Main clinical trials investigating the effectiveness of probiotic supplementation in autism spectrum disorders.
Evidence is mounting to a possible link between autism spectrum disorder (ASD) and gut microbiota through the well-known gut-brain axis. Numerous mechanisms have been suggested including bacterial metabolites that could involve in chemokines, antimicrobial peptides, or neuropeptides production. Hence, numerous studies reported dysbiosis in autistic patients. Antibiotic courses are known to more or less improve neurobehavioral symptoms; however, it could lead to side effects. Modulation of the gut microbiota using pro- and/or prebiotics is therefore an appealing way of treatment. Fecal microbiota transfer is suggested to be an alternative new approach that could be promising. The aim of our chapter will be first to briefly review the current data concerning the possible role of the gut microbiota and its mechanisms in ASD and second to review the interest and limits of the pre- and probiotic supplementations in ASD treatment. Lastly, we will discuss on the potential interest of the microbiota transfer in ASD.
- autism spectrum disorder
- gut microbiota
- fecal microbiota transplantation
1. The human microbiota
1.1 Definition and functions
The term microbiota describes the entirety of all bacterial, viral, fungal, protozoal, and archaeal microorganisms living on almost every cutaneous and mucosal surface of the body . The gut microbiota (GM) inhabited by several trillion microorganisms that live in a symbiotic relationship with the host represents the most heavily colonized area of the human body. It is mainly dominated by organisms belonging to four major phyla that together account for more than 90% of the total bacterial population:
During recent decades, the development of high-throughput sequencing technology has hugely contributed to increased understanding of host-microbe interactions in health and disease . First, GM offers a barrier, protecting against external factors and proliferation of pathogenic microbes, through various mechanisms such as increasing mucus production, reinforcing intestinal epithelium permeability, and production of bacteriocins and antimicrobial peptides. GM is also involved in many fundamental metabolic functions such as synthesis of essential nutrients, hormones, vitamins, supply of energy from dietary sources otherwise unavailable to host and clearance of drugs, and toxins. Furthermore, GM is shown to be involved in the maturation of the host immune system, where specific strains such as
Lastly, very recently there is mounting evidence of the significant influence of GM in the modulation of brain activity and behavior across the so-called “microbiota-gut-brain axis (GBA)” . The GBA consists of bidirectional communication between the central nervous system (CNS), the enteric nervous system, and the gut linking emotional and cognitive centers of the brain with peripheral intestinal functions . The exact mechanisms of signal transmission within this network are not completely elucidated. The CNS asserts its role over the GM through influencing gut motility patterns, altering the equilibrium in the gut permeability, and modulating mucus secretion which are known to exert control over gut microbial composition . Conversely, the GM claims its influence over the CNS by regulating the hypothalamic-pituitary-adrenal axis and the production and turnover of cytokines and neurotransmitters. In addition to their effects on development and maturation of the enteric nervous system, these neuroactive metabolites can signal beyond the local gastrointestinal (GI) tract to the distant CNS potentially through signaling pathways that include the vagus nerve. Catecholamines can modulate important processes, including neurogenesis, myelination, microglia activation, brain plasticity, and blood-brain barrier permeability . Indeed, recent studies demonstrated that, under extreme conditions (e.g., in a germ-free environment or during antibiotic (ATB) treatment), GM absence is associated with several abnormalities in brain gene expression and neurophysiology . Interestingly, these aberrations are reversed after colonization with a conventional GM  or even specific bacterial species . Thus, the disruption of neural, endocrine, immune, and metabolic mechanisms that are involved in gut-CNS signaling seems to be involved in neuropsychiatric, neurobehavioral, neurodegenerative, and mental disorders.
