotic, it may revert back to homeostatic dysbiosis as a result of gene expression, brain function, etc. This could mean that probiotics would require lifelong ingestion to counteract faulty homeostatic programming.
- Side effects: Most would consider probiotics to have few unwanted side effects, however, they may not be totally devoid of side effects. At high doses, they may alter the microbial population of the gut, but other bacteria may die off in the process. If large amounts of new gut bacteria overtake older bacteria, this may lead to side effects related to “die off” of the older bacteria. It is also possible that prebiotic interventions could inadvertently feed pathogenic bacteria, thereby exacerbating unwanted symptoms. Equally possible is that certain species and/or subspecies of a bacterial family may be difficult to tolerate for some.
- Tolerance onset: Many therapeutic interventions for neurological conditions are associated with the gradual onset of tolerance. After tolerance is established, dosage of medication is often increased to amplify its effect. Though tolerance generally results only after many months or years during pharmaceutical treatment, it is possible that tolerance may also occur from a probiotic. The probiotic may generate neuroactive molecules and peptides within the ENS that get shuttled to the CNS. The therapeutic effect may initially appear pronounced, but diminish as receptors in the brain adapt to uptake of new molecules, resulting in tachyphylaxis.
- Unproven: Currently there’s no strong evidence to support the usage of probiotics or other forms of GI modulation for the mitigation of autism-related symptoms in humans. Evidence from randomized controlled trials (RCTs) needs to be compiled before we’ll actually know whether altering gut microbiota yields therapeutic benefit. Additionally, even if gut bacteria modification appears effective, the efficacy is likely subject to variation based on the specific species and/or subspecies of bacteria – each of which will need to undergo clinical evaluation.
- Worsening of symptoms: What if a probiotic that’s effective for a subset of individuals with autism (or hypothesized to be efficacious) turns out to exacerbate autistic symptoms in another? Though researchers understand which species of bacteria likely need elimination in a majority of autistic patients (e.g. Clostridium), not all may respond well to the introduction of new bacterial species. Certain probiotics may exacerbate autism symptoms through generation of individually-incompatible neuroactive compounds and/or generate a reaction of bacterial “die off” in which endotoxins compromise neurological function.
Autism and Gut Bacteria (Review of Research)
A significant amount of research has been conducted in effort to determine the role of gut bacteria in autism spectrum disorders (ASD). Many studies quantify bacteria within fecal excrement of children with ASD and neurotypical children to pinpoint compositional differences. Other research involves collecting gastrointestinal biopsies to get an in-depth understanding of bacterial colonization within specific subregions of the GI tract among those with ASD.
Preliminary evidence suggests that the severity of a person’s GI issues often correlates with the degree of behavioral deficits implicated in autism. These GI issues may be caused by dysbiosis or imbalances in gut bacteria (at least in a subset of cases). Many researchers theorize that correcting states of dysbiosis by increasing healthy bacteria could counteract GI issues and simultaneously reduce symptoms of autism.
One means by which autism symptoms may improve is through the modulation of gut-bacteria-mediated metabolites. There appear to be higher concentrations of toxic SCFA metabolites (produced by pathogenic gut bacteria) among those with autism than those without. Animal model studies suggest that introducing beneficial strains of bacteria in the form of a probiotic could prove effective for treating autism.
2016: Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms.
Research by Kushak, Buie, Murray, et al. (2016) assessed GI function of 61 children with autism and 50 non-autistic persons with GI-related symptoms. In their study, the team documented markers of intestinal inflammation, permeability, and disaccharidase activity. To note, disaccharidase activity refers to the activity of specific enzymes (glycoside hydrolases) associated with converting disaccharides to monosaccharides (simple sugars).
The duodenum (or smallest portion of the small intestine) was biopsied and analyzed for enzymatic activation of lactase, sucrase, maltase, and palatinase. High-performance liquid chromatography was used to gauge permeability of intestines, and immunosorbent assays of stool samples determined intestinal inflammation. The findings indicated that a subset of the children with autism exhibited mild mucosal inflammation compared to the non-autistic sample, however, no other differences were discovered.
Follow-up research may help explain why greater mucosal inflammation was reported among persons with autism. Nonetheless, intestinal permeability and disaccharidase activity were noted as similar among the autistic and neurotypical individuals. Authors of the study concluded that children with GI issues exhibit similar gastrointestinal abnormalities – irrespective of an autism diagnosis.
It was also mentioned that, based on the results, there doesn’t appear to be a gastrointestinal problem “specific to autism.” Despite a lack of dissimilarity in GI dysfunction among autistic and neurotypical populations with gastrointestinal disorders, it is plausible that modulation of gut bacteria may improve GI-related symptoms in both groups. Improving GI-related symptoms may favorably affect neurological function and correspondingly autism-related behaviors.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26913756
2016: The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder.
Li and Zhou (2016) discuss the relationship between gut microbes and autism spectrum disorders. Authors document the fact that although the causal underpinnings of autism are unknown, some cases of the condition may have been caused [partially] by bacterial imbalances within the gastrointestinal tract. These imbalances may have been a direct result of antibiotic administration or a bacterial infection.
Knowing that gut bacteria may be implicated in symptomatic severity of autism, altering microbial composition of the gut may improve cognitive and/or behavioral outcomes. The theorized mechanism of action involves the ANS, immune system, and endocrine system. Overall, the evidence compiled by Li and Zhou supports a connection between gut bacteria and autism and evaluates therapeutic interventions (e.g. dietary, parasitic, bacterial, etc.).
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26964681
2015: Gastrointestinal microbiota in children with autism in Slovakia.
Tomova, Husarova, Lakatosova, et al. (2015) conducted a study comparing the GI microbiome of children with ASD compared to those without. They collected stool samples from 10 children with autism and 9 neurotypical siblings, plus 10 unrelated neurotypical children. Using real-time PCR, they quantified concentrations of bacteria within each of the stool samples and made comparisons.
The samples revealed significantly lower ratios of Bacteroidetes to Firmicutes in fecal samples of those with ASD compared to the others. In addition, children with ASD exhibited heightened concentrations of Lactobacilli and Desulfovibrio compared to others. Researchers identified a convincing link between quantity of Desulfovibrio species and severity of repetitive behavior symptoms (in accordance with data from an Autism Diagnostic Interview).
