About the lab
The focus of the Hill-Yardin lab is on the gut-brain axis. We are interested in understanding how synaptic mutations impact endophenotypes in mouse models of autism. Specifically, we are investigating the impact of autism-associated synaptic gene mutations on gastrointestinal function and structure, including changes in how neurons might interact with microbes and the immune system in the gut.
Featured projects (1)
https://www.frontiersin.org/research-topics/9426/interactions-of-the-nervous-system-with-bacteria The gastrointestinal system hosts more than 10,000 classes of bacteria of about 1,800 distinct phyla. Interestingly, these microbiota are able to influence brain function and development. For instance, microbiota can influence the brain by modulating immune responses. Hereby, the activation of the immune system and/or the release of mediators that are able to cross the blood brain barrier plays an important role.
Featured research (4)
Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. Their ability to keep the gut from chronic inflammation despite constantly facing foreign antigens has been an important focus in gastrointestinal research. However, the heterogeneity of intestinal macrophages has impeded our understanding of their specific roles. It is now becoming clear that subsets of intestinal macrophages play diverse roles in various gastrointestinal diseases. This occurs through a complex interplay between cytokine production and enteric nervous system activation that differs for each pathological condition. Key diseases and disorders in which intestinal macrophages play a role include post-operative ileus, inflammatory bowel disease, necrotizing enterocolitis as well as gastrointestinal disorders associated with Human Immunodeficiency Virus and Parkinson’s disease. Here, we review the identification of intestinal macrophage subsets based on their origins and functions, how specific subsets regulate gut physiology and the potential for these heterogeneous subpopulations to contribute to disease states. Furthermore, we outline the potential for these subpopulations to provide unique targets for the development of novel therapies for these disorders.
Interactions between the gut microbiome and the brain affect mood and behaviour in health and disease. Using preclinical animal models, recent discoveries begin to explain how bacteria in the gut affect our mood as well as highlighting new findings relevant to autism. Autism-associated gene mutations known to affect synapse function in the CNS also affect the inflammatory response and alter the enteric nervous system resulting in abnormal gastrointestinal motility and structure. Strikingly, these mutations additionally affect the gut microbiome in mice. This review describes the changes in gut physiology and microbiota in mouse models of autism with modified synapse function. The rationale for different regions of the gastrointestinal tract having variable susceptibility to dysfunction is also discussed. To dissect underlying biological mechanisms involving gut-brain axis dysfunction in preclinical models, a range of multidisciplinary approaches are required. This research will provide insights into the role of the gut-brain axis in health and neurodevelopmental disorders including autism.
Mucus is integral to gut health and its properties may be affected in neurological disease. Mucus comprises a hydrated network of polymers including glycosylated mucin proteins. We propose that factors that influence the nervous system may also affect the volume, viscosity, porosity of mucus composition and subsequently, gastrointestinal (GI) microbial populations. The gut has its own intrinsic neuronal network, the enteric nervous system, which extends the length of the GI tract and innervates the mucosal epithelium. The ENS regulates gut function including mucus secretion and renewal. Both dysbiosis and gut dysfunction are commonly reported in several neurological disorders such as Parkinson's and Alzheimer's disease as well in patients with neurodevelopmental disorders including autism. Since some microbes use mucus as a prominent energy source, changes in mucus properties could alter, and even exacerbate, dysbiosis-related gut symptoms in neurological disorders. This review summarizes existing knowledge of the structure and function of the mucus of the GI tract and highlights areas to be addressed in future research to better understand how intestinal homeostasis is impacted in neurological disorders.
The intrinsic nervous system of the gut interacts with the gut-associated lymphoid tissue (GALT) via bidirectional neuroimmune interactions. The caecum is an understudied region of the gastrointestinal (GI) tract that houses a large supply of microbes and is involved in generating immune responses. The caecal patch is a lymphoid aggregate located within the caecum that regulates microbial content and immune responses. People with Autism Spectrum Disorder (ASD; autism) experience serious GI dysfunction, including inflammatory disorders, more frequently than the general population. Autism is a highly prevalent neurodevelopmental disorder defined by the presence of repetitive behavior or restricted interests, language impairment, and social deficits. Mutations in genes encoding synaptic adhesion proteins such as the R451C missense mutation in neuroligin-3 (NL3) are associated with autism and impair synaptic transmission. We previously reported that NL3R451C mice, a well-established model of autism, have altered enteric neurons and GI dysfunction; however, whether the autism-associated R451C mutation alters the caecal enteric nervous system and immune function is unknown. We assessed for gross anatomical changes in the caecum and quantified the proportions of caecal submucosal and myenteric neurons in wild-type and NL3R451C mice using immunofluorescence. In the caecal patch, we assessed total cellular density as well as the density and morphology of Iba-1 labeled macrophages to identify whether the R451C mutation affects neuro-immune interactions. NL3R451C mice have significantly reduced caecal weight compared to wild-type mice, irrespective of background strain. Caecal weight is also reduced in mice lacking Neuroligin-3. NL3R451C caecal ganglia contain more neurons overall and increased numbers of Nitric Oxide (NO) producing neurons (labeled by Nitric Oxide Synthase; NOS) per ganglion in both the submucosal and myenteric plexus. Overall caecal patch cell density was unchanged however NL3R451C mice have an increased density of Iba-1 labeled enteric macrophages. Macrophages in NL3R451C were smaller and more spherical in morphology. Here, we identify changes in both the nervous system and immune system caused by an autism-associated mutation in Nlgn3 encoding the postsynaptic cell adhesion protein, Neuroligin-3. These findings provide further insights into the potential modulation of neural and immune pathways.
- School of Health & Biomedical Sciences
About Elisa Hill-Yardin
- Our work in the Gut-brain Axis lab focuses on understanding the functions of the second brain in the gastrointestinal tract. Our research themes include i) identifying the cause of gut dysfunction in transgenic mouse models of neurological disease ii) determining how neurons communicate with the lymphoid system and inflammation and iii) understanding interactions between the nervous system and bacteria.