Obese pregnant mice exhibit changes in social behavior, oxytocin cells, synaptic plasticity, and the microorganism composition of the microbiota, but Lactobacillus reuteri could reverse these changes [46]. Because gut flora imbalance can increase the permeability of the intestinal mucosa, the metabolic products of gut microorganisms and certain cytokines can enter the circulation system and cause damage to the CNS, resulting in a delay in the early neurological development in child patients. Christensen used metabolomics to identify a large number of bacteria-derived metabolites that might be associated with ASD-related behaviors [47].

Adams found that the levels of SCFAs, which are very important for the development of neurological functions, in the stool samples of autistic children were lower than those of normal children [42]; similarly, the PPA levels were also reduced. The exposure of pregnant rats to PPA before giving birth impaired the social behavior of their newborn and adolescent rats [48]. Moreover, following PPA injection into the brain ventricles of adult rats, the rats exhibited a behavioral change similar to that of human ASD, and the injection also induced changes in ASD-related genes, including genes for neurotransmitters, nerve cell adhesion factors, and oxidative stress [18].

The bacterial metabolites, 4-ethyl-phenylsulfate and 3-(3-hydroxy phenyl)-3-hydroxypropionic acid, can cause mice to develop ASD-like symptoms [49, 50]. In addition, the serum lipopolysaccharide (LPS, cell wall components of gram-negative bacteria) levels are significantly higher in ASD patients than in normal subjects, and LPS has a clear association with social disorders [51]. Most children with ASD have a history of infection before age 2, and the frequency of their use of antibiotics is also significantly higher than that of normally developed children [52].

Antibiotics destroy the physiological balance of the inherent gut flora, and the newly colonized microorganisms produce neurotoxins, thereby inducing chronic diarrhea and ASD. For example, an abnormal increase in Clostridia and Bacteroidetes in the gut can promote gastrointestinal symptoms and ASD behaviors [18]. Therefore, both the imbalance of gut flora and the entry of excessive amounts of bacterial metabolites into the brain through the circulation are associated with the onset of ASD.