Furthermore, there were significant links between severity of ASD and gastrointestinal distress. Administration of probiotic supplements appeared to improve the ratio of Bacteroidetes to Firmicutes, reduce Desulfovibrio, and increase of Bifidobacterium in fecal excretions. An interesting finding reported by researchers was that GI bacteria were not associated with serum levels of hormones such as oxytocin, testosterone, or DHEA.
This study included a small sample size, but found significant differences in bacteria within stools of those with ASD. These differences were consistent with findings of other research, suggesting that they may accurately reflect ASD. That said, more research needs to be conducted to determine whether modulating gut bacteria could improve symptoms and/or prevent onset of ASD.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25446201
2015: Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection.
Researchers Son, Zheng, Rowehl, et al. (2015) conducted a study assessing differences in fecal microbiomes between children (7 to 14 years old) with autism spectrum disorder and neurotypical siblings. These assessments were carried out with targeted quantitative polymerase chain reaction (qPCR) assays of bacteria. In addition to bacterial assays, GI function and problematic behaviors were documented using the ROME III questionnaire and Child Behavior Checklist, respectively.
Data revealed that 25 of 59 children with autism exhibited a functional gastrointestinal disorder compared to 13 of 44 neurotypical siblings. Intriguingly, constipation occurred more often as a specific GI issue among those with autism compared to the neurotypical siblings. A correlation was also noted between autism OR GI disorders and more severe behavioral abnormalities compared to neurotypical siblings devoid of GI dysfunction.
Analyses of food consumption patterns suggested no major differences in dietary intake among autistic and neurotypical siblings. Furthermore, severity of autism symptoms was not associated with GI issues; children with autism, regardless of GI comorbidities, experienced equally problematic symptoms. Finally, there were no data indicating that composition of gut bacteria differed among autistic and neurotypical siblings.
In summary, evidence from this study does not support the idea of significant differences in populations of gut bacteria among those with autism spectrum disorder compared to non-autistic siblings. Additionally, it does not support the idea that GI disorders affect the severity of autism symptoms. That said, it would be interesting to evaluate whether behavioral abnormalities may improve among those with ASD plus GI disorders after receiving treatment for the GI issues.
It also warrants mentioning that, despite assessing neurotypical siblings to those with ASD, all individuals in this study may differ from neurotypical persons devoid of autistic siblings. More research is necessary to compare those with autism to unrelated neurotypical persons. Finally, authors of the study mention that given the myriad of variables examined, their sample size is only modest – possibly affecting results.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26427004
2015: Approaches to studying and manipulating the enteric microbiome to improve autism symptoms.
A report by Frye, Slattery, MacFabe, et al. (2015) outlines possible therapeutic mechanisms by which symptoms of autism could be treated via gut-microbiome modulation. In the report, they discuss the fact that the gut contains trillions of microbes, each of which can affect a person’s health. Disturbances in a person’s gut microbiome may induce certain medical conditions and, in a subset of individuals, exacerbate symptoms of autism spectrum disorder.
With knowledge that the gut may dictate symptomatic severity of autism, modulation of gut bacteria could ameliorate autism-related behaviors, as well as oft-occurring GI comorbidities. In order to determine the efficacy of gut-bacteria modulation as an intervention for autism spectrum disorder, controlled clinical trials [in humans] necessitate coordination. To devise a trial of gut-bacteria modulation for autism, it is necessary to: ensure patient safety, implement a robust design (e.g. RCT), and match patients with bacterial species (or specific modulations) based on their most prominent symptoms.
In other words, someone with severe repetitive behaviors may benefit from bacterial species (or subspecies) different from a person with severe social deficits. Understand that not everyone with autism will benefit from modifying microbes in their ENS. It is suspected that ASD children with severe dysbiosis may derive greater benefit than ASD children with seemingly normative gut flora.
At this time, it would be useful to conduct more proof-of-concept trials in animal models and gather further data from humans with ASD to determine specific microbial abnormalities. Clearly the work by Fry, Slattery, MacFabe, et al. supports additional investigation of the gut microbiome in autism.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25956237
2015: Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children.
In effort to elucidate GI-bacterial abnormalities among persons with autism, researchers Gabriele, Sacco, Altieri, et al. (2015) evaluated concentrations of the metabolite “p-cresol” (4-methylphenol). They recruited 53 children with autism spectrum disorder and collected urine samples. The urine samples were subject to HPLC (High Performance Liquid Chromatography) and tested for concentrations of “p-cresol.”
Other tests included fecal samples (to detect Clostridium bacteria) and LA/MA tests (to determine intestinal permeability). Researchers noted antibiotic usage and infections of all children (until age 2), as well as their stool composition with the Bristol Stool Form Scale. Associations were noted between levels of p-cresol in urinary excretion and ongoing constipation, however, there didn’t appear to be any associations between p-cresol and other variables (Clostridium, intestinal permeability, antibiotic usage).
It was concluded that urinary p-cresol levels are greater among autistic children with regular constipation. That said, it does not provide any explanation as to how the p-cresol levels may have increased. Perhaps a combination of a person’s environment and/or genes are to blame?
Of adjacent interest is the fact that p-cresol is chemically similar to the substance 4-EPS (4-ethylphenylsulfate). In animal model studies, concentrations of 4-EPS are markedly elevated among newborns with autism-like symptoms. Reducing 4-EPS levels with introduction of a probiotic formula is capable of attenuating the autism-like symptoms.
It may be of benefit to analyze the relationship between the quantity of p-cresol excretion and severity of autism symptoms. If there’s a direct correlation, perhaps interventions aimed at specifically reducing p-cresol would be of therapeutic benefit to those with ASD. Possible sources of p-cresol include: antibiotics, gastrointestinal abnormalities, and environmental exposure; this study supports the idea that most exposure may be of environmental origin.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26437875
2015: Autism spectrum disorders and intestinal microbiota.
A report by De Angelis, Francavilla, Piccolo, et al. (2015) highlights a symbiotic evolutionary relationship between bacteria and humans. It is understood that many strains of bacteria inhabiting the intestinal wall can favorably affect our physical health and neurological function through the gut-brain axis. However, infiltration of pathogenic bacteria may compromise our health and play a causal role in the onset of neuropsychiatric conditions such as autism spectrum disorder.