1.2 Colonization of intestinal ecosystem in early life and its evolution
The composition of the GM varies widely from fetal life to adult age. Until recently, babies were believed to be born sterile and only populated by microbes on exposure to their first postdelivery environments. Recent research suggests that the process of microbial colonization of the GI tract could begin prenatally as acquisition of maternal microbiota might occur during intrauterine life via placenta . However, these findings are questionable, and recent data strongly suggest that bacteria isolated in utero are rather a contamination linked to the sampling methods than a specific microbiota . Neonates show unstable and highly dynamic intestinal microbiota with a low microbial diversity. First colonizers in healthy neonates are enterobacteria,
Interestingly, the brain of neonates grows to approximately 90% of its future adult volume until the age of two, and the formation of new synapses in the brain peaks during this period . Thus, the critical window for establishment of a healthy microbial composition falls into the same critical time window for brain development. Therefore, understanding GM establishment and its critical developmental window in early childhood is important because any perturbation during this period causes long-lasting effects on the development of the CNS. Being more flexible at infantile in contrast to the subsequent life, this temporal requirement may have important ramifications for potential preventative and therapeutic remediation strategies.
2. Autism spectrum disorder and the gut microbiota
2.1 Gut microbiota involved in the pathogenesis of autism spectrum disorders
Microbiota role in health and disease is as crucial as is complex. Alterations in normal commensal GM (known as dysbiosis) have been widely reported as a key contributor to the etiology and/or pathogenesis of various diseases including several neurobehavioral conditions, such as Parkinson’s disease, schizophrenia, Alzheimer’s disease, depression, anxiety, and most compellingly autism spectrum disorder (ASD) .
ASD refers to a group of heterogeneous and complex neurodevelopmental disorders characterized by impaired social interactions and reciprocal communication skills as well as restricted, repetitive, and stereotyped patterns of behavior, interests, and activities . Over the last decades, a steady increase of ASD prevalence has been reported worldwide. ASD is currently estimated to affect about 1 in every 68 children, with greater incidence found among boys (4:1) . To date, the etiology of ASD remains elusive, and it is thought to involve both genetic predisposition and different environmental triggers. Although several genetic factors are known to influence the etiology of different types of ASD, these only apply to a minor part of the autistic population. By estimate, the heritability accounts approximately for only 35–40% of the contributing elements and the remaining 60–65% results from the combination of prenatal, perinatal, and postnatal environmental factors as well as related medical disorders . Besides, along with significant psychiatric symptoms, ASD is often characterized by a number of medical comorbidities, the most prominent of which implicates the GI tract. Children with ASD experience significantly more GI symptoms than children without ASD occurring nearly at a fourfold greater rate . Symptoms include constipation, diarrhea, abdominal pain, bloating, gastroesophageal reflux, and food selectivity and seem to be strongly associated with the severity of ASD behaviors. Clinical abnormalities such as altered GI motility and increased gut permeability have also been reported . The cause of ASD-associated GI problems is difficult to ascertain, but it appears to partly relate to the excessive use of oral ATBs which can alter GM. Indeed, several studies report increased use of oral ATBs in children with ASD compared to neurotypical children. By eliminating beneficial indigenous GM, long-term ATB use destabilizes microbial community and creates favorable environment for colonization by potentially harmful (toxin-producing) microorganisms. Thus, considering the potential interactions between intestinal microbes and the CNS, loss of the protective commensal microbiota along with the overgrowth of pathogenic microorganisms is hypothesized to cause or contribute not only to GI dysfunction but also to ASD-related behavioral symptoms. All these findings have gained an insight into the influence of GM in ASD as potential mediator of risk factors.
2.2 Disruptions of microbial colonization in autism spectrum disorder
Imbalances in GM composition at the first stages of life and concomitant behavioral changes have been related to various prenatal and early-life events .
