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dc.contributor.advisorFlægstad, Trond
dc.contributor.authorFlygel, Trym Thune
dc.date.accessioned2024-03-15T09:35:23Z
dc.date.available2024-03-15T09:35:23Z
dc.date.embargoEndDate2026-04-19
dc.date.issued2024-04-19
dc.description.abstractMore than half of the population with HIV in the world live in sub-Saharan Africa. HIV-associated chronic lung disease is the most prevalent comorbidity among children and adolescents with HIV in this region. The pathogenesis is multifactorial and thought to be a result of chronic immune activation and repeated lung injury. CD4+ T-cells are the main target for HIV infection. As the majority of CD4+ T-cells reside in the gut, HIV can cause a disrupted gut barrier and gut microbial dysbiosis, contributing to maintain systemic immune activation. We used data from a randomized, placebo-controlled trial of 347 children and adolescents with HIV-associated chronic lung disease in Zimbabwe and Malawi, investigating the effect of azithromycin on lung function. Rectal swabs were collected at inclusion, after 48 weeks of treatment and 6 months after cessation of study drug. 16S rRNA sequencing was performed to assess the gut microbiota. The overall aim of this thesis was to investigate the the gut microbiota of children and adolescents with HIV, and to study the effects of antibiotic (azithromycin) treatment on gut microbial composition and on local lung inflammation. We found that participants with HIV had a reduced gut microbial diversity compared to participants without HIV. Diversity improved with longer time on antiretroviral therapy. Azithromycin reduced the overall gut microbial diversity, but these changes did not persist 6 months after cessation of antibiotics. Exhaled nitric oxide, a measure of local inflammation in the lungs, was associated with acute respiratory exacerbations and biomarkers of inflammation. We found no effect of azithromycin on exhaled nitric oxide. This work highlights the association between HIV and gut microbial dysbiosis and the effect of long-term antibiotics on lung inflammation and composition of gut microbiota. It adds knowledge to the field of HIV-associated comorbidities and can be helpful when designing new studies on gut microbiota and potential microbiota-related targets for interventions in the future.en_US
dc.description.abstractOver halvparten av de som lever med HIV i verden bor i Afrika, sør for Sahara. HIV-assosiert kronisk lungesykdom er den vanligste følgesykdommen av HIV hos barn og ungdom i denne regionen. Årsaken er ikke kjent, men kan være et resultat av kronisk immunaktivering og gjentatt lungeskade på grunn av infeksjoner. Angrepspunktet for HIV er CD4+ T-celler. Siden størsteparten av CD4+ T-cellene befinner seg i tarmen, kan HIV føre til en dårligere tarmbarriere og endret tarmflora, som igjen kan opprettholde systemisk immunaktivering. Vi har brukt data fra en randomisert, placebokontrollert studie med 347 barn og ungdom med HIV-assosiert kronisk lungesykdom i Zimbabwe og Malawi. Denne studien så på effekten av antibiotikumet azithromycin på lungefunksjon. Vi samlet rektale penselprøver ved inklusjon, etter 48 uker behandling og 6 måneder etter avsluttet behandling. Vi brukte 16S rRNA-sekvensering for å undersøke tarmfloraen. Formålet med studien var å undersøke tarmfloraen til barn og ungdom med HIV, og å se på effekten av azithromycin på tarmflora og inflammasjon i lungene. Vi fant at de med HIV hadde mindre mangfold i tarmfloraen sammenlignet med HIV negative. Tarmfloraen bedret seg jo lengre de hadde vært behandlet med antiretroviral behandling. Azithromycin reduserte mangfoldigheten av tarmfloraen, men disse forandringene gikk tilbake 6 måneder etter avsluttet behandling. Utåndet nitrogenoksid, et mål for lokal inflammasjon i lungene, var assosiert med akutt forverring av lungefunksjon og inflammatoriske biomarkører. Vi fant ingen effekt av azithromycin på utåndet nitrogenoksid. Denne oppgaven belyser assosiasjoner mellom HIV og endret tarmflora, samt effekten av antibiotika på lungeinflammasjon og sammensetning av tarmfloraen. Oppgaven tilfører ny kunnskap om HIV-relaterte følgesykdommer og kan brukes til å designe nye studier på tarmflora og mulige angrepspunkter for behandling av tarmflora og følgesykdommer av HIV i fremtiden.