Researchers presented findings comparing the fecal microbiota and metabolites of children with autism or pervasive developmental disorder (NOS) those of neurotypical children. It appeared as though children with autism or pervasive developmental disorder (NOS) exhibited noticeable differences in the composition of fecal microbiota and metabolites compared to neurotypical children. Based on these findings, it was theorized that symptomatic severity of ASD and PDD-NOS may be contingent upon extent to which microbiota differs from neurotypical individuals.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25835343
2014: Altered gut microbiota and activity in a murine model of autism spectrum disorders.
Research by de Theije, Wopereis, Ramadan et al. (2014) utilized a mouse model of autism spectrum disorders to investigate the relationship between gut microbes and behavior. Mice were exposed to valproic acid (VPA) in utero and their gut bacteria was assayed with sequencing technology to determine SCFA, lactic acid, and caecal concentrations. Findings suggested that exposure to VPA in the uterus resulted altered concentrations of Bacteroidetes, Firmicutes and Desulfovibrionales in offspring – akin to evidence from human studies.
Compared to females, male offspring in the VPA-exposed model exhibited greater levels of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis. This may have explained elevations in caecal butyrate and ileal neutrophil infiltration, but lower concentrations of serotonin and sociability. Since autism tends to occur more often in boys than girls (among humans), perhaps more significant sex-specific microorganism changes in males are to blame.
These findings share similarities to microbiome changes reported in humans with ASD. Researchers believe that it may be possible to modulate the GI microbiota to reduce the severity of autism spectrum disorders. It may also be possible to develop technology that detects in-utero dysbiosis or bacterial abnormalities and make an effort to increase healthy bacteria to prevent onset of lifelong neurodevelopmental conditions such as autism.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24333160
2014: Altered brain-gut axis in autism: comorbidity or causative mechanisms?
Mayer, Padua, and Tillisch (2014) write an article questioning whether gut-brain axis (GBA) dysregulation is a cause or comorbidity of autism. Like many researchers, they note that GI disorders are common among those with ASD. The theory that autism may be induced by maternal immune activation (MIA) associated with infection during pregnancy is discussed.
It seems as though the researchers side with the possibility that probiotics could improve behavioral abnormalities in some patients with autism. This opinion is based off of preliminary evidence from animal model trials in which probiotic species effectively reversed autism-related behaviors. Then again, it’s possible that gut-brain axis function is either causally, correlatively, or unrelatedly associated with autism depending on the specific individual with ASD.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25145752
2013: Towards effective probiotics for autism and other mental disorders?
It is documented that autism diagnoses have increased significantly from 2000 to 2010. As of 2000, the CDC reported that autism occurred at a rate of 1 out of 150 births, whereas after 2010, rates spiked to 1 out of 88 births. While it is possible that underreporting and/or failure to accurately diagnose the condition may explain the discrepancies in occurrence rates (from past to present), it is equally possible that rates of autism are increasing for reasons currently unknown.
Gilbert, Krajmalnik-Brown, Porazinska, et al. (2013) inquire as to whether autism spectrum disorder may be associated with dysbiosis and whether probiotics could serve as an effective treatment. Researchers document the relationship gut bacteria and a myriad of general health conditions, as well as neuropsychiatric disorders. An example cited by researchers involved knocking out the TLR5 gene (Toll-Like Receptor 5) in mice.
When mice lack TLR5, they develop obesity not because their metabolism becomes wonky, but because their microbiome is substantially altered in such a way that they exhibit insatiable appetite. Another example referenced was a mouse model of multiple sclerosis in which demyelination (damage to myelin sheath) appeared to have been directly induced from pathogenic gut bacteria. Other research involving mice shows that modifications to their gut bacteria influences anxiety and social behaviors.
The bulk of their report reflected upon results from an innovative study by Hsiao et al. (2013). Before conducting the study, Hsiao et al. knew that maternal immune activation resulting from an infection (bacterial or viral) was associated with increased likelihood of autism. However, the possible mechanisms by which an infection during pregnancy may lead to autism remained unclear.
In attempt to better understand the ways an infection may induce autism, they injected mice with an immunostimulant (polyinosinic:polycytidylic acid (Poly(I:C)) to mimic a viral infection and induce maternal immune activation (MIA). Maternal immune activation is known to compromise the barrier of the gut and cause dysbiosis. It was theorized that metabolites from pathogenic gut bacteria (associated with MIA-induced dysbiosis and leaky gut) undergo transfer to a fetus, potentially compromising neurological and immune development to cause autism.
Findings of the study suggested that shifts in gut flora occur a result of MIA-related intestinal leakage. The newborn mice from mothers with MIA underwent gut assays which revealed significant abnormalities in concentrations of circulating bacterial metabolites. Furthermore, the newborn mice from mothers with MIA exhibited pronounced autism-like symptoms.
This confirmed that maternal immune activation can cause autism, and illustrated that its mode of causal effect may involve the transfer of pathogenic bacteria from mother to fetus. It was then hypothesized that administration of the immune-boosting probiotic Bacteroides fragilis may improve functionality of these mice. Upon administration of Bacteroides fragilis, favorable effects were observed including: restoration of gut barrier integrity, normalization of gut microbiome (indicative of non-ASD states), and attenuation of ASD-like symptoms.
Among the newborns from MIA mothers, concentrations of serum 4-ethylphenylsulfate (4-EPS) were initially 46-times greater than in neurotypical newborns. Pathogenic gut bacteria and states of dysbiosis are known to upregulate production of 4-EPS. It is known that 4-EPS is related to p-cresol, a biomarker observed in urinary samples of children with autism spectrum disorder.
The other metabolite significantly elevated among newborns from MIA mothers was is known as indolepyruvate. This indolepyruvate metabolite is related to indolyl-3-acryloylglycine, a biomarker of autism in humans. Not only did Bacteroides fragilis reduce 4-EPS and indolepyruvate, but it increased a variety of other metabolites such as N-acetylserine which may have reduced certain autism symptoms.
This study was unique in that it showed how MIA can alter gastrointestinal function, as well as that MIA-induced gastrointestinal abnormalities can be reversed with administration of probiotics. It is possible that humans with MIA-induced autism would derive substantial benefit from the right probiotic supplement. Not only might specific probiotics repair the gastrointestinal tract among ASD patients with GI disorders, but they may consequently reduce ASD symptoms.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24360269
2013: The gut microbiome: a new frontier in autism research.
