**7. Possible connection of gut microbiome and behavior; microbiome and behavioral abnormalities in ASD**

The intestinal microbiome participates in the development of the HPA axis (Sudo et al., 2004) and is critical to the development of appropriate stress response later in life, which occurs during a narrow, critical developmental window. This process involves both the regulation of the levels of brain derived neurotrophic factor (BDNF) and NMDA receptors (Sudo et al., 2004). The microbiome also plays an important role in anxiety-like behavior (Messaoudi et al., 2011), depressive behaviors (Neufield et al., 2011; Messaoudi et al., 2011), but the effects are diminished in vagatomized animals, suggesting either the direct communication between the bacteria and the brain (Bravo et al., 2011) or through the brain-gut axis. The latter possibility is an indirect action of bacteria on an afferent vagal pathway via gut immune, endocrine and enteric nervous system (ENS) controlling mechanisms.

Animal studies have also shown that stress can change the composition of the microbiome, where the changes are associated with increased vulnerability to inflammatory stimuli in the GIT (Gareau et al., 2006); here the microbiome plays an important role in memory dysfunction (Gareau et al., 2011). Stress is known to inhibit gut contraction, one of the crucial defense strategies against bacterial colonization of gut mucosa. Early psychological trauma of maternal separation resulted in persistent mucosal barrier dysfunction in neonatal rats, including host defense to luminal bacteria, by mechanisms involving peripheral CRH receptors (Gareau et al., 2006).

Oral antibiotics disrupt the microbiome and favor environment for opportunistic bacteria. *Clostridium tetani*, an anaerobic bacillus produces a potent neurotoxin, tetanus neurotoxin (TeNT) that is transported by the vagus nerve from the GI to the CNS. In the brain TeNT disrupts the release of neurotransmitters by the proteolytic cleavage of synaptobrevin, a synaptic vesicle membrane protein. This inhibition may be related to a variety of behavioral deficits characteristic of autism. Some children with autism treated with anti-clostridia antibiotics have shown a reduction in stereotyped behavior (Bolte, 1998).
