**8. The role of the reward system in gut-brain communication, the interaction between food-reward and social-reward systems; altered gutmicrobiome regulation of the reward loop in autism?**

Autism is characterized by both severe deficits in social interaction and communication and significant eating difficulties with a highly restricted range of food choices (Williams et al., 2000). It seems logical to hypothesize that altered composition of the gut microbiome under a "leaky gut" condition in autism interferes with the normal activity of the reward circuitry including both social and feeding behavior, as illustrated in Fig. 3. In support of this hypothesis are the neuroimaging, electrophysiological and neurochemical data suggesting a disruption in reward seeking tendencies in ASD, and especially in social contexts (Kohls et al., 2012). It has been proposed that this disruption is caused by abnormalities of the dopaminergicoxytocinergic "wanting circuitry" that includes the ventral striatum, amygdale, and the ventromedial prefrontal cortex (Kohls et al., 2012). Indeed, Individuals with ASD are charac‐ terized by low responsiveness to social rewards (Dawson et al., 2005; Schultz, 2005; Neuhaus et al, 2010). Recent studies of the left amygdala and orbito-frontal cortex, which are the main components of the social brain, showed neuronal dysfunctions in these structures in autism (Mori et al, 2012). Furthermore, brain levels of serotonin, the "happy hormone" are regulated by gut bacteria as evidenced by studies involving germ-free animals (Clarke et al., 2012). Abnormalities in blood serotonin levels are consistently altered in a subset of children with ASD.

cortex and ventral anterior cingulated cortex with the central relay located in ventral striatum

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

http://dx.doi.org/10.5772/55425

73

It is interesting, that the ventral striatum is associated with both social-reward and food-reward circuitry (Adam et al., 2007). Although it is generally assumed that the two centers are separate, the observation of altered sucrose preference and positive correlation with ventral striatum dopamine levels under conditions of social isolation stress in perinatal rats lends support to the speculation of inter-connectivity of the two centers (Brenes and Fornaguera, 2008).

The "leaky gut" during development may be potentially more vulnerable to environmental insults than the normally developing GIT. Consequently, alterations in the gut microbiome may play an important role in autistic pathology. Evidence is growing that points to an early developmental abnormality in establishing GIT and innate microbial milieu. The gut micro‐ biome, regulated by both intrinsic and extrinsic factors, may be further jeopardized by recurrent infections and/or recurrent use of antibiotics. A developmentally abnormal gut microbiome may in turn affect both the gut-brain axis and brain development and contribute to the etiology of ASD. Abnormalities in the gut-brain axis may further lead to the aberrant development of both the social and the food reward system(s) in autism. Future studies targeting the gut-brain/brain-gut axis in autism and the gut microbiome are warranted, but must take into consideration individual variation in gut microbiomes and intrinsic and extrinsic sensitivities and sex. Results of these studies will likely contribute to our under‐

standing of ASD and advance new and viable therapies.

Elizabeth M. Sajdel-Sulkowska1\* and Romuald Zabielski2

1 Dept. Psychiatry Harvard Medical School and BWH, USA

\*Address all correspondence to: esulkowska@rics.bwh.harvard.edu

2 DDept. Physiological Sciences, Warsaw University of Life Sciences, Poland

[1] Adam TC, Epel ES. Stress, eating and the reward system. Physiology and Behavior

(Kohls et al., 2012).

**9. Conclusions**

**Author details**

**References**

2007; 91:449-458.

It is also possible that the abnormalities in vagus nerve functions may further contribute to social deficits in autism (Goetz et al., 2010). ). It is thus of interest (Ito and Craig, 2008) that there is a possibility that the vicerosensory information is sent via the vagus nerve directly to the reward centers. The vagus nerve is involved in our emotional responses and in feelings of compassion as shown in vagal stimulation, suggesting that the social bond is related to the gut-brain axis (Goetz et al., 2010). Studies utilizing single-photon emission tomography (SPET) provide evidence for the limbic system-vagal nerve connection (Barnes et al., 2003). Vagotomy was for decades a method of choice in treating a number of gastric diseases in adults; it would be of interest to address it in context of autistic pathology.

Furthermore, the intestinal microbiome regulates the HPA during both development and adulthood (Sudo et al., 2004) and plays an important role in the stress response. Activation of the HPA axis involves the release of endogenous opioids which are components of the brain reward system (Adam et al., 2007).

In humans, sensory factors, such as taste and smell, have an important role in reward-related feeding (Rolls, 2011); gustatory, olfactory, visual and somatosensory aspects of food are regulated by the orbitofrontal cortex. Environmental cues, as well as cognitive, reward, and emotional factors play an important role in food intake which may override the homeostatic requirements (Berthoud, 2006). Environmental cues regulate endocannabinoid and opioid systems which play an important role in reward-related feeding and have wide receptor distributions within the CNS (Cota et al., 2006). Hypothalamic endocannabinoids increase food intake through a leptin-regulated mechanism. The nucleus accumbens is a key limbic pathway and may be implicated in regulation of hedonistic and homeostatic feeding (Berthoud, 2006). Dopamine appears to be associated with reward-related food intake and with behaviors required to maintain feeding essential for survival (Di Marzo et al., 2001).

The neural circuit mediating reward-related behavior is a complex network that includes the midbrain, substantia nigra, the amygdala, the ventral striatum, the ventromedial prefrontal cortex and ventral anterior cingulated cortex with the central relay located in ventral striatum (Kohls et al., 2012).

It is interesting, that the ventral striatum is associated with both social-reward and food-reward circuitry (Adam et al., 2007). Although it is generally assumed that the two centers are separate, the observation of altered sucrose preference and positive correlation with ventral striatum dopamine levels under conditions of social isolation stress in perinatal rats lends support to the speculation of inter-connectivity of the two centers (Brenes and Fornaguera, 2008).