Mulle, Sharp, and Cubells (2013) reflect upon the multifaceted relationship between gut microbiota, development of the nervous system, and onset of autism spectrum disorders. Preliminary evidence suggests that a person’s gastrointestinal bacteria may be indicative of autism spectrum disorder. The researchers note that, based on studies in animal models, the gut microbiome likely has a profound impact on neurological development.
Particularly high concentrations of pathogenic gut bacteria during critical developmental years were implied as being culpable for induction and/or exacerbation of neurological disorders, including autism. Nonetheless, as of current, research of gut microbiota has generated seemingly more questions than conclusions. Assuming researchers unveil more about the microbiome in autism, it may be possible to treat the condition with: antibiotics, dietary protocols, or probiotics.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23307560
2013: Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified.
De Angelis, Piccolo, Vannini, et al. (2013) have published multiple works in effort to better understand the relationship between the gut microbiome and developmental disorders like autism. In this particular study, they collected fecal samples from three groups including: healthy children (devoid of neurological conditions), children with PDD (Pervasive Developmental Disorder), and children with ASD (autism spectrum disorder). They used a pyrosequencing technique to evaluate and compare concentrations of bacteria and bacterial metabolites among the three distinct populations.
Interestingly, children with ASD were discovered to harbor the highest bacterial diversity. This finding may have been surprising given speculation from previous research suggesting that microbial diversity may be reduced among persons with ASD. Phyla of bacteria appearing in the samples included: Firmicutes, Bacteroidetes, Fusobacteria and Verrucomicrobia.
Results discovered high concentrations of Caloramator and Sarcina among children with autism spectrum disorder (ASD) compared to healthy and PDD children. Another finding was that Faecalibacterium and Ruminococcus levels were significantly higher among healthy and PDD children compared to those with ASD. Children with ASD and PDD shared a similarity of differences in composition of Lachnospiraceae bacteria compared to healthy children, and also exhibited elevations in Bacteroidetes plus subsets of Alistipes and Akkermansia species.
What’s more, free amino acids and volatile organic compounds (VOCs) were elevated among those with ASD and PDD. Levels of Sutterellaceae and Enterobacteriaceae were higher, whereas concentrations of Bifidobacterium were markedly lower among those with ASD than other groups (PDD and neurotypical controls). Researchers postulate that differences in microbial populations among those with ASD and PDD may be useful in diagnosis, prevention, or treatment for each condition.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24130822
2013: Autism: metabolism, mitochondria, and the microbiome.
Macfabe (2013) outlines the connection between gut bacteria and autism spectrum disorders. In the article, it is mentioned that many cases of autism are associated with: chronic antibiotic usage, food cravings, and GI disorders. Incidentally, all of the aforestated associations are also linked to gut flora abnormalities.
Abnormal gut flora may generate deleterious short-chain fatty acid (SCFA) metabolites such as propionic acid. It is the SCFA metabolites (e.g. propionic acid) that may be responsible for directly cause autism for a subset of persons and/or exacerbating symptoms. Macfabe believes that partial metabolizers of propionic acid may lead to its accumulation and toxic effects (e.g. neurotoxicity).
Administration of propionic acid to animal models induces autism-related behaviors (e.g. antisocial tendencies, repetition, etc.). Moreover, propionic acid is understood to unfavorably modulate neurochemistry, acidification, calcium release, fatty acid metabolism, immune function, and gene expression. This may explain biomarkers of neuroinflammation, reactive oxygen species, mitochondrial dysfunction, and downregulated glutathione.
One obvious way to reduce propionic acid production is to alter microbial composition of the gut. By altering the gut microbiome in such a way that less propionic acid is generated, neurobiological functions of those with ASD may improve. Rather than attempting to pinpoint differences in gut bacteria of those with ASD compared to neurotypical patients, it may be more helpful to identify differences in toxic short chain fatty acids.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24416709
2013: Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.
Though already discussed above in other reports, researchers Hsiao, McBride, Hsien, et al. (2013) induced autism-like symptoms in mice using the metabolite polyinosinic:polycytidylic acid (Poly(I:C). This chemical mimics biologic responses associated with viral infections and effects of maternal immune activation (MIA). Upon induction of this MIA-related effect, the gastrointestinal barrier of mice becomes dysfunctional, their microbial composition is altered, and autism-related symptoms manifest.
After creating mouse models of MIA-induced autism, researchers administered the probiotic Bacteroides fragilis, a healthy bacterium in humans. Results of their study showed that the B. fragilis improved gut permeability, modified composition of gut bacteria, and most importantly – corrected all autism-related behavioral impairments. The mice no longer exhibited repetitive nor anxious behaviors, and their ability to communicate with other mice appeared normal.
Several metabolites were modified after exposure to B. fragilis, most of which were likely responsible for the behavioral alterations of the mice. This study shows that modifying metabolites of animals can affect their behavior. It is theorized that similar findings may occur among humans with autism, as well as other neurological disorders.
Despite the promising findings of this study, it should be emphasized animal models may respond differently to gut bacteria modulation than humans. It may be that neurological function and/or behavior of mice is influenced to a greater extent by gut bacteria (and corresponding metabolites) than humans. Another possibility is that age at which the probiotics are administered matters; perhaps they’ll only work if administered before a specific neurodevelopmental window.
Still, this study shows proof-of-concept that probiotics may be effective for some cases of autism in humans, particularly those resulting from MIA. It also showcases the concept that reducing concentrations of pathogenic GI metabolites could attenuate symptoms of autism. Furthermore, modulation of GI metabolites may not necessarily always necessitate administration of probiotics.
Assuming problematic metabolites (e.g. SCFAs) can be pinpointed on an individual basis among those with autism, any agents that reduce production of these metabolites could be useful. More research is needed to connect the dots between problematic GI metabolites in humans, gut bacteria, and autism. That said, like this study by Hsiao, McBride, Hsien, et al., it may turn out that one specific strain of probiotics is able to reverse autism symptoms in a subset of patients.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24315484
2012: Intravenous secretin for autism spectrum disorders (ASD).
Williams, Wray, and Wheeler (2012) review evidence of the GI-hormone secretin for the treatment of autism spectrum disorders. Researchers begin their publication by stating that secretin was first noted as anecdotally efficacious for the treatment of autism-related symptoms in 1998. Their aim of conducting a review was to determine whether IV-administered secretion could attenuate prominent symptoms of autism and/or quality of life among persons with ASD.
