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Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity
Thesis (MSc)--Stellenbosch University, 2022.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867614066653003776 |
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| access_status_str | Open Access |
| author | Paarwater, Brandon Antony |
| author2 | Glanzmann, Brigitte |
| author_browse | Glanzmann, Brigitte Paarwater, Brandon Antony |
| author_facet | Glanzmann, Brigitte Paarwater, Brandon Antony |
| author_sort | Paarwater, Brandon Antony |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/125131 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:46:07.073Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/125131 Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity Paarwater, Brandon Antony Glanzmann, Brigitte Moller, Marlo Kinnear, Craig Glashoff, Richard Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Gut microbiome Precision medicine Genomics Interleukins UCTD Thesis (MSc)--Stellenbosch University, 2022. ENGLISH ABSTRACT: Purpose: Here, we describe the genomic, immunological, and gut microbial profile of an index patient suspected of an inborn error of immunity (IEI). This study aimed at understanding the underlying pathological mechanisms involved in the context of precision medicine by utilizing different omics strategies. Background: Precision medicine has been used in the treatment of several immune mediated diseases such as IEIs. IEI classifications are complex due to the heterogeneity at the clinical, immunological, genetic, and microbial levels. Here, we describe a patient with a rare suspected IEI phenotype. This case study is uniquely complex; and the presentation is unlikely as a result of only one specific IEI. This study explores how the triad-therapeutic intervention approach: hematopoietic stem cell transplantation (HSCT), immunoglobulin replacement therapy, and nutritional intervention affect the gut microbiota of the suspected IEI patient. Study method and design: The research approach was an intrinsic longitudinal case study IEI using different omics platforms for the pathological stratification of the index patient. Comparisons for readouts were made before and after HSCT. Whole-genome sequencing (WGS) was used for variant discovery and Sanger validated for genomic profiling. Multiplex Cytokine/Chemokine analyses were used to measure soluble immune mediator responses in plasma. 16S rRNA gene sequencing of the V1-V2 region were used for gut microbial profiling. Clinical data were further prompted to monitor specific immune markers and immune cell subsets over the course of the triad therapeutic intervention approach. Results: WGS identified two candidate gene variants, interleukin-12 receptor, beta-2, IL12RB2 (c.C1187T), and NFKB inhibitor zeta (NFKBIZ)(c.1935+2-> GTA) involved in the genetic signature driving the clinical phenotype and are classified as de novo for the index patient. The immunological profile of the patient shifted post-HSCT. The production of interleukin (IL) -6 and IL-8, Interferon gamma-induced protein 10, CD40- Ligand, and Fms-like tyrosine kinase 3 ligand (FLT-3 Ligand) waned post-HSCT. An overall decrease in the levels of monocytes, lymphocytes, white blood cells, and red blood cell counts were observed post-HSCT. The gut microbial profile pre-HSCT was dominated by obligate anaerobic bacteria such as Bacteroides pre-HSCT, and facultative anaerobes such as Providencia post-HSCT in relative abundances. Stellenbosch University https://scholar.sun.ac.za iii Differential abundance testing revealed two genera enriched at both time points, Ruminococcus torques and Lachnoclostridium. Gastroenterological symptomology remained post-HSCT, together with slow immune reconstitution. Concluding remarks: Overall, we utilized the knowledge gained through the different profiles generated to monitor and adjust treatment response. Herewith illustrating that the triad-therapeutic intervention approach implemented influence gut microbial signatures over time. Furthermore, highlighting that the microbial signature together with genetic and immunological signatures contribute to the clinical phenotype of the index patient. Consequently, these microbial signatures may serve as predictors of treatment response. Finally, showing great promise that an integrative analysis utilizing various omic platforms provides to the pathophysiology of immune-mediated diseases, especially in the context of IEI. AFRIKAANSE OPSOMMING: Doel: Hier beskryf ons die genomiese, immunologiese en ingewande mikrobiese profiel van 'n indekspasiënt wat verdink word van 