The effect of altered trace aminergic signalling and estrogen on intestinal inflammation, within an IBS context

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dc.contributor.advisorSmith, Carineen_ZA
dc.contributor.advisorVan Staden, Anton du Preezen_ZA
dc.contributor.authorPretorius, Leshaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Physiological Sciences.en_ZA
dc.date.accessioned2022-10-12T08:32:19Z
dc.date.accessioned2023-01-16T12:40:41Z
dc.date.available2022-10-12T08:32:19Z
dc.date.available2023-01-16T12:40:41Z
dc.date.issued2022-12
dc.descriptionThesis (PhD)--Stellenbosch University, 2022.en_ZA
dc.description.abstractENGLISH ABSTRACT: Irritable bowel syndrome (IBS) is a widespread (≈10% global prevalence) female predominant functional gastrointestinal (GI) disorder. While it is known that IBS is underpinned by relative microbial dysbiosis and chronic microinflammation, current therapeutic strategies often only provide transient symptomatic relief (with relative neglect of inflammation) and are thus unsatisfactory in many cases. As such, the development of targeted therapeutics to alleviate GI inflammation and consequential symptomologies are required. We suggest that the trace aminergic system, which connects several IBS risk factors (sex, dysbiosis, diet, inflammation and anxiety), may be a pretermitted regulatory system that could be manipulated as a therapeutic target. In addition, existing data supports an interpretation of sex dependence in trace aminergic signalling. As such, fluctuations of female reproductive hormones, such as 17β-estradiol (E2), may alter subsequent signalling cascades. Therefore, this thesis aimed to investigate the GI modulatory effects of selected trace amines (TAs), with consideration of the context of female predominance. To elucidate mechanisms at play, a multidisciplinary approach was necessitated. As such, multiple model systems were utilised, including both in vitro (microbial cultures and human tissue cultures) and in vivo (zebrafish larval) models. In this regard, microbial (probiotic and commensal strains) culturing techniques, coupled with the development of a novel multianalyte mass spectrometry methodology, allowed for the accurate assessment of microbial TA generation. Indeed, data generated in these studies highlighted firstly, the dependence of probiotic secretome profile on host hormonal status, and secondly, that specific rooibos supplementation strategies may be able to negate E2-induced alterations in secretome TA profiles, both of which have important implications in TA-associated symptom management in females with GI disorders. Data generated in vitro in HT-29 colon adenocarcinoma cells and in vivo in zebrafish larvae, in which the effects of increased TA load were assessed, demonstrated potential differences in the mechanisms of actions between TYR and AGM in particular. In this regard, extensive occludin redistribution was observed following TYR-exposure, which was associated with increased reactive oxygen species and pro-inflammatory cytokine levels, as well as tight junction disruption – an outcome prevented by E2 treatment. In contrast, AGM administration promoted the colocalization of ZO-1 and occludin to promote tight junction integrity but was also associated with risk of pro-oxidant damage when AGM metabolism was insufficient. In conclusion, this dissertation contributes significantly to our understanding of the role of TAs in GI physiology, consistently illustrating (across in vitro and in vivo models), that while some TAs may promote disease symptomology, others may have therapeutic benefit when responsibly administered. From a therapeutics standpoint, data presented here crucially highlights the importance of dosage and administration optimisation to achieve benefit and minimize adverse side effects when targeting TA signalling in the context of functional GI disease. In addition, potential mechanistic insights by which E2 - or rather the transient cyclic lack thereof - is associated with trace aminergic signalling, was elucidated.