To gather evidence, the trio of researchers evaluated databases for studies published from 1998 to 2010. Inclusion criteria consisted of only randomized controlled trials (RCT) of IV-administered secretion among persons with ASD. A total of 16 studies met inclusion criteria incorporating 900 children.
Based on results of the randomized controlled trials (RCTs), administration of secretin appears ineffective for reducing prominent symptoms of autism spectrum disorder. Authors of the study concluded that neither single/multi-dose IV-secretion can be recommended as an intervention at this time. Though secretin administration may not alter gut bacteria, if it is effective, it is though to work via the gut-brain axis, hence the reason for discussing this systematic review.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22513913
2012: Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders.
Macfabe (2012) suspects that short-chain fatty acids (SCFAs) may be directly to blame for symptoms of autism spectrum disorders. Though gut bacteria may be implicated in autism spectrum disorders, it is the fermented metabolites of the gut bacteria in the form of SCFAs that may lead to deleterious behavioral outcomes. One of many SCFAs that could play a significant role in autism is propionic acid (PPA).
Propionic acid is a fermentation metabolite of Clostridia, Desulfovibrio, and Bacteroidetes. As was already mentioned, studies have shown that both Clostridia, Desulfovibrio, and Bacteroidetes appear in abnormally high concentrations among those with autism. Macfabe points out the fact that administration of PPA and other SCFAs to rat models leads to repetitive behaviors, cognitive deficits, social impairment, and poor motor skills – analogous to humans with autism.
It is also known, that in these rat models, PPA damages mitochondria function and scrambles neurochemistry. Knowing this, it seems plausible that SCFAs, especially PPA could be associated with autism in humans. Finding the specific SCFAs that may be culpable for symptoms, and identifying ways to reduce them (e.g. with probiotics) could prove valuable in treating autism.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23990817
2011: Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity.
A study conducted by Adams et al. (2011) attempted to compare gastrointestinal flora of children with autism and healthy neurotypical children. The motive for the study was based on previous findings that children with autism often report a greater number of gastrointestinal issues than those without the condition. Researchers speculated that these gastrointestinal issues may somehow be related to colonization of pathogenic bacteria within the gastrointestinal tract, thereby causing dysbiosis.
To gather data, researchers collected stool samples from 58 children diagnosed with ASD and 39 neurotypical children. Thereafter the fecal samples were comprehensively analyzed using bacterial and yeast culture tests. Various biomarkers were recorded, including: lysozyme, lactoferrin, secretory IgA, elastase, digestion markers, short chain fatty acids (SCFA’s), pH, and blood presence.
In addition to analyzing fecal samples, gastrointestinal function and severity of autism symptoms were assessed using the GI Severity Index questionnaire (GSI) and Autism Treatment Evaluation Checklist (ATEC), respectively. Results indicated that severity of gastrointestinal symptoms (in accordance with the GSI) was linked with severity of autism symptoms. In other words, the greater the number of gastrointestinal issues a person had, the more severe his/her autism.
Specifically, children presenting scores on the GSI exceeding “3” also exhibited elevated scores on the ATEC compared to those with lower scores (GSI < “3”). What’s more, children with autism appeared to have significantly reduced concentrations of SCFAs (short-chain fatty acids) such as: acetate, proprionate, and valerate. Intriguingly, slightly more prominent reductions in SCFAs were seen among children with autism utilizing probiotics compared to those refraining from probiotic usage.
Another finding was that compared to neurotypical children, children with autism exhibited significant reductions in Bifidobacter species (-43%) and elevations in Lactobacillus species (+100%). Besides these bacterial differences, it was noted that slightly reduced levels of lysozyme were recorded (-27%) among those with autism, but researchers speculate that decreased lysozyme may have been a direct result of increased probiotic usage. No other statistically significant differences in biomarkers associated with digestive function were discovered.
In summary, there appears to be a bidirectional relationship between gastrointestinal and autism symptoms in that, increased severity of one (autism symptoms) is associated with increased severity of the other (gastrointestinal symptoms) – and vice-versa. Researchers surmise that autism symptoms can be exacerbated by severe gastrointestinal dysfunction. It should’ve also been mentioned that gastrointestinal dysfunction may worsen as a result of neurological dysfunction related to autism.
It is important to realize that this was a sample of children only, so it’s unclear as to whether similar findings would be reported when comparing adults with ASD to neurotypical adults. That said, there appear to be some overt differences in microbiota of children with ASD compared to those without the condition. While further research is warranted to support these findings, it is reasonable to speculate that microbiota modulation with specific probiotic strains (e.g. Bifidobacterium) may reduce severity of autism spectrum symptoms.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21410934/
2011: The Potential Role of Probiotics in the Management of Childhood Autism Spectrum Disorders
Critchfield, van Hemert, Ash, and Ashwood (2011) discussed the therapeutic potential of gut bacteria modification [using probiotics] among persons with ASD. In their paper, researchers emphasized associations of GI dysfunction, immune responses and autism-related symptoms such as aggression, irritability, outbursts, and irregular sleep. They also mention the finding that a brief course of antibiotics is often effective for symptomatic reduction in a subset of ASD patients.
Antibiotics may work by annihilating pathogenic species of bacteria in the gut (e.g. Clostridium). Another gut-based intervention for autism involves populating the gut with healthy bacteria in the form of probiotics. Probiotics are capable of repairing intestinal integrity, shifting immune function, and restoring microbial balance within the GI tract to improve autism-related behaviors. Authors are in favor of evaluating the therapeutic effect of probiotics for autism.
- Source: https://www.researchgate.net/publication/51826269
2010: Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report.
A report by Buie, Campbell, Fuchs, et al. (2010) discussed associations between autism spectrum disorder and gastrointestinal disorders. Researchers noted that gastrointestinal disorders are reported at high rates among those with autism, however, it is unclear as to how they should be evaluated and/or treated. Among the most prominent of challenges is fully understanding the scope of gastrointestinal symptoms incurred by those with autism, primarily due to the fact that individuals with the condition have difficulty observing and/or conveying their experience of such symptoms.
All preexisting literature was examined by a large panel of experts for a comprehensive review. Their goal was to develop guidelines for clinical evaluation and treatment of gastrointestinal dysfunction among individuals with autism spectrum disorder. Assessment of the literature revealed that there was insufficient evidence to construct any formal diagnostic and/or treatment guidelines.