Mode of birth, whether through natural birthing process or Cesarean section (C-section), greatly affects the initial microbial settlement. Vaginally delivered babies harbor bacteria similar to their mothers’ fecal and vaginal microbiota with dominance of
In terms of gestational age at birth, preterm neonates (PT) are characterized by a delayed microbial colonization, missed or reduced acquisition of
Early feeding pattern also interferes greatly in the regulation of the intestinal colonization, with breastfed infants harboring a less diverse but more stable and uniform GM. Specific biological markers of healthy GM, including early colonization of
Additional modifications are induced by exposure to drugs either directly or indirectly from the mother. ATB-induced shifts in the gut microbial composition can persist several months after cessation of the treatment, inducing long-term dysbiosis . An association between long-term ATB use, hospitalization, abdominal discomfort, and the onset of ASD symptoms has been shown . Likewise, a population-based cohort study revealed the use of various ATBs during pregnancy as a potential risk factor for ASD . Using animal models, periconceptional exposure to nonabsorbable ATB was shown to induce variations in GM composition in offspring associated to reduction in social interactions and increased anxiety . Other drugs lead to similar observations. In mice, modeling maternal exposure to valproic acid, an antiepileptic drug induced lasting changes in the offspring GM composition, which was associated with neuroinflammation, abnormal GI physiology, and ASD-like behavioral abnormalities . All these observations point to the common hypothesis that early exposure to drugs can modify GM composition transiently or permanently, possibly affecting the severity of non-GI-related symptoms of ASD patients.
Apart from exposition to drugs, another emerging explanation for the difference in GM between ASD and healthy individuals is immunological. Maternal infection during pregnancy was shown to alter microbial composition and is a primary environmental risk factor for ASD . GM alterations (especially in the bacterial classes clostridia and bacteroidia) and higher gut permeability are seen in a maternal immune activation model of ASD . Male progenies of pregnant mice injected during pregnancy with a viral mimetic develop abnormal communication and sociability, repetitive behaviors, and increased anxiety. Another well-established brain-gut connection is the role of stress and its mediators in altering the GM. Maternal separation is a typical model of early-life stress employed in animal studies. In rats, early maternal separation does not only lead to a dysbiotic state of the GM that persists into adulthood but also results in functional GI symptoms and long-term cognitive and behavioral deficits . Likewise, psychological stress was shown to alter colonic mucosa-associated microbiota, with significant decrease in abundance of health-benefit bacteria, such as
Further, metals and other contaminants have also been identified to increase the risk for ASD knowing their capacity to interfere with the composition and metabolic activity of the GM. In fact, results of a study evaluating the interaction between environmental chemicals and GI microorganisms suggest that alterations in the levels of seven elements (Pb, As, Cu, Zn, Mg, Ca, and Hg) and nine genera of GM (
Taken together, ASD is thought to be a result of a combination of different interacting mechanisms that each contributes a fraction of disease risk.
2.3 Microbial and metabolic dysregulations in autism spectrum disorder
Previously, much research effort on ASD focused on genetic, neurological, and behavioral aspects of disease. Recently, the evidence of the impact of dysbiosis on CNS raised interest in the analysis of the potential link between GM and ASD. So far, various studies demonstrated that children with ASD exhibit different compositions of GM compared to healthy controls [36, 37, 38, 39, 40, 41, 42, 43]. Moreover, exciting work with animal models widely deepened the possible role of gut microorganisms in the pathogenesis of such disorders [44, 45]. These evidences have led to the hypothesis that GM alteration is not only associated with ASD but may play a key role in the exacerbation of ASD symptoms and/or its pathogenesis, at least for some ASD subgroups . Overall, most studies agree that GM composition is distinctive in ASD compared to healthy controls, but results are often inconsistent as to the nature and/or extent of GI bacterial community differences, failing to generate a coherent picture. Microbiota analyses reported tenfold higher counts of pathogenic
Thus, the existence of a GI dysbiosis as an actor in the ASD etiopathogenesis remains a controversial topic. Indeed, other studies comparing children with ASD and their healthy siblings reported no meaningful difference in GM composition [53, 54]. According to the authors, other explanations for the GI dysfunction in this population should be considered, including elevated levels of anxiety and self-restricted diets. Therefore, given the higher incidence of ATB usage and often different diets compared with neurotypical individuals, both of which can alter the composition of the GM, such data should be interpreted with care.
