Issues for patchy tissues: defining roles for gut-associated lymphoid tissue in neurodevelopment and disease.

Individuals diagnosed with neurodevelopmental conditions such as autism spectrum disorder (ASD; autism) often experience tissue inflammation as well as gastrointestinal dysfunction, yet their underlying causes remain poorly characterised. Notably, the largest components of the body's immune system, including gut-associated lymphoid tissue (GALT), lie within the gastrointestinal tract. A major constituent of GALT in humans comprises secretory lymphoid aggregates known as Peyer's patches that sense and combat constant exposure to pathogens and infectious agents. Essential to the functions of Peyer's patches is its communication with the enteric nervous system (ENS), an intrinsic neural network that regulates gastrointestinal function. Crosstalk between these tissues contribute to the microbiota-gut-brain axis that altogether influences mood and behaviour. Increasing evidence further points to a critical role for this signalling axis in neurodevelopmental homeostasis and disease. Notably, while the neuroimmunomodulatory functions for Peyer's patches are increasingly better understood, functions for tissues of analogous function, such as caecal patches, remain less well characterised. Here, we compare the structure, function and development of Peyer's patches, as well as caecal and appendix patches in humans and model organisms including mice to highlight the roles for these essential tissues in health and disease. We propose that perturbations to GALT function may underlie inflammatory disorders and gastrointestinal dysfunction in neurodevelopmental conditions such as autism.

The Emerging Role of the Gut-Brain-Microbiota Axis in Neurodevelopmental Disorders.

Autism spectrum disorder (ASD; autism) is a prevalent neurodevelopmental disorder associated with changes in gut-brain axis communication. Gastrointestinal (GI) symptoms are experienced by a large proportion of individuals diagnosed with autism. Several mutations associated with autism modify cellular communication via neuronal synapses. It has been suggested that modifications to the enteric nervous system, an intrinsic nervous system of the GI tract, could contribute to GI dysfunction. Changes in gut motility, permeability, and the mucosal barrier as well as shifts in the large population of microbes inhabiting the GI tract could contribute to GI symptoms. Preclinical research has demonstrated that mice expressing the well-studied R451C missense mutation in Nlgn3 gene, which encodes cell adhesion protein neuroligin-3 at neuronal synapses, exhibit GI dysfunction. Specifically, NL3R451C mice show altered colonic motility and faster small intestinal transit. As well as dysmotility, macrophages located within the gut-associated lymphoid tissue of the NL3R451C mouse caecum show altered morphology, suggesting that neuro-inflammation pathways are modified in this model. Interestingly, NL3R451C mice maintained in a shared environment demonstrate fecal microbial dysbiosis indicating a role for the nervous system in regulating gut microbial populations. To better understand host-microbe interactions, further clarification and comparison of clinical and animal model profiles of dysbiosis should be obtained, which in turn will provide better insights into the efforts taken to design personalized microbial therapies. In addition to changes in neurophysiological measures, the mucosal component of the GI barrier may contribute to GI dysfunction more broadly in individuals diagnosed with a wide range of neurological disorders. As the study of GI dysfunction advances to encompass multiple components of the gut-brain-microbiota axis, findings will help understand future directions such as microbiome engineering and optimisation of the mucosal barrier for health.