**1. Introduction**

The function of the gut microbiome and the bidirectional communication between the gastrointestinal tract (GIT) and the brain is increasingly recognized in health and disease and disruption in its composition is not unique to the autistic pathology. However, the bidirectional communication between the gut and the brain, "the gut-brain/brain-gut axis" in autism has been relatively understudied. In general, this communication between gut and brain occurs through a direct neuronal pathway via the vagus nerve, the hormonal pathway of several hormones involved in the regulation of food intake, such as cholecystokinin (CCK), ghrelin, leptin and insulin, and by the immunological signaling pathway involving cytokines. Recent studies indicate that the vagus nerve is involved in immunomodulation as suggested by its ability to attenuate the production of proinflammatory cytokines in experimental models of inflammation (de Jonge and Ullola, 2007). Furthermore, the gut microbiome emerges as a major player not only in the maturation of GIT tissue and the gut brain axis but also in brain maturation, through its effect on both the immune and endocrine systems. Many toxins, toxicants, infectious agents, diet or stress, affect an individual's gut microbiome, which may be especially sensitive during the critical developmental period. Disruption of the developing microbiome may have profound consequences on the developing gut-brain axis including the brain as well as long-term effects on both the physical and psychological development.

This chapter attempts to bridge basic animal studies with clinical findings pertaining to the brain-gut and gut microbiome in autism, and includes a discussion of various strategies in managing autistic symptoms. The discussion also includes possible changes in the reward

properly cited.

© 2013 Sajdel-Sulkowska and Zabielski; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

system(s) in autism as a consequence of altered gut microbiome. It is possible that aberrant regulation of the reward system(s) underlines behavioral abnormalities in ASD that could be targeted by future microbiome-targeting therapies.

LPS exposure is one of the most acceptable models of infection; LPS is a sufficient trigger for cytokine production. LPS administered to the pregnant mother are transferred to the fetus through the placenta (Kohmura et al., 2000), and result in increased cytokines levels in the amniotic fluid (Urakabo et al., 2001; Gayle et al., 2004) and the fetal brain (Urakabo et al., 2001). Bacterial infection of lactating mothers also results in an increased level of cytokines in milk (Bannerman et al., 2004). Pretreatment of suckling rats with LPS (10 mg/kg-day x 5 days – the dose which produces weak, transient signs of endotoxemia) results in reduced pancreatic secretion and attenuates acute pancreatitis at adult age due to an increased concentration of the antioxidative enzyme SO in the pancreatic tissue, and to the modulation of cytokines production (Jaworek at al., 2007a, b). This late-effect of LPS is accompanied by dose-dependent reduction of mRNA signal for CCK1 receptor on pancreatic acini as well as modified expres‐ sion of acinar pro-apoptotic heat shock protein-60 (HSP60) and Bax proteins (Jaworek et al., 2007b, 2008). Early postnatal LPS exposure results in inceased expression of toll-like receptor 4 (TLR4) and caspase-3 and 9- proteins in the pancreatic tissue of adult rats (Bonior et al., 2012). These studies clearly indicate that perinatal exposure to LPS may have long lasting consequences on the GIT function, and as expected, though not studied in detail, on the brain-

Gut Microbiome and Brain-Gut Axis in Autism — Aberrant Development of Gut-Brain Communication…

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Perinatal maternal exposure of two strains of rats, SHR or SD rat dams to LPS (200 µg/kg body weight) resulted in increased rollover time, delayed startle, and decreased motor learning, with the effects being both strain- and sex-specific. LPS challenge also resulted in a trend towards an increase in cerebellar levels of 3-NT and a decrease in D2 activities in LPS-exposed pups (Xu et al., submitted). Several genes were affected by LPS. Notably Type 2 deiodinase 2 (DIO2) and brain derived neurotrophic factor (BDNF) expression was significantly elevated, while transthyretin (TTR) expression was decreased following LPS exposure. *In vitro*, acute exposure of cerebellar cultures to LPS resulted in a decreased size of the dendritic area of Purkinje cells. Our data thus demonstrate that perinatal infection impacts the developing cerebellum in a sex- and strain-dependent manner via mechanisms involving oxidative stress, enzymes involved in maintaining local TH homeostasis, and downstream gene expression. Interestingly, gene changes observed in the brains of LPS-exposed rats were distinct from TMassociated gene effect suggesting that the underlying macromolecular mechanism may be

Perinatal LPS exposure could have a profound effect on the gut microbiome similar to the effect of repeated treatment with antibiotics. Experiments in healthy mice have shown that disrupting the normal balance of the gut microbiome with antibiotics caused changes in mice behavior and was accompanied by changes in BDNF which has been linked to depression and anxiety (Bercik et al., 2011; Neufeld et al., 2011). Perinatal LPS exposure most likely affects gut motility as suggested by studies of irritable bowel syndrome (IBS), where mild bacterial overgrowth-associated motility disorder can be reversed by antimicrobials (Scarpignato and Pelosini, 1999). 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. Could gut dysbiosis be induced by recurrent infections? We have observed an increase in neurotrophin levels in the cerebella of rats exposed to LPS (Sajdel-Sulkowska et

gut axis.

trigger-specific.
