TY - GEN

T1 - Characterising gut dysbiosis in rodent models relevant to psychiatric and neurodevelopmental disorders

AU - Ellis, Jodie

PY - 2020/5/4

Y1 - 2020/5/4

N2 - Background: The microbiota is central to gut homeostasis and overall health, with dysbiosis linked to multiple morbidities. The gut and brain are linked via multiple, bidirectional, communication mechanisms including the vagus nerve, immune system, and neurotransmitter metabolism. Increased attention has been given to the microbiota’s impact on the brain and its potential role in psychiatric and neurodevelopmental disorders (PNDs), such as schizophrenia and autism. We aim to investigate the role of the microbiome and gut dysfunction in these disorders to further understand the potential mechanisms involved. The Phencyclidine (PCP) and Neurexin1α heterozygous (Nrxn1α+/-) mouse models are relevant to schizophrenia and autism.Materials and Methods: Bacterial DNA, extracted from the intestinal contents of PCP and Nrxn1α+/- mice, were subject to community profiling by Denaturing Gradient Gel Electrophoresis (DGGE). Gut tissue were analysed histologically to determine the impact on gut architecture and EECs.Results: Subchronic PCP treatment significantly increased the depth of the muscle layer in the colon but had no effect on gut architecture or the microbiome composition. Nrxn1α+/-significantly decreased the depth of the muscle layer in the colon and caecum in mice of both sexes. Nrxn1α+/- impacted on gut architecture in female but not in male mice. By contrast, Nrxn1α+/- selectively decreased GLP-1 positive EEC number in males. Nrxn1α+/- also significantly affected gut microbiome composition. Liraglutide did not reverse the impact of Nrxn1α+/- on the gut. However, Liraglutide treatment selectively decreased EEC number in the caecum of Nrxn1α+/- males. Liraglutide treatment also significantly decreased goblet cell size in the colon, and increased goblet cell size in the caecum of male mice, independent ofgenotype. Liraglutide-treated mice had a significantly different microbiome composition in the mucus layer of the colon and caecum.Conclusions: As PCP had no effect on the gut architecture or microbiome, it is unlikely that it models the gut dysfunction seen in schizophrenia. Therefore, the behaviour changes in PCP mice are independent of effects on the gut. Nrxn1α+/- impacted on the gut and microbiome which may be relevant to the behavioural changes seen in Nrxn1α+/- mice. Changes to the gut and microbiome may be one mechanism by which Nrxn1α+/- increases the risk of developing PNDs. Liraglutide did not reverse the impact of Nrxn1α+/- on the gut. However, Liraglutide did modify gut architecture and the microbiome which could be relevant to the use of the drug in type II diabetes.

AB - Background: The microbiota is central to gut homeostasis and overall health, with dysbiosis linked to multiple morbidities. The gut and brain are linked via multiple, bidirectional, communication mechanisms including the vagus nerve, immune system, and neurotransmitter metabolism. Increased attention has been given to the microbiota’s impact on the brain and its potential role in psychiatric and neurodevelopmental disorders (PNDs), such as schizophrenia and autism. We aim to investigate the role of the microbiome and gut dysfunction in these disorders to further understand the potential mechanisms involved. The Phencyclidine (PCP) and Neurexin1α heterozygous (Nrxn1α+/-) mouse models are relevant to schizophrenia and autism.Materials and Methods: Bacterial DNA, extracted from the intestinal contents of PCP and Nrxn1α+/- mice, were subject to community profiling by Denaturing Gradient Gel Electrophoresis (DGGE). Gut tissue were analysed histologically to determine the impact on gut architecture and EECs.Results: Subchronic PCP treatment significantly increased the depth of the muscle layer in the colon but had no effect on gut architecture or the microbiome composition. Nrxn1α+/-significantly decreased the depth of the muscle layer in the colon and caecum in mice of both sexes. Nrxn1α+/- impacted on gut architecture in female but not in male mice. By contrast, Nrxn1α+/- selectively decreased GLP-1 positive EEC number in males. Nrxn1α+/- also significantly affected gut microbiome composition. Liraglutide did not reverse the impact of Nrxn1α+/- on the gut. However, Liraglutide treatment selectively decreased EEC number in the caecum of Nrxn1α+/- males. Liraglutide treatment also significantly decreased goblet cell size in the colon, and increased goblet cell size in the caecum of male mice, independent ofgenotype. Liraglutide-treated mice had a significantly different microbiome composition in the mucus layer of the colon and caecum.Conclusions: As PCP had no effect on the gut architecture or microbiome, it is unlikely that it models the gut dysfunction seen in schizophrenia. Therefore, the behaviour changes in PCP mice are independent of effects on the gut. Nrxn1α+/- impacted on the gut and microbiome which may be relevant to the behavioural changes seen in Nrxn1α+/- mice. Changes to the gut and microbiome may be one mechanism by which Nrxn1α+/- increases the risk of developing PNDs. Liraglutide did not reverse the impact of Nrxn1α+/- on the gut. However, Liraglutide did modify gut architecture and the microbiome which could be relevant to the use of the drug in type II diabetes.

KW - microbiome

KW - microbiota

KW - Neurexin

KW - PCP

KW - Gut

KW - dysbiosis

KW - Schizophrenia

KW - mice

KW - cognitive

KW - Gut bacteria

KW - Enteroendocrine cells

KW - Goblet cell

KW - gut muscle

KW - crypt

KW - colon

KW - caecum

KW - autism

KW - intestine

U2 - 10.17635/lancaster/thesis/967

DO - 10.17635/lancaster/thesis/967

M3 - Master's Thesis

PB - Lancaster University

ER -