Autism Spectrum Disorder (ASD) is a highly heterogeneous and complex disorder characterized by two major groups of core symptoms: (1) persistent deficits in social communication and interaction and (2) restricted and repetitive patterns of behavior, interests, or activities ^{[1][2][3][4][5]}[1,2,3,4,5]. Current epidemiology statistics indicate that the disorder affects approximately 1 in every 160 children worldwide [6].

Characteristic deficits are often associated with a range of gastrointestinal symptoms such as abdominal pain, diarrhea, or constipation ^[7][8][7,8]. Several studies have found that both the composition of the intestinal microbiota and metabolic activities may be altered in individuals with the disorder ASD ^[9][10][9,10]. Therefore, several authors concur that disruptions in the microbiota and intestinal microbiome, i.e., the collection of microorganisms present in the human gastrointestinal tract and their respective genomes ^[3][11][3,11], could trigger many of the gastrointestinal issues experienced by children with ASD, as well as exacerbate some of the core symptoms of the disorder ^[12][13][12,13].

Microbial colonization begins in infancy via the acquisition of maternal microbiota during vaginal delivery [3]. Subsequently, beneficial microorganisms feed on breast milk, which has a high content of oligosaccharides [14]. Similarly, the composition of the microbiota in the early years may be subject to alterations influenced by the delivery method, hygiene habits, and feeding practices and routines. Among these factors, formula feeding has a particularly significant impact [3].

It has been shown that the intestinal microbiota affects the function and development of the immune, metabolic, and nervous systems. Regarding the immune and metabolic systems, intestinal microbiota and its metabolites impact host physiology by regulating the function of the intestinal barrier, redox and mitochondrial metabolism, and mucosal inflammatory response via the regulation of intestinal lymphocytes that provide resistance against potential pathogens ^{[15][16][17][18][19][20]}[15,16,17,18,19,20]. On the other hand, intestinal microbiota can influence neurochemistry, function, gene expression, and the development of the central nervous system (CNS) through the gut–brain axis, which represents a bidirectional link between the cognitive and emotional functions of the CNS and peripheral intestinal function ^{[15][21][22][23]}[15,21,22,23]. It is worth noting that the genus Bifidobacterium can metabolize gamma-aminobutyric acid (GABA), Lactobacillus spp. can metabolize acetylcholine, Bacillus spp. and Serratia spp., dopamine, and Escherichia spp. and Saccharomyces spp., noradrenaline. All these neurotransmitters are essential for the proper functioning of the nervous system as they can enter circulation and directly affect neural processes throughout the body, including the brain ^[3][24][3,24]. Additionally, intestinal proinflammatory cytokines, particularly TNF and IL-6, can have an impact on the brain because they make the blood–brain barrier (BBB) more permeable, allowing peripheral immune cells to enter the brain and stimulating brain cells to produce additional proinflammatory mediators ^[25][26][25,26].

All of this has led to the hypothesis that the development of symptoms related to ASD may be influenced by the disturbance of the gut–brain–microbiota axis caused by changes in the intestinal microbiota. ASD is a complex disorder characterized by inflammatory processes, high oxidative stress, and gastrointestinal disturbances. These issues may be attributed to changes in the intestinal microbiome, resulting in microbial dysbiosis in children with ASD. Polyphenols have demonstrated sufficient antioxidant and anti-inflammatory capacity to counteract ASD symptoms.

The Firmicutes (40–60%) and Bacteroidetes (20–40%) are the two major phyla of bacteria in the healthy human intestinal flora, followed by Proteobacteria, Actinomycetes, Clostridium spp., and Verruciformis ^[3][27][3,27]. However, compared to a healthy population, increased levels of bacterial genera such as Clostridium, Desulfovibrio, and Ruminococcus have been observed ^[15][28][15,28], in ASD, along with species that synthesize BCAA such as Bacteroides vulgatus and Prevotella copri. On the other hand, lower quantities of Bacteroides fragilis, Akkermansia muciniphila, Bifidobacterium spp., and Enterococcus spp. Have been found ^[29][30][29,30]. Additionally, the ratio of the Escherichia/Shigella genera is altered, as Shigella spp. is present at higher levels, while Escherichia coli is decreased [31].

It should be noted that, despite the consensus regarding these alterations, it is important to consider that not all studies quantifying the microbiota in ASD analyze the same species or genera, leading to some heterogeneity in the results, and various studies emphasize the relationship between the composition of the human intestinal microbiota and the individual’s diet, which can lead to variations in composition depending on the region where the analyses were conducted [32]. In fact, a study in the United States highlighted that children with ASD had lower levels of Bifidobacterium spp. And Prevotella spp., but higher levels of Lactobacillus spp., compared to healthy children [33]. Another study in China described that children with ASD had higher levels of the Actinobacteria and Proteobacteria phyla than the control group [34].

Furthermore, the review conducted by Ho et al. (2020) concluded that although the results of different studies are not entirely consistent [35], some articles indicate that individuals with ASD exhibit a decrease in the percentage of the phylum Bacteroidetes ^[10][35][10,35] or no significant difference ^[31][36][37][31,36,37] compared to the control group of healthy individuals. This could be due to the fact that within the phylum Bacteroidetes, there are bacteria of the genus Bacteroides spp. that are increased, such as B. vulgatus, while others are decreased, such as B. fragilis, potentially leading to a compensatory effect that results in an unclear profile [30].

The genus Prevotella presents a more variable pattern. In the aforementioned review, the authors noted a lower relative abundance of Prevotella spp. in children diagnosed with ASD compared to the control group. However, multiple studies indicate an elevated prevalence of Prevotella spp. in children with ASD ^{[15][30][31][38]}[15,30,31,38], and this variability could be due to dietary factors. Filippo et al. (2010) compared the composition of Prevotella spp. in the microbiota of children following European and African diets and observed a significant increase in Prevotella spp. In the microbiota of African children, likely due to their consumption of a grain-rich diet [39].

Finally, to establish a correlation between gastrointestinal issues and behavioral problems with the microbiota, the high growth rates of Clostridium histolyticum, Clostridium difficile, Clostridium perfringens, and Sutterella spp., the alteration in the Escherichia/Shigella genera ratio, and the decreased Bacteroidetes/Firmicutes phylum ratio have been identified as factors associated with gastrointestinal problems. Furthermore, the relative abundance of Desulfovibrio spp., Clostridium spp., and Bacteroides vulgatus has been linked to behavioral disorders [40].