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Prikkelbare derm-sindroom (IBS) is ‘n wydverspreide (≈10% global voorkoms) vroulik- oorheersde funksionele gastroïntestinale (GI) versteuring. Alhoewel dit bekend is dat IBS gekenmerk word deur onderliggende relatiewe mikrobiese disbiose en chroniese mikro- inflammasie, bied huidige terapeutiese strategieë dikwels net verbygaande simptomatiese verligting (met relatiewe verwaarlosing van inflammasie) en is dus in baie gevalle onbevredigend. Die ontwikkeling van geteikende terapeutika om GI-ontsteking en gevolglike simptome te verlig, is dus nodig. Ons stel voor dat die spoor-aminergiese stelsel, wat verskeie IBS-risikofaktore (seks, disbiose, diëet, inflammasie en angs) verbind, ‘n voorafbepaalde regulatoriese stelsel kan wees wat as terapeutiese teiken gemanipuleer kan word. Daarbenewens ondersteun bestaande data ‘n interpretasie van geslagsafhanklikheid in spoor-aminergiese seinoordrag. As sodanig kan wisseling in vlakke van vroulike voortplantingshormone, soos 17β-estradiol (E2), daaropvolgende seinoordrag verander. Daarom het hierdie tesis gemik om die GI modulerende effekte van geselekteerde spoor- amiene (TAs) te ondersoek, met inagneming van die vroulike konteks. Om betrokke meganismes toe te lig, was ‘n multidissiplinêre benadering genoodsaak. Dus is veelvuldige modelstelsels gebruik, insluitend beide in vitro (mikrobiese kulture en menslike selkulture) en in vivo (sebravislarwe) modelle. In hierdie verband het (probiotiese en kommensale) mikrobiese kweektegnieke, tesame met die ontwikkeling van ‘n nuwe multi- analiet massaspektrometrie metodologie, die akkurate assessering van mikrobiese TA profiele moontlik gemaak. Inderdaad, data wat in hierdie studies gegenereer is, het eerstens aangedui dat probiotiese sekretoomprofiel van gasheer se hormonale status afhanklik is. Tweedens beklemtoon data dat spesifieke rooibos aanvullings moontlik E2-geïnduseerde veranderinge in sekretoom TA-profiele kan verhoed, wat albei belangrike implikasies vir TA- geassosieerde simptoombestuur by vroue met GI-afwykings inhou. Data gegenereer in vitro in HT-29 kolon adenokarsinoomselle en in vivo in sebravislarwes, waarin die effekte van verhoogde TA-lading ge-evalueer is, het potensiële verskille in die meganismes van aksies tussen veral π-tiramien (TYR) en agmatien (AGM) getoon. In hierdie verband is omvattende okludien herverspreiding waargeneem na TYR-blootstelling, wat geassosieer is met verhoogde reaktiewe suurstofspesies en pro-inflammatoriese sitokienvlakke, sowel as stywe aansluiting proteïen ontwrigting – ‘n uitkoms wat deur E2 behandeling voorkom is. Daarteenoor het AGM-toediening die ko-lokalisering van ZO-1 en okludien bevorder om stywe aansluitingsintegriteit te bevorder, maar was ook geassosieer met risiko van pro-oksidantskade wanneer AGM metabolisme onvoldoende was. Ten slotte, dra hierdie proefskrif aansienlik by tot ons begrip van die rol van TAs in GI fisiologie, wat konsekwent illustreer (in beide in vitro en in vivo modelle) dat hoewel sommige TAs siekte simptomologie kan bevorder, ander terapeutiese voordeel kan hê wanneer dit verantwoordelik toegedien word. Vanuit ‘n terapeutiese oogpunt beklemtoon data wat hier aangebied word, die belang van dosis- en toedieningsoptimering om voordeel te bewerkstellig en nadelige effekte te verminder wanneer TA-seinoordrag in die konteks van funksionele GI-siekte geteiken word. Daarbenewens is potensiële meganistiese insigte verkry, waaronder die rol van E2 – of eerder die tydelike sikliese vermindering daarvan – in spoor-aminergiese seinoordrag.af_ZA
dc.description.versionDoctoralen_ZA
dc.format.extentviii, 193 pages : illustrations (some color)en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/125905
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectIrritable bowel syndromeen_ZA
dc.subjectGastrointestinal system -- Microbiologyen_ZA
dc.subjectProbiotics -- Therapeutic useen_ZA
dc.subjectPrebiotics -- Therapeutic useen_ZA
dc.subjectRooibos tea -- Health aspectsen_ZA
dc.subjectZebrafish larvaeen_ZA
dc.subjectTrace amines (TA) -- Receptorsen_ZA
dc.subjectUCTDen_ZA
dc.titleThe effect of altered trace aminergic signalling and estrogen on intestinal inflammation, within an IBS contexten_ZA
dc.typeThesisen_ZA
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