Elizabeth M. Sajdel-Sulkowska1 and Romuald Zabielski2
[1] Dept. Psychiatry Harvard Medical School and BWH, USA
[2] DDept. Physiological Sciences, Warsaw University of Life Sciences, Poland
1. Introduction
Possible connection of gut microbiome and behavior; microbiome and behavioral abnormalities in ASD
The “leaky gut” during development may be potentially more
vulnerable to environmental insults than the normally developing GIT. ... A developmentally abnormal gut microbiome
may in turn affect both the gut-brain axis and brain development and
contribute to the etiology of ASD. Results
of these studies will likely contribute to our understanding of ASD and
advance new and viable therapies.
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 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.
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 dopaminergic-oxytocinergic “wanting circuitry” that includes the ventral striatum, amygdale, and the ventromedial prefrontal cortex (Kohls et al., 2012). Indeed, Individuals with ASD are characterized 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.
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).