Dysbiosis in ASD involves not only bacterial species but also yeasts, as reported in recent studies [40, 41, 55, 56]. One culture-based study showed significant presence of
Moreover, correlations between ASD and GI disturbances may not alone be driven by the composition of the GM but also by differences in its functionality, such as the bacterial metabolites that could play a role in the GBA. Indeed, overproduction of bacterial metabolites (e.g., p-cresol) and SCFA (e.g., propionic acid) is frequently described in infants with ASD [30, 49, 57]. These compounds induce intracellular signaling and modulate host gene expression related to neurotransmission systems and behavior . P-cresol seems to negatively affect the homeostasis of colonic epithelial cells in children with ASD. When tested
Dysbiosis can also affect the functional intestinal barrier that can lead to an alteration in the intestinal permeability referred to as “leaky gut” state, a fundamental factor underlying the relationships between ASD and the GM . Indeed, several reports show increased gut permeability in ASD patients . Disrupted barrier function facilitates the translocation of bacterial metabolites from the gut into the bloodstream to possibly reach the otherwise sterile CNS inducing directly inflammatory reactions. One important bacterial component is the lipopolysaccharide (LPS) that was shown to increase the activity of areas deputed to the emotionalism control such as amygdale . It also leads to the production of inflammatory cytokines that critically alter the physiological brain activity, modulating the neuropeptides synthesis . Moreover, it has been demonstrated that the administration of low doses of LPS in healthy subject is associated to increased pro-inflammatory cytokines and plasma norepinephrine, with higher depression rates, fatigue, and apathy . Consistent with this, a study showed LPS serum levels were significantly higher in autistic patients compared to heath individuals and correlated with socialization scores in an inverse and independent manner .
3. Restoring the gut ecosystem: therapeutic outlooks for autism spectrum disorder
Despite increased ASD diagnoses, there remains no US Food and Drug Administration (FDA)-approved pharmaceutical treatment to alleviate core symptoms of ASD . Currently, recommended management strategies essentially involve rehabilitation, educational interventions, speech therapies, psychiatric medications, and specific treatments for individual comorbidities , all with limited success . Considered the emerging role of gut dysbiosis in ASD, interest in rebalancing human GM as a possible therapeutic approach is growing . Indeed, targeting the GM in children with ASD through administration of ATBs, pro- and prebiotics, and nutritional approaches or, more recently, through fecal microbiota transplantation (FMT) has been shown to improve not only GI disturbances but also behavioral and neurophysiological abnormalities associated with ASD [18, 24].
ATB therapy is used for the management of ASD and is routinely prescribed to treat ASD symptoms associated with several underlying disorders like pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) . Short-term administration of vancomycin was shown to provide significant improvement in both GI and behavioral disturbances in a subset of children with ASD . Unfortunately, this attempt had only partial success since children relapsed, and benefits waned upon treatment termination. As vancomycin is a poorly absorbed ATB known to destroy Gram-positive anaerobes, observed improvement is believed to be the consequence of temporary elimination of toxin-producing clostridia population. Hence, symptomatic relapse was attributed to the spore-forming capacity of these bacteria, and spores resistant to ATB would later germinate into vegetative forms once treatment has stopped .
Children with ASD, particularly those with GI disease, are sometimes treated with antifungal agents, as they may have increased incidence of fungal infection. Despite the lack of evidence of fungal overgrowth in children with ASD, parents find that antifungal therapies can often be beneficial and may be a useful adjuvant for the treatments of ASD .
Thus, it is possible to speculate that anti-infectives, through modulation of GM, should be able to influence symptoms and expression of psychiatric disorders. However, ATB resistance (and to some extent antifungal resistance) is a major public health concern, making the safety of ATB/antifungal treatments ethically problematic, if they do prove to be beneficial. Therefore, extensive and prolonged use of ATB/antifungal treatments may not be advisable as a long-term therapy for ASD.
