Browsing by Author "Graham, Amy Sarah"

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    HIV/ART exposure effects in infants within an auditory-gut-brain axis framework
    (2026) Graham, Amy Sarah; Holmes, Martha; Jankiewicz, Marcin
    Introduction: In utero HIV exposure affects hearing and language outcomes in infants. Yet, no work has examined the influence of HIV and antiretroviral therapy (ART) exposure on early development of auditory white matter connections in the brain. Mechanisms through which HIV/ART exposure could affect the brain and auditory system include the immune system, diet/nutrition, the HPA axis and neurotransmitter signalling. Although researchers have demonstrated HIV/ART exposure effects on the gut microbiome, the role that this may play in mediating in utero exposure effects on neurodevelopment and auditory pathways remains to be explored. In an infant cohort, we sought to establish the effects of HIV and ART exposure on auditory white matter tract development and language outcomes. Moreover, we aimed to investigate their impacts on bacterial microbiome composition and to explore whether the infant gut microbiome could mediate HIV/ART exposure effects on auditory tract development. We motivate for the existence of an auditory-gut-brain axis, outlining potential pathways by which HIV/ART exposure could affect the infant central auditory system. Methods: Infants who were HIV-exposed but uninfected (iHEU) and infants who were HIV-unexposed (iHU) were enrolled into the Healthy Baby Study, additionally comparing iHEU whose mothers began treatment before conception (iHEU-pre) and those who began treatment during their pregnancy (iHEU-post). Structural and diffusion-weighted magnetic resonance images were acquired at the age of 0-5 weeks. Using full probabilistic diffusion tensor imaging (DTI) tractography, we explored the development of central auditory white matter tracts in the brain. The relationships between auditory tract DTI measures and language outcomes at 9-14 months, obtained using the Griffiths Mental Development Scales, were also assessed. Short-read, multiple variable region 16S rRNA sequencing with Illumina Miseq was done to characterise stool and rectal swab samples collected at the time of scan. To compare the gut microbial compositions of HIV and ART exposure groups, we utilised diversity, differential abundance and presence/absence analyses. Mediation analysis was carried out in R using the Linear Decomposition Model package, to explore the relationship between HIV/ART exposure, the gut microbiome and central auditory tract development. Furthermore, a scoping and narrative review was performed to investigate whether the auditory system, gut and brain are interconnected. Results: Among our unadjusted results, HIV/ART exposure was found to particularly impact the maturation of auditory tracts connected to the left medial geniculate nucleus (MGN). Within a small percentage of the tracts affected by HIV/ART exposure, a relationship between measures of tract development at 0-5 weeks and language performance at 9-14 months was seen only in iHU. We report that the abundances of individual taxa, namely Bacteroides fragilis and Veillonella dispar, were altered in iHEU, with longer in utero ART exposure driving these results. Bacteroides fragilis notably featured in our mediation analysis, being identified as a mediator for a third of the auditory tracts in which delayed maturation was observed for iHEU-pre compared to controls. Moreover, through a review of existing literature, we explore key anatomical, extracellular, immune and dietary players that could connect the auditory system, gut and brain. Conclusion: This work provides some evidence of HIV/ART exposure-related alterations in central auditory white matter tract development, with possible involvement of the infant gut microbiome. Our findings point to the impact of ART exposure from conception on development of the infant gut microbiome, which may in turn affect auditory tract maturation. Within an auditory-gut-brain axis framework, we suggest that researchers should consider the potential involvement of gut-derived short-chain fatty acids (SCFAs), and the maternal gut microbiome influence, in the impacts of HIV/ART exposure on neurodevelopment and particularly central auditory tract development.