Professionals concluded that persons with autism should receive the same degree of care for gastrointestinal complaints as non-autistic individuals. It was emphasized that medical care should be integrated with behavioral interventions for managing symptoms. Clearly, further research is justified to understand correlations between gastrointestinal disorders and autism – and determine appropriate management strategies.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20048083/
2010: Intestinal microflora of autistic children.
A study by Ekiel, Aptekorz, Kazek, et al. (2010) sought to determine whether children with ASD differed from neurotypical children in gut-microbe composition. Stool samples were collected and compared. Results suggested that Clostridium, Enterococci, and Lactobacilli species were more common in fecal samples of those with ASD than without.
Quantification of microbes revealed Clostridium perfringens, Candida species, and Staphylococci elevations in autism compared to neurotypical controls. Since autism-related symptoms are often accompanied by GI symptoms, it is possible that intestinal microflora are to blame for both. Researchers propose that correcting microbial abnormalities may be a viable therapy for ASD.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21114016
2003: Intestinal pathophysiology in autism.
A report by White (2003) documented that autism affects approximately 1 out of 500 children, and is a chronic, lifelong condition. Analogous to other reports, White notes that the underlying causes of autism remain largely unknown. Nonetheless, it was discussed that gastrointestinal abnormalities appear more frequently among children with autism compared to children without the condition.
Specifically, intestinal permeability tends to be greater among those with autism, possibly increasing susceptibility to leaky gut syndrome, as well as dysbiosis. It is understood that the gut signals to the brain, and is capable of influencing brain function. Rampant leaky gut syndrome and intestinal permeability may send deleterious signals to the brain, thereby exacerbating various behavioral symptoms associated with autism.
There are many ways in which gastrointestinal dysfunction may worsen symptoms of autism and impair sufferers’ quality of life. Conceivably, making a concerted effort to normalize gut function may reduce symptomatic severity in certain cases of autism. Moreover, the observation that specialized diets and/or probiotic supplementation sometimes decrease symptomatic severity may be associated with favorable gut-brain signaling.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12773694/
2002: Autism and gastrointestinal symptoms.
Horvath and Perman (2002) mention that individuals with autism tend to exhibit social and communication deficits, as well as stereotypic behaviors. These communication deficits are especially noticeable among children within the first few years of a child’s life. Unfortunately, the causal underpinnings of autism haven’t been elucidated and currently-available treatments are often ineffective for symptomatic attenuation.
Researchers mention that, from the 1990s to the 2000s, more studies have endeavored to pinpoint specific biological abnormalities implicated in autism. Interestingly, a subset of these studies report increased rates of gastrointestinal dysfunction and upregulation of proinflammatory biomarkers among individuals with autism compared to non-autistic counterparts. Assessments of the intestinal tract of those with autism reveal mild-to-moderate inflammation.
Furthermore, it appears as though children with autism exhibit the following features: chronic intestinal permeability (i.e. “leaky gut”), downregulated digestive enzymes, heightened reactivity to injections of secretin (a gastrointestinal hormone), and suboptimal hepatic sulfation capacity. Incidentally, symptoms of autism such as behavioral abnormalities often improve upon the correction of gastrointestinal dysfunction. It was concluded that the [bidirectional] brain-gut axis may warrant further research in effort to understand autism.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12010627/
Limitations of Research associated with Gut Bacteria and Autism
There are some limitations associated with the research of gut microbe modulation and autism. The most prominent limitation is that there are no human studies (or even case studies) suggesting that modifying gut bacteria is associated with improvement in the core symptoms of autism (e.g. repetitive behavior, communication deficits, etc.). Other limitations include: age-restricted research (focusing primarily on children with ASD – rather than adults), an inability to determine whether dysbiosis is a cause or effect of autism, and conflicting evidence (in bacterial species implicated in autism).
- Age restricted: Autism is understood to be a lifelong disorder, first noticeable in early childhood (between ages 1 and 3). Most research analyzing gut bacteria of individuals with autism involves collecting stool samples from children with the disorder. Though children with ASD may yield some critical insights regarding ASD-specific gut bacteria, adults with ASD should also be studied. It is possible that findings of gut bacteria differences in autism may be age-related. Perhaps adults with ASD exhibit abnormalities that differ from children with ASD.
- Autism subtypes: Autism is a broad disorder diagnosed across a “spectrum.” Some individuals exhibit symptomatic nuances that differ from another with the same condition. Not all persons with ASD will exhibit equally severe social impairment nor repetitive behaviors – these are contingent upon the individual. It is reasonable to suspect that bacteria composition in the GI tract may reflect specific subtypes of the condition (e.g. higher levels of certain bacteria among ASD patients with severe repetitive behaviors). Furthermore, there may be specific subtypes of autism in which gut bacteria does not play an influential role in symptomatic severity. Additional research should attempt to determine which patients with the condition are most likely to benefit from gut-based therapies.
- Bacteria or metabolites: While it is understood that gut bacteria are linked with generation of metabolites (e.g. short-chain fatty acids), it isn’t known as to whether the bacteria themselves or their metabolites have a greater influence on function of the host. It is possible that they could have equal and/or shared influence, but it is also possible that the metabolites are more to blame for symptoms of ASD than bacteria. Though MacFabe has done some research attempting to pinpoint metabolite differences in ASDs compared to NTs, more focus may be needed in this niche.
- Cause, comorbidity, or effect: There’s a possibility that dysbiosis in autism is nothing more than an unrelated comorbidity and/or effect of the condition. Some evidence suggests that gut bacteria may not be as different as initially hypothesized among those with autism and neurotypical individuals. Although even if the gut plays zero role in causing autism symptoms, this is not to say that administering certain probiotics would yield no benefit. However, it may be less likely that gut-based interventions would treat autism.
- Conflicting evidence: There’s conflicting evidence regarding levels of microbes and microbial diversity within the gut. Some research suggests that individuals with autism spectrum disorders exhibit a lack of bacterial diversity in their GI tract, whereas other studies have showed that diversity exceeds that of neurotypical individuals. This conflicting evidence may mean that one of the studies is invalid OR that there are no definitive differences in microbial diversity among ASD and NT persons. Additionally, some evidence is conflicting as to whether GI issues are more common among those with autism compared to the general population. Moreover, contradictory findings have been reported for the appearances of certain bacteria in stool samples compared to neurotypical individuals.
