Figure 3.

The endocrine (systemic) pathway and the neuronal pathway. (A) The HN axis and the HPA axis play an important role in the endocrine (systemic) pathway. The neuropeptide oxytocin acts as an important component of the HN axis, modulates the interplay within the serotonergic system in the nucleus accumbens and the marginal activity in the amygdala, thus regulating social functions. Along the HPA axis, peripheral cortisol levels have been found to be significantly higher in patients with ASD and bacterial species, such as Enterococcus faecalis, inhibit the elevated glucocorticoid levels after social stress and promote social behaviors in mice, indicating that the gut microbiota is capable of influencing HPA axis. (B) The gut microbiota can produce neuroactive molecules (e.g., 5AV, taurine, and 4EPS) directly and these molecules have diverse effects on neurodevelopment processes (i.e., myelination, oligodendrocytes maturation). The gut microbiota also regulates the production of 5-HT in ECCs. However, metabolites like 5-HT cannot across the blood–brain barrier without the vagus nerve. Microbial-derived metabolites and other substances not only interact with the vagus nerve but also impact the ENS and the intestinal mechanosensory. The vagus nerve is an important agent between the endocrine (systemic) pathway and the neuronal pathway.