The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior

Abstract

Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognition receptors (PRRs) of the innate immune system. Using expression-profiling techniques, we demonstrate that two families of PRRs that specifically detect PGN (that is, PGN-recognition proteins and NOD-like receptors), and the PGN transporter PepT1 are highly expressed in the developing brain during specific windows of postnatal development in both males and females. Moreover, we show that the expression of several PGN-sensing molecules and PepT1 in the developing striatum is sensitive to manipulations of the gut microbiota (that is, germ-free conditions and antibiotic treatment). Finally, we used the PGN-recognition protein 2 (Pglyrp2) knockout mice to examine the potential influence of PGN-sensing molecules on brain development and behavior. We demonstrate that the absence of Pglyrp2 leads to alterations in the expression of the autism risk gene c-Met, and sex-dependent changes in social behavior, similar to mice with manipulated microbiota. These findings suggest that the central activation of PRRs by microbial products could be one of the signaling pathways mediating the communication between the gut microbiota and the developing brain.

A Brain-Region-Specific Neural Pathway Regulating Germinal Matrix Angiogenesis

“…Furthermore, epidemiological studies have discovered a strong relationship between vascular risks and depression (Valkanova and Ebmeier, 2013). In parallel, recent findings indicate that gut microbiota-derived molecules can also translocate into the brain and have life stage- as well as brain region-specific effects on the striatum (Arentsen et al, 2017; Diaz Heijtz et al, 2011). Thus, region-specific neurovascular interaction may have a unique role in the development and function of brain reward circuitry and, as a result, implications for a large number of neuropsychiatric diseases.…”

“…Interestingly, many striatum-based neurobiological processes are strongly influenced by blood-borne endocrine signals (Jang et al, 2013; Mak et al, 2007; Moaddab et al, 2015; Schoffelmeer et al, 2011), especially during early life (Lajud et al, 2013; Miller and Caldwell, 2015; Panagopoulos and Ralevski, 2014), and by vascular risk factors (Valkanova and Ebmeier, 2013), suggesting a unique role of regional vasculature. Gut microbiota-derived molecules have also been found to translocate into the brain and exert stage- and region-specific impacts on striatum (Arentsen et al, 2017; Diaz Heijtz et al, 2011). Thus, understanding GM angiogenesis may not only provide insights into mechanisms of region-specific neurovascular communication and GM hemorrhage, but may also have implications for understanding brain reward circuit development and function.…”

Recent developments in understanding the role of the gut microbiota in brain health and disease

“…However, emerging studies are providing some insight into the mechanisms underlying how gut bacteria influence social behaviors. In a recent study from the Karolinska Institute, the authors identify a role for bacterial‐sensing molecules in regulating social development . Genetic knockdown of the peptidoglycan‐sensing molecule PGLYRP2 was found to increase social behaviors in both male and female mice in the three‐chamber test while also modulating the expression of genes related to synaptic plasticity .…”

“…In a recent study from the Karolinska Institute, the authors identify a role for bacterial‐sensing molecules in regulating social development . Genetic knockdown of the peptidoglycan‐sensing molecule PGLYRP2 was found to increase social behaviors in both male and female mice in the three‐chamber test while also modulating the expression of genes related to synaptic plasticity . The authors argue that bacterial components, such as peptidoglycan, cross the blood–brain barrier during postnatal development and bind to molecules, such as PGLYRP2, to influence neuronal circuits linked to social behaviors …”

Gut Brain Axis and Its Microbiota Regulation in Mammals and Birds

“…For example, in 1 study, bacterial peptidoglycan (PGN) was derived from the commensal gut microbiota and it was shown that PGN was able to translocate into the brain and was sensed by specific patternrecognition receptors within the innate immune system. 40 Furthermore, the absence of these bacterial factors was associated with increased risk for autism-like behavior in a mouse model. Similarly, in mice, polysaccharide A from the capsule of the commensal bacterium Bacteroides fragilis was protective of experimental autoimmune encephalomyelitis, which is the experimental model of human multiple sclerosis.…”