- Title
- The influence of neonatal immune activation and sex on the development of gut microbiota, immunity and behaviour
- Creator
- Cuskelly, Annalisa
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2023
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- There is a distinct association between psychological and gastrointestinal (GI) disorders. Both disorders share common pathologies that have been shown to be linked to early life stress (i.e., neonatal immune activation). Events occurring in early life can induce long-term physiological and behavioural changes through the process of perinatal programming. The early life environment is critical to the establishment of the microbiota-gut-brain-axis (MGBA), a bidirectional communication system which links the gut with neuroimmune pathways. The MGBA axis is highly plastic throughout the perinatal period and is a possible mediator of sex-based disparities in psychological and GI disorders. Animal models have been used to investigate the relationship between early life adversity and developmental outcomes. Specifically, neonatal immune activation has been demonstrated to modulate several components of the MGBA with persistent long-term changes in the hypothalamic-pituitary-adrenal (HPA) axis, neuroimmune functioning and behaviour. Neonatal immune activation has also been reported to be sensitive to the influence of sex, with sexually dimorphic behavioural and immunological responses to neonatal Lipopolysaccharide (LPS). The overarching aim of this thesis is to investigate the influence that early life immunological stress has on the development of the MGBA and implications for long-term health outcomes. To do this, this thesis utilised the Wistar rat model of neonatal immune activation (NIA) via intraperitoneal administration of 0.05mg/kg LPS on postnatal (P) days 3 and 5. The timing of LPS exposure occurs at a critical window in the development of the brain and GI tract, signalling it as an effective model to study the effects of perinatal programming on the MGBA. The specific aim of this thesis was to explore the development of anxiety-like behaviour, gut microbiota and gut immunology in male and female rodents following neonatal LPS exposure which was explored through each data chapter of this thesis. Chapter 3 of this thesis (Cuskelly et al., 2022) firstly aimed to determine if neonatal LPS exposure would lead to a distinct anxiety-like phenotype, as previously established in this model, and if this would be associated with a differential microbiota profile. This chapter reported sexually dimorphic behavioural and microbial responses in adults following neonatal LPS exposure. Moreover, this chapter established an association between behaviour and the gut microbiota modulated by both sex and LPS exposure. Given the novel findings of Chapter 3 we then aimed to characterise the development of the gut microbiota across the lifespan in male and female rodents. In chapter 4 we assessed the colonic mucosal associated microbiota (MAM) composition following neonatal LPS at critical developmental time points. Neonatal LPS exposure was found to alter the developmental trajectory of the colonic MAM in males and females, with sexually dimorphic microbial composition persistent across the lifespan. Furthermore, LPS-exposed animals displayed sexually dimorphic alterations in functional pathways pre-puberty. This chapter demonstrated prominent and persisting gut microbiota changes following neonatal LPS-exposure at key developmental periods. Given these gut microbiota changes we then aimed to assess the gut immune system at key developmental time points in male and female rodents following neonatal LPS exposure. Chapter 5 explored cellular and molecular markers of inflammation, GI architecture, and epithelium integrity at weaning, adolescence, and adulthood. Neonatal LPS exposure was linked with a subtle but significant change in the gut immune system. While no distinct immune profile was observed, sexually dimorphic immune responses were observed following neonatal LPS exposure. This chapter further revealed the salient role of sex, with sexually dimorphic immune responses to neonatal LPS exposure. Taken together, the studies presented in this thesis demonstrate that neonatal immune activation contributes to the programming of behaviour and the gastrointestinal system, fundamentally influencing the MGBA. This thesis presents novel insights into the longitudinal development of gut microbiota composition and immune functioning at key developmental periods. Most saliently, this thesis demonstrates the influence of sex on the MGBA, indicating sexually dimorphic developmental trajectories in response to neonatal immune activation. Placing these findings in the context of the broader literature, this thesis significantly contributes to the understanding of the critical influence of the early life environment, with sex as a major modulating factor, potentially predicting resilience or vulnerability to psychopathology and/or gut disorders.
- Subject
- gut; brain; development; microbiome; rat model; early life stress
- Identifier
- http://hdl.handle.net/1959.13/1478688
- Identifier
- uon:50212
- Rights
- Copyright 2023 Annalisa Cuskelly
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 25 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 175 KB | Adobe Acrobat PDF | View Details Download |