'n ingebore fout met immuniteit (IEI). Hierdie studie het ten doel gehad om die onderliggende patologiese meganismes wat betrokke is in die konteks van presisie medisyne te verstaan deur verskillende omikastrategieë te gebruik. Agtergrond: Presisie medisyne word geïmplementeer in die behandeling van verskeie immuun-gemedieerde siektes soos IE's. IEI-klassifikasies is ingewikkeld vanweë die heterogeniteit op kliniese, immunologiese, genetiese en mikrobiese vlak. Hier, ons beskryf 'n pasiënt met 'n seldsame vermoedelike IEI-fenotipe, hierdie gevallestudie is uniek kompleks, en die aanbieding is onwaarskynlik as gevolg van slegs een spesifieke IEI. Hierdie studie ondersoek hoe die triadimatiewe intervensiebenadering: hematopoiëtiese stamseloorplanting (HSCT) ,immunglobulienvervangingsterapie, en voedingsintervensie die derm-mikrobiota van die vermeende IEI-pasiënt beϊnvloed. Studiemetode en ontwerp: Die navorsingsbenadering was 'n intrinsieke longitudinale gevallestudie IEI met behulp van verskillende omika-platforms vir die patologiese stratifikasie van die indekspasiënt. Vergelykings vir lesings is voor en na HSCT getref. Volgorde van die hele genoom (WGS) is gebruik vir die ontdekking van variante en Sanger is gevalideer vir genomiese profilering. Multiplex Cytokine / Chemokine-ontledings is gebruik om oplosbare immuunrespons op immuunbemiddelings in plasma te meet. 16S rRNA-geenvolgorde van die V1-V2- streek is gebruik vir mikrobiese profilering van die ingewande. Kliniese gegewens is verder gevra om spesifieke immuunmerkers en immuunsel-subsets te monitor gedurende die drie-terapeutiese intervensiebenadering. Resultate: WGS geïdentifiseer van twee kandidaatgeenvariante, interleukin-12- reseptor, beta-2, IL12RB2 (c.C1187T), en NFKB-inhibitor zeta (NFKBIZ) (c.1935 + 2- > GTA) wat betrokke is by die genetiese handtekening wat die kliniese fenotipe bestuur en word geklassifiseer as de novo vir die indekspasiënt. Die immunologiese profiel van die pasiënt het na-HSCT verskuif. Die produksie van interleukin (IL) -6 en IL-8, Interferon gamma-geïnduseerde proteïen 10, CD40- Ligand, en Fms-agtige tyrosinkinase 3 ligand (FLT-3 Ligand) afgeneem na-HSCT. 'n Algehele afname in die vlakke van monosiete, limfosiete, witbloedselle, en rooibloedseltellings is na-HSCT waargeneem. Die ingewande mikrobiese profiel voor die HSCT is oorheers deur verpligte anaërobiese bakterieë soos Bacteroides voor-HSCT, en fakultatiewe anaërobe soos Providencia na-HSCT in relatiewe oorvloed. Die toetsing vir diffrensϊele oorvloed het aan die lig gebring dat twee geslagte op albei tydpunte verryk is, Ruminococcus torques en Lachnoclostridium. Gastro-enterologiese simptomologie het na-HSCT gebly, tesame met 'n stadige immuunrekonstitusie. Slotopmerkings: In die algemeen gebruik ons die kennis wat opgedoen is deur die verskillende profiele wat gegenereer is om die reaksie op behandeling te monitor en aan te pas. Hiermee word geïllustreer dat die triadimatiewe intervensiebenadering wat geïmplementeer is, beïnvloed mikrobiese handtekeninge van die ingewande mettertyd. Verder word beklemtoon dat die mikrobiese handtekening tesame met genetiese en immunologiese handtekeninge bydra tot die kliniese fenotipe van die indekspasiënt. Gevolglik kan hierdie mikrobiese handtekeninge dien as voorspellers van die reaksie op die behandeling. Ten slotte, met 'n groot belofte dat 'n integrerende analise met behulp van verskillende omikplatforms voorsiening maak vir die patofisiologie van immuun-gemedieerde siektes, veral in die konteks van IEI Masters 2022-03-03T16:58:40Z 2022-04-29T12:55:19Z 2023-03-18T03:00:13Z 2022-03 Thesis http://hdl.handle.net/10019.1/125131 en_ZA Stellenbosch University xvi, 126 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Gut microbiome Precision medicine Genomics Interleukins UCTD Paarwater, Brandon Antony Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| title | Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| title_full | Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| title_fullStr | Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| title_full_unstemmed | Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| title_short | Describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| title_sort | describing the effect of therapeutic interventions on the gut microbiome of a patient with a suspected inborn error of immunity |
| topic | Gut microbiome Precision medicine Genomics Interleukins UCTD |
| url | http://hdl.handle.net/10019.1/125131 |
| work_keys_str_mv | AT paarwaterbrandonantony describingtheeffectoftherapeuticinterventionsonthegutmicrobiomeofapatientwithasuspectedinbornerrorofimmunity |