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractHIV-associated chronic lung disease is the most prevalent comorbidity among children and adolescents with HIV in sub-Saharan Africa. HIV causes a disrupted gut barrier and gut microbial dysbiosis. This can lead to systemic immune activation, thought to contribute to the development of HIV-associated comorbidities. We investigated the composition of gut microbiota and studied the effects of antibiotic treatment on gut microbial composition and lung inflammation among children and adolescents with HIV-associated chronic lung disease in Zimbabwe and Malawi. Participants with HIV had reduced gut microbial diversity compared to HIV negative, but diversity improved with antiretroviral therapy. The antibiotic azithromycin reduced gut microbial diversity, but these changes did not persist 6 months after cessation of antibiotics. Exhaled nitric oxide, a measure of local inflammation in the lungs, was associated with acute respiratory exacerbations and biomarkers of inflammation. This work highlights the association between HIV and gut microbial dysbiosis and the effect of long-term antibiotics on lung inflammation and composition of gut microbiota. It can be helpful when designing new studies on gut microbiota and potential microbiota-related targets for interventions in the future.en_US
dc.description.sponsorshipNorwegian Research Council - Global Health and Vaccination Research (GLOBVAC) programme Helse Nord RHF (HNF 1387-17 and HNF 1539-20)en_US
dc.identifier.urihttps://hdl.handle.net/10037/33175
dc.language.isoengen_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.relation.haspart<p>Paper I: Flygel, T.T., Sovershaeva, E., Claassen-Weitz, S., Hjerde, E., Mwaikono, K.S., Odland, J.Ø., … Flægstad, T. (2020). Composition of Gut Microbiota of Children and Adolescents with Perinatal Human Immunodeficiency Virus Infection Taking Antiretroviral Therapy in Zimbabwe. <i>Journal of Infectious Disease, 221</i>(3), 483-492. Also available in Munin at <a href=https://hdl.handle.net/10037/16913>https://hdl.handle.net/10037/16913</a>. <p>Paper II: Flygel, T.T., Hameiri-Bowen, D., Simms, V., Rowland-Jones, S., Ferrand, R.A., Bandason, T., … Sovershaeva, E. (2023). Exhaled nitric oxide is associated with inflammatory biomarkers and risk of acute respiratory exacerbations in children with HIV-associated chronic lung disease. <i>HIV Medicine, 25</i>(2), 223-232. Also available in Munin at <a href=https://hdl.handle.net/10037/32193>https://hdl.handle.net/10037/32193</a>, <p>Paper III: Flygel, T.T., Abotsi, R.E., Claassen-Weitz, S., Simms, V., Hjerde, E., Mwaikono, K.S., … Sovershaeva, E. Long Term Azithromycin Treatment Reduces Gut Microbial Diversity in Children and Adolescents with HIV-associated Chronic Lung Disease. (Manuscript).en_US
dc.rights.accessRightsembargoedAccessen_US
dc.rights.holderCopyright 2024 The Author(s)
dc.subject.courseIDDOKTOR-003
dc.subjectHIVen_US
dc.subjectGut Microbiotaen_US
dc.subjectAfricaen_US
dc.subjectChildrenen_US
dc.subjectAntibioticsen_US
dc.subjectChronic lung diseaseen_US
dc.subjectInflammationen_US
dc.subjectExhaled nitric oxideen_US
dc.titleHIV Infected African Children: Gut microbiota in relation to chronic lung disease and long-term antibiotic treatmenten_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


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