- Gastrointestinal comorbidities: A considerable amount of research examines the gastrointestinal microbiome of persons with ASD, but only if they have comorbid GI-related issues. While it may turn out that modulating the gut microbiome is more effective as a treatment for those with ASD plus GI disorders, it is necessary to understand whether microbiota abnormalities are more related to ASD or the GI dysfunction. More research should be conducted to determine microbial contents of persons with ASD devoid of GI-related issues – compared to ASD persons with GI disorders and neurotypical individuals (with and without GI issues).
- Lack of human trials: It appears as though modulation of gut bacteria in humans is relatively low risk. Introducing healthy bacteria to the gut (such as with probiotics) isn’t associated with severe side effects or adverse reactions. Even other strategies such as administration of antibiotics appear relatively tolerable. As of current, there aren’t any human trials that have tested modulation of gut bacteria in humans with autism. This means we don’t have any way of determining the efficacy of gut modulation as a treatment or preventative strategy.
- Specific bacterial species: There’s fairly convincing evidence that Clostridium bacteria are high among children with ASD compared to neurotypical children. If an intervention were to be devised based on current evidence, eradicating Clostridium would likely be the most logical strategy. Increasing Bifidobacterium species may be another viable option. That said, it may be necessary to conduct gut assays on an individual basis and come up with a personalized treatment protocol to restore healthy gut bacteria.
- Type of microbial modulation: As was outlined, there are many different ways to modulate a person’s gut microbiome including: fecal transplants, ingestion of parasites, and probiotic supplements. It may turn out that one of these therapies is more effective than others for the treatment of autism. Further investigation is warranted to understand the effectiveness and/or efficiency of a particular modality of microbial modulation for symptomatic reduction.
Is modulating the gut microbiome useful for the treatment of autism?
Though gut-bacteria modulation may prove useful as an intervention for autism spectrum disorders (ASD) in humans, there’s currently insufficient evidence to make any definitive claims regarding its efficacy. Nonetheless, there is some evidence suggesting that gut-bacteria modulation may be useful for treating symptoms of certain gastrointestinal conditions. Given the findings that GI disorders tend to occur at a higher rate among persons with autism [than the general population], ensuring that individuals with ASD seek proper evaluation and treatment for any GI complaints should be a priority.
It is unclear as to whether treating GI disorders also improves symptoms of autism, however, when considering the direct relationship between ASD and GI symptoms, it is certainly plausible. Multiple studies suggest that the severe a person’s gastrointestinal complaints, the more pronounced his/her autism symptoms tend to be. Many speculations can be made as to why ASD and GI symptoms appear correlated.
Perhaps the most logical explanation is that GI symptoms provoke psychological distress, which exacerbates overt symptoms of ASD. When GI symptoms are treated, a person with ASD may exhibit concurrent reduction of autism-related symptoms because he/she is no longer experiencing the GI disorder-induced psychological distress. That said, this may be too simplistic of an explanation given evidence suggesting that gut-microbiota are capable of influencing GI function plus brain activity via the gut-brain axis (GBA).
This bidirectional relationship between the gut and brain has lead many researchers to examine differences in bacterial concentrations among those with autism compared to those without. Evidence suggests that gut bacteria composition of persons with autism primarily differs from that of the general population in that they generally exhibit elevated levels of bacteria from the Clostridium genus. Other differences in concentrations of bacteria of various taxonomic categorizations (i.e. phylum, family, genus, species, etc.) have been reported such as reduced quantities of bacteria from the Bifidobacterium genus.
Anecdotal reports and case studies suggest that certain individuals with ASD experience significant improvement in ASD-related symptoms after receiving antibiotics (e.g. amoxicillin), possibly related to modulation of gut bacteria. Still, it is necessary to consider that antibiotics could deliver their therapeutic effects through mechanisms other than modulation of gut bacteria. The most convincing evidence to suggest that modulation of gut bacteria may treat autism comes from work by Hsiao, McBride, Hsien, et al. published in 2013.
These researchers created a rodent MIA (maternal immune activation) model of autism and successfully treated symptoms by administering a healthy strain of human bacteria known as Bacteroides fragilis. The reason for administering Bacteroides fragilis was related to the fact that this species of bacteria was capable of reducing toxic 4-EPS metabolites. This provides proof of concept that, if administered in a timely manner, specific strains of probiotics may be useful for the treatment of autism subtypes (e.g. maternal immune activation) in humans.
That said, it is important to avoid extrapolating these findings to humans – we are not the same as rodent models. It may be that behavior and/or neurological activity of rodents is under greater influence of gut bacteria compared to humans. In summary, despite mounting preliminary evidence linking gut microflora markers to autism, further research is necessary to understand whether gut microbe modification would be safe and effective treatment [for a subset of ASD patients].
Autism, Gut Bacteria, and Probiotics: Critical Thinking
The connection between autism, gut bacteria, and probiotics isn’t fully understood. For this reason, it is important to think critically about any purported connections. Listed below are a few things to consider in the complex relationship between autism, gut bacteria, and probiotics – including: certain autism subtypes may respond better to gut modulation than others, gut-based treatment may require personalization, and that gut-related abnormalities may be nothing more than a consequence of autism or distinct/unrelated to autism – rather than an aspect of causation.
Autism subtypes: Not all individuals with autism respond equally to the same therapies and interventions. Although there is a general set of diagnostic criteria for autism spectrum disorder, each case is nuanced. Some individuals experience more severe symptoms than others, and two cases of equally severe autism may be nuanced in terms of the specific behaviors exhibited. As of current, researchers have been able to use genetic testing to subtype approximately 10% of autism diagnoses.
The subtype of a person’s autism may dictate whether they respond to modification of gut bacteria. It is possible that certain autism subtypes exhibit normative gut bacteria and may respond poorly to microbiota-based interventions. Perhaps only those with a specific autism subtype or for whom gut dysbiosis is heavily implicated in pathogenesis may benefit from probiotics or gut microbiota-centric therapies.
