Of these metabolites, propionate and butyrate readily cross the gut-blood and blood–brain barriers via a monocarboxylate transporter ( Karuri et al., 1993,

Bergersen et al., 2002 and Conn et al., 1983). In the brain, propionate and other SCFAs impact neuronal metabolism as well as the synthesis and release of neurotransmitters during early buy MLN0128 neurodevelopment ( Peinado et al., 1993 and Rafiki et al., 2003). Importantly, a careful balance of brain SCFAs must be achieved, as excessive levels have been associated with neural mitochondrial dysfunction and severe behavioral deficits in rodents ( Macfabe, 2012, de Theije et al., 2014a, de Theije et al., 2014b and de Theije et al., 2011). In addition to their direct role in fermentation, commensal gut microbiota express many enzymes with immunomodulatory and neuromodoulatory implications. For example, the gene encoding histidine decarboxylase (HDC), which catalyzes the conversion

of l-histidine to histamine, was recently identified in Lactobacillus STI571 clinical trial reuteri, a beneficial microbe found in the gut of rodents and humans ( Thomas et al., 2012). Critically, circulating histidine availability is also directly proportional to histidine content and histamine synthesis in the brain ( Schwartz et al., 1972 and Taylor and Snyder, 1971). Histaminergic fibers originate from the tuberomamillary region of the posterior hypothalamus and project widely to most regions of the developing brain, including the hippocampus, dorsal raphe, cerebellum, and neighboring nuclei of the hypothalamus ( Panula et al., 1989). The because ability of microbiota to modulate synthesis of a vast array of neuromodulatory

molecules highlight the need for additional studies characterizing of the role of microbiota-derived metabolites on broad neurodevelopmental events. Accumulating evidence draws associations between microbe-generated metabolites during early development and endophenotypes of neuropsychiatric disease. Studies in GF mice revealed that microbial exposure during early life modulated dopamine signaling, neuronal mitochondrial function, neuroplasticity, and motivational behaviors in adult animals (Diaz Heijtz et al., 2011 and Matsumoto et al., 2013). Further, in a mouse model of maternal immune activation during pregnancy, decreased abundance of the beneficial Bacteroides fragilis and increased serum levels of microbe-derived metabolites 4-ethylphenylsulfate and indolepyruvate were observed in exposed offspring. Direct administration of these metabolites to unexposed offspring increased adult anxiety-like behaviors similar to those observed following maternal immune activation, supporting that microbe-generated metabolites may affect brain programming ( Hsiao et al., 2013).