One of the most nutritional popular approaches selectively modulating the GM is probiotic supplementation due to ease of use, wide availability, and good safety profile. Probiotics are defined as live microorganisms that when administered in adequate amounts confer a health benefit to the host . The main species used are one
Hence, because ASD patients present GI dysbiosis, which may exacerbate the disease, these patients could benefit from GM modulation through probiotic supplementation. Conversely, other investigations have shown that probiotic administration could act independently from GM alterations by inducing a stabilization of the microbial communities making them less susceptible to perturbations from stressors such as ATBs, poor diet, and psychological stress . Moreover, probiotics may correct the imbalance in the activity of the GM without changing its composition, via their metabolites released in the gut lumen or by potentially correcting the overproduction of harmful and underproduction of beneficial gut bacterial products . The increased intestinal permeability in ASD may also be ameliorated by probiotics which are able to enhance the mucosal barrier. This supports the concept that probiotics can provide protective effect by preventing the metabolites of exogenous toxic substances from leaving the gut and entering the bloodstream to affect the brain . Probiotics may therefore maintain or improve gut barrier integrity and aid in ASD rehabilitation by promoting “leaky gut” healing. Lastly, given the multiple findings of aberrant immune activation and higher levels of gut inflammation in a subset of individuals with ASD, that a major part of the immune system is concentrated in/around the intestinal mucosa, and that the GM plays an important role in the maturation and the regulation of the immune response, another mechanism of action of probiotics may be on the immune system . Probiotics can downregulate gut and CNS inflammatory pathways in a species- and strain-specific manner , by promoting the production of regulatory T cells, diminishing the levels of LPS, providing tolerogenic signals, and boosting the brain-derived neurotrophic factor (BDNF). BDNF is a protein that promotes the survival of existent neurons in the developing brain, fosters the growth and differentiation of new neurons, and regulates the formation and plasticity of synaptic connections, thereby playing an essential role in the normal neurological development . Impairment in BDNF signaling in early developmental phases is thought to be related to CNS abnormalities, the most severe forms of ASD, as well as intellectual disability . Probiotics have been shown also to modulate the intestinal immune system by the production of secreted factors and metabolites that affect growth and function of intestinal epithelial and immune cells . Moreover, probiotic immunomodulation may occur through inhibiting the production of pro-inflammatory cytokines such as IL-12, TNF-α, and INF-α or increase the expression of anti-inflammatory mediators such as IL-10 and transforming growth factor beta (β-TFGF). Thus, by alleviating gut inflammation and suppressing dysregulated immune functions, probiotic supplementation may be effective for improving both gut microbial and behavioral problems in ASD. Lastly, probiotics could act via the vagus nerve-mediated GBA to influence neurotransmission and mood states . They can exert central actions by influencing several neuroactive metabolites such as gamma-aminobutyric acid (GABA) and serotonin which are also associated with neuropsychiatric disorders [87, 88]. Consequently, administration of probiotics regulates the behavior in a way that significantly reduces anxiety, depression, and stress and promotes positive emotional changes. Therefore, probiotic administration might be a useful new therapeutic option to restore normal GM, reduce inflammation, restore epithelial barrier function, and possibly improve some behavioral symptoms associated with ASD.
A role for probiotics has been suggested for children with ASD as well, as preliminary findings from experimental animals studies provide some evidence that administration of selected probiotics may be effective in reducing neurologic signs and symptoms associated with gut dysbiosis. In a summary of studies to date, several probiotic strains, i.e.,
To date only few studies explored the effects of probiotics on ASD clinical features in humans. Table 1 synthesizes available evidence on the efficacy and safety of probiotic supplementation as an adjunctive treatment for ASD [49, 51, 73, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106]. In these studies, probiotic interventions varied across all of the trials. Concentrations of the probiotic strains administered ranged from 107 to 1010 colony-forming units (CFU)/dose, and their usage by recipients differed. Strains were administered alone or as mixed strains with or without other additives (immunomodulators  and ATBs ). In summary, despite the variability in species, strains, dosages, and duration utilized, all studies pointed toward a similar trend of improvement in both caregiver-reported ASD and GI symptoms after probiotic therapies. Accordingly, a recent survey found that almost 20% of physicians treating ASD patients encourage probiotic use, and almost 60% accept their use . In a recent study, the positive effect of probiotic treatment was represented not only by the ability to consistently normalize the
|Authors||Study design||Diagnosis||Probiotic therapy|
|Blades M., 2000, UK ||Case report of a 6 y with ASD||Not reported||Strain and dosage not provided Administration for 2 mo|
|Sandler et al., 2000, USA ||Open-label with self-control study|
11 ASD subjects
(10 M, 3.5–7 y)
QD for 4 wk
|Parracho et al., 2010, UK ||Randomized, double-blind, PBO-controlled, cross overdesigned feeding study|
17 ASD subjects
(14 M, 4–16 y)
4.5 × 1010 CFU
QD for 3 wk
|Ray et al., 2010, USA ||Open-label with self-control study|
10 ASD subjects
(Gender not reported, 4–15 y)
Dosage not provided
BID for 21 d
|Adams et al., 2011 USA ||Retrospective case cohort study|
57 ASD subjects:
19 PS vs. 38 no PS
(50 M, 3–9 y)
|ATEC||Strain and dosage not provided|
|Kałzuna-Czaplinska et al., 2012, Poland ||Open-label with self-control study|
22 ASD subjects
(20 M, 4–10 y)
5 × 109 CFU/g
BID for 2 mo
|West et al., 2013, USA ||Open-label with self-control study|
33 ASD subjects
(Gender not reported, 3–16 y)
1 × 1010 CFU/capsule
One capsule TID for 6 mo
|Partty et al., 2015, Finland ||Randomized, double-blind, PBO-controlled prospective follow-up study 75 ASD subjects|
40 PS (24 M, 13 y) vs. 35 PBO
(16 M, 13 y)
1 × 1010 CFU
QD for 6 mo
|Tomova et al., 2015, Slovakia ||Case control cohort study|
10 ASD subjects (9 M, 2–9 y)
9 non-ASD siblings (7 M, 5–17 y)
10 non-ASD controls (10 M; 2–11 y)
|ICD-10||3 strains of |
Dosage not provided
One capsule TID for 4 mo
|Grossi et al., 2016, Italy ||Case report of a 12 y boy with ASD||DSM-V + ADOS-2|
9 × 1010 CFU/g
8 × 1010 CFU/g
20 × 1010 CFU/g
QD for 4 months
|Shaaban et al., 2017, Egypt ||Prospective, open-label cohort study|
30 ASD subjects (19 M, 5–9 y)
30 age/sex-matched non-ASD siblings
|DSM-V + ADOS + ADI-R|
10 × 107 CFU/g
5 g QD for 3 mo
|Liu et al., 2019, Taiwan ||A double-blind, randomized, PBO-controlled, parallel feeding study|
71 ASD subjects:
36 PS (36 M, 7–15 y) vs. 35 PBO
(35 M, 7–15 y)
|DSM-V + ADI-R|
3 × 1010 CFU/capsule
1 capsule QD for 4 wk
|Kobliner et al., 2019, USA ||Case report of a 16 y child with ASD||Not reported|
3 × 109 CFU/capsule
Week 1: 6 capsules QD. Weekly increases reaching a final dose of 12 capsules BID. After 3 mo, weaning down to 3 capsules BID
|Sanctuary et al., 2019, USA ||Double-blind, crossover, randomized clinical trial|
8 ASD subjects
(7 M, 4–11 y)
2 × 1010 CFU
QD for 5 wk
At last, though probiotics are considered a relatively risk-free option for individuals with ASD, the current literature cannot confidently state their safety as there is a paucity of systematic reporting of adverse events. However, among the studies that monitored side effects, the reported ones (bloating, skin rash, worsening constipation or diarrhea, and weight loss) appear to be mild, transient, and infrequent [96, 99, 102, 105]. Conclusively, due to the large heterogeneity between trials, studies provide only suggestive but not conclusive evidence regarding the efficacy of probiotics on GI and behavioral symptoms among ASD patients. Thus, future probiotic research holds hopes for discovering the optimal species, strains, strength, and length of probiotic therapy for the particular comorbidity profile of different individuals with ASD.
The International Scientific Association for Probiotics and Prebiotics (ISAPP) defines prebiotics as substrates “selectively utilized by host microorganisms, conferring a health benefit” . Such benefits are not limited to gut homeostasis but can extend elsewhere in the organism, leading to improvements of the immune, metabolic, endocrine, or nervous functions. Fructans, comprising fructooligosaccharides (FOS) and inulin, and galactans (galactooligosaccharides (GOS)) are the most recognized prebiotics. Differently from most dietary fibers, which promote growth of a wide variety of microorganisms, prebiotics display a selective effect, being a substrate for beneficial strains only, while excluding metabolism by pathogenic bacteria . Thus, the main reason for a potential influence of prebiotics on the treatment of ASD concerns the selective enrichment of
3.4 Fecal microbiota transplantation
The process of FMT consists in the delivery of feces from a healthy donor to a patient with gut dysbiosis, with the aim of replacing an impaired microbiota with a healthy one. Unlike probiotics, where only a restricted number of bacterial species are supplemented, FMT allows the transplantation of thousands of different components of the healthy GM. In fact, FMT is one of the most effective techniques recently considered in treating recurrent ATB-refractory
3.5 Dietary interventions
A number of nutrition intervention strategies have been explored to treat behavioral symptoms and comorbid GI distress , but evidence is still relatively weak and sometimes inconsistent, as in the case with gluten-free and/or casein-free (GF/CF) diet and ketogenic diet (KD).
Various observational studies reported alleviation of GI problems and/or significant behavioral improvements in ASD children following an extended GF/CF diet [118, 119]. However, elimination diets for ASD patients should not be recommended as standard treatment and only be considered after reaching a diagnosis of an adverse food reaction since dietary restrictions are likely to limit variety of food intake and provoke nutritional deficiencies in developing children . Moreover, GF/CF diet can also exacerbate the already disrupted gut microbial composition in ASD by reducing beneficial and increasing opportunistic bacteria .
Improvements in neurobehavioral symptoms have also been reported in ASD as a result of following a KD. KD is a high-fat and low-carbohydrate diet that, due to its beneficial effects on GM composition, has been suggested as a treatment for ASD. In humans, administration of KD to individuals with ASD results in increased sociability, improved communication, and decreased repetitive comportments . In animal models, both improvement of behavioral symptoms and compositional remodeling of GM after KD have been described [123, 124]. However, KD causes an “antimicrobial”-like effect by significantly decreasing the total gut microbial abundance. Moreover, it results in an increase in clostridia species and may lead to adverse effects such as dehydration . So, side effects and increase in harmful bacteria in the GM associated with limited number of positive results constitute insufficient evidence for the practicability of KD as a treatment for ASD.
4. Conclusion and perspectives
In the last few years, the importance of GM in the maintenance of physiological state into the CNS is supported by several studies that have shown qualitative and quantitative alterations of the intestinal flora in a number of neuropsychiatric diseases. Within neurobehavioral disorders, it seems that at least a subset of the cases comprising ASD are connected to, and perhaps dependent on, the health and well-being of the GM. In recent years the increased prevalence of ASD, along with the evidence of a significant link between ASD and GI disturbances, raised a special interest in exploring the reciprocal influences between GM and brain under the so-called GBA. Alterations of GM composition in children with ASD presented in the literature mainly consist in reduced levels of
|ASD||autism spectrum disorders|
|BDNF||brain-derived neurotrophic factor|
|CNS||central nervous system|
|FDA||Food and Drug Administration|
|FMT||fecal microbiota transplantation|
|GF/CF||gluten-free and/or casein-free|
|ISAPP||International Scientific Association for Probiotics and Prebiotics|
|MTT||microbiota transfer therapy|
|PANDAS||pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections|
|PANS||pediatric acute-onset neuropsychiatric syndrome|
|SCFA||short-chain fatty acids|
|TNF||tumor necrosis factor|
|TFGF||transforming growth factor|