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Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis
Thesis (PhD)--Stellenbosch University, 2025.
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Stellenbosch : Stellenbosch University
2025
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| author | Dicks, Leon Milner Theodore |
| author2 | Engelbrecht, Anna-Mart |
| author_browse | Dicks, Leon Milner Theodore Engelbrecht, Anna-Mart |
| author_facet | Engelbrecht, Anna-Mart Dicks, Leon Milner Theodore |
| author_sort | Dicks, Leon Milner Theodore |
| collection | Thesis |
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| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134601 |
| institution | Stellenbosch University (South Africa) |
| language | English |
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| publishDate | 2025 |
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| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
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| spelling | oai:scholar.sun.ac.za:10019.1/134601 Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis Dicks, Leon Milner Theodore Engelbrecht, Anna-Mart Botha, Alfred Stellenbosch University. Faculty of Science. Dept. of Microbiology. Intestines -- Microbiology Gastrointestinal tract -- Diseases Cardiovascular system -- Diseases Atherosclerosis Diet -- Health aspects Nutrition -- Physiological effect Lipoproteins -- Metabolism UCTD Thesis (PhD)--Stellenbosch University, 2025. Dicks, L. M. T. 2025. Gut Microbiota and Cardiovascular Disease: Exploring Microbial Metabolites, Inflammation, and Arterial Specificity in Atherosclerosis. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/031842e0-a1b2-4b9f-9272-915d62056133 ENGLISH ABSTRACT: The uptake of micro- and macronutrients in the adult human gut is regulated by seven bacterial Phyla (Bacillota, Bacteroidota, Pseudomonadota, Fusobacteriota, Verrucomicrobiota, Cyanobacteria, and Actinomycetota). Gut microbiota coexist in a harsh environment through communication via quorum sensing (QS). The molecular signals they generate communicate with the host by interacting with receptors (e.g, G-protein-coupled receptors, GPCRs) embedded in the intestinal epithelium. The levels of butyrate and variation of signalling molecules produced depend on the composition of the gut microbiome, diet, and external factors (e.g., stress, mental state, medication, and social behaviour). Butyrate supplies 70% of the energy required by intestinal epithelial cells (IECs) and keeps them in close contact. This prevents the leakage of lumen contents into the bloodstream, which may overstimulate the immune system. Binding of butyrate to GPCRs in the intestinal epithelium suppresses the activities of interferon γ (IFN-γ), Toll-like receptor 2 (TLR2), and Nod-like receptor pyrin domain 3 (NLRP3), and downregulates the production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. This suppresses the recruitment of leukocytes and the production of pro-inflammatory cytokines. By suppressing IFN-γ and TLR2, the levels of isoleucine (IL)-10 increase. Butyrate bound to GPCR initiates the inhibition of transmembrane glycoprotein CD36 (cluster of differentiation 36), which decreases the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages. The decline in lipid-rich macrophages (foam cells) prevents the deposit of ox-LDL onto the intima and plaque formation. Butyrate released into the bloodstream binds to TLR4 and activates NADPH, mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) pathways. NF-κB stimulates endothelial nitric oxide synthase (eNOS) to increase the production of nitric oxide (NO), an important vasodilator. The interaction between butyrate and peroxisome proliferator-activated receptor gamma (PPARγ) stimulates the activity of IkBα, an inhibitor of the NF-κB pathway. The deactivation of NF-κB elevates IL-10 levels. PPARγ stimulates adipogenesis, which prevents arterial plaque formation. The dysregulation of PPARγ results in hypertension, obesity, increased blood sugar and serum triglycerides, and a decrease in high-density lipoprotein (HDL). CD36 acts as an ox-LDL scavenger, thus preventing the translocation of fatty acids to arterial walls. CD36 on the surface of foam cells accumulates advanced glycation end products (AGEs), which accelerate the formation of