It should also be considered that two individuals with different subtypes of autism may each exhibit gut dysbiosis, yet require different probiotic strains for therapeutic benefit. For example, one patient may benefit significantly from Bifidobacterium Longum – whereas another may necessitate an entirely different genus of bacteria to correct his/her dysbiosis. Researchers may need to evaluate dysbiosis based on the specific patient with ASD and engineer personalized bacterial interventions.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/17505203/
Probiotics unlikely “cure”: Sensationalized news headlines have lead many to believe that probiotics may be a cure for autism. While it is possible that administration of certain probiotics to pregnant mothers and/or newborns may reduce risk of autism, there is no evidence to suggest that probiotics will “cure” autism. Even if they are effective in reducing a particular set of autism-related symptoms, it is unlikely that treatment with probiotics can eventually be discontinued without symptomatic worsening.
While taking a probiotic everyday may improve functionality among those with autism, an every-day treatment is not the same thing as a cure. Furthermore, even if the treatment proved effective over a long-term, it is unlikely that it would reverse every single symptom of autism. Autism may have genetic underpinnings that cannot be reversed without simultaneous, targeted genetic reengineering (e.g. via Cas-9/CRISPR).
Think of the microbiome as being a single component of a larger system. Correcting dysbiosis in the gut may improve functionality among those with autism via the gut-brain axis, however, suggesting that the gut microbiome is the only underlying abnormality in autism is blatantly incorrect. It is likely that there are numerous genetic and neurological abnormalities that will persist even after “normalizing” the gut.
Effective without addressing root cause: Just because a treatment is effective for attenuating unwanted symptoms of a condition does not mean that it’s targeting the chief neurobiological underpinnings of autism. To illustrate this point, consider that individuals with depression may report significant mood enhancement after administering opioids. Just because the opioids alleviate a depressed mood does not mean that the underlying depression was caused by dysregulation or dysfunction of endorphins.
Similarly, just because a certain strain of bacteria effectively attenuates symptoms of autism spectrum disorder, does not mean that gut bacteria was necessarily the underlying cause (or even a partial cause) of the condition. It could be that by populating the gut with a specific strain of bacteria generates a therapeutic response by enhancing production of various neurotransmitters or decreasing cytokines. More complex, even if it were determined that gut-induced neurotransmitter and cytokine modulation reduce autism symptoms, it does not necessarily mean that neurotransmitters and cytokines were directly causing the condition.
Manipulating gut bacteria or altering any neurobiological processes may reduce autism symptoms by compensating for another deficiency that’s more implicated as a legitimate cause. In short, there’s a big difference between interventions that improve a condition and interventions that target its underlying cause(s). Avoid concluding that because probiotics decrease symptoms of autism that the dysbiosis is a cause – it may just be a connection.
Cause or consequence: In regards to the relationship between autism and gut bacteria, multiple possibilities warrant proposal. The first is that gut bacteria are implicated in causality of autism such as that they play some sort of role (no matter how significant) in autism onset and/or symptomatic exacerbation. Under the assumption that gut bacteria are associated with causing autism or exacerbating its symptoms, gut microflora modification would seem promising as a means of treatment.
The second possibility is that gut bacteria abnormalities are nothing more than a consequence of autism. It could be that certain genes and biomarkers associated with autism spectrum disorders give rise to altered populations of gut bacteria than neurotypical individuals. In theory, there may be zero causal influence of gut bacteria on autism development and/or autism symptoms.
Though likely inaccurate, one could go as far as to theorize that atypical microflora among persons with autism is some sort of an adaptive mechanism (unique to ASD) that enhances ability to function – rather than hinders it. It is also reasonable to hypothesize that degree of causality may differ based on the individual with ASD. In other words, gut bacteria may have a causal influence upon autism symptoms for some, a slight influence on symptoms for another subset, and zero influence on symptoms for others.
Animal model studies: Few animal model studies exist to support the idea that modulation of the gut microbiome may alleviate symptoms of autism. Hsiao et al. (2013) documented that probiotic B. fragilis appeared to reverse autism-like symptoms in an animal model of MIA-induced autism, however, no other studies have replicated these effects. Even if more animal model studies emerge demonstrating similar reductions in autism-related symptoms from probiotic strains, it would still remain unknown as to whether they’d correspondingly prove effective in humans.
Animal models of autism may not accurately depict the complexities of autism in humans. Even under the assumption that an animal model sufficiently reflected a specific subtype of autism in humans, this does not mean that effective gut microbiome-related treatments in the animal model would work equally as well in humans. As was mentioned earlier, the influence of the gut and/or gut bacteria on neurological function and behavior may be more prominent in animals than humans – making gut-microbial therapies comparatively less useful.
While the preliminary proof that probiotics may treat autism in animal models is exciting, these findings should not be extrapolated to humans. More work needs to be conducted in animal models and proof that the gut microbiota directly affects autism symptoms necessitates establishment in humans. Until legitimate human trials are conducted, the efficacy of gut bacteria modulation for autism remains unclear.
Do you know anyone modifying gut bacteria to treat autism?
If you [or someone you know] has experimented with gut bacteria modulation for the treatment of autism, share the experience in the comments section below. Mention the specific modality of gut bacteria modulation utilized, such as: antibiotics, probiotics/prebiotics, fecal transplants, helminths, fermented foods – or any combination. Also document whether the experimental gut modulation proved effective or useless by rating the perceived efficacy on a scale of 1 to 10 (with “10” being highly effective and “1” being ineffective).
To help others get a better understanding of the experience, provide details including: age of the person with ASD, frequency of bacterial modulation (e.g. daily), total duration of gut bacteria modulation (e.g. 2 weeks), and any concurrent interventions used for ASD (e.g. behavioral therapy, pharmaceutical drugs, etc.). If gut modification was perceived as effective for improving symptoms of ASD, yet other drugs were used simultaneously, how can you be sure that these improvements weren’t more related to the pharmaceuticals? Among those that found gut microbiome modulation to be effective for autism, report how long it took for noticeable changes to occur.
If symptomatic reduction was attained from gut microbe modulation, was this sustained over an extended duration or was it transient? For those that found microbiota modulation to be ineffective for ASD, did any symptoms become worse in the process? For those that conducted gut assays before modulation and/or after – what changes were noticed? Did any of these changes correlate with degree of overall behavioral change and/or specific behavioral change?
Overall, it is apparent that the gut microbiome may have a therapeutic a role in treating autism, however, this role may be subject to individual variation. Although coordination of randomized controlled trials (to test gut bacteria modulation as a treatment) is underway, favorable results from these trials will be needed before gut-based modulation can be recommended as a safe, evidence-based intervention for the management of ASD. At this time, the gut remains one piece of the autism “puzzle” that demands increased attention in forthcoming years.