**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 *Clostridium difficile* infection [113] and has shown varying levels of success in patients with other GI diseases such as irritable bower syndrome [114], and non-GI diseases like autoimmune disorders, obesity, and insulin sensitivity [115]. Given the growing evidence for a role of GM disruption and GI symptoms in ASD, clinical trials are under way using FMT to treat children with ASD. In a recent open-label study, ASD children with chronic GI problems underwent a modified FMT protocol, termed microbiota transfer therapy (MTT), consisting of a 2-week vancomycin treatment followed by bowel cleansing, and administration of a high dose of standardized human gut microbiota [24]. After this 10-week treatment, MTT induced an 80% improvement of GI function and a slow but steady improvement in behavioral ASD scoring, both of them maintained at least 8 weeks after treatment stopped. In line with previous reports, few adverse events were described, and the most commonly reported include mild diarrhea, abdominal tenderness, flatulence, and nausea thus confirming treatment safety and tolerability in autistic patients. Coincident with these clinical improvements, FMT confirmed its ability in modifying GM composition by significantly increasing bacterial diversity and the relative abundance of *Bifidobacterium* and *Prevotella* [24]. Two years after this original clinical trial was completed, re-evaluation of the participants showed that GI benefits were mostly maintained and ASD symptoms were reported to have improved significantly since the end of treatment [116]. Changes in the GM also persisted for 2 years. According to these encouraging observations, intensive FMT intervention can be considered an effective and well-tolerated promising approach in treating children with ASD who have GI problems. However, the safety of FMT should be considered as it carries many risks including aspiration and transmission of opportunistic pathogens to recipients. Therefore, major efforts at refinement are necessary before FMT can be adopted widely.

### **3.5 Dietary interventions**

A number of nutrition intervention strategies have been explored to treat behavioral symptoms and comorbid GI distress [117], 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).

**183**

**Abbreviations**

4EPS 4-ethylphenylsulfate ASD autism spectrum disorders

BDNF brain-derived neurotrophic factor

ATB antibiotic

*Could Gut Modulation through Probiotic Supplementation Be Beneficial in Autism Spectrum…*

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 [120]. Moreover, GF/CF diet can also exacerbate the already disrupted gut microbial composition in

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 [122]. 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 [125]. 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.

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 *Bifidobacterium* and increased levels of *Clostridium* spp. and *Desulfovibrio*. However, the available data do not allow to define a characteristic and unique profile of ASD. If dysbiosis is confirmed to be a precipitating factor in ASD, then several potential therapeutic approaches ranging from ATBs, probiotics, prebiotics, up to FMT and other nutritional strategies may be useful adjuvant treatments in these patients. Future research, together with the application of state-of-the-art "omics" methods, could address possible unequivocal microbial biomarkers for ASD. Further, as dysbiosis contributes to a significant subset of ASD, specific identification of ASD endophenotypes will allow patient stratification and personalized interventions. Addressing microbial processes could be the aim of the next pharmacological therapy of ASD that will potentially help to alleviate the burden of this disorder for the millions of people affected worldwide.

ASD by reducing beneficial and increasing opportunistic bacteria [121].

*DOI: http://dx.doi.org/10.5772/intechopen.89375*

**4. Conclusion and perspectives**

*Could Gut Modulation through Probiotic Supplementation Be Beneficial in Autism Spectrum… DOI: http://dx.doi.org/10.5772/intechopen.89375*

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 [120]. Moreover, GF/CF diet can also exacerbate the already disrupted gut microbial composition in ASD by reducing beneficial and increasing opportunistic bacteria [121].

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 [122]. 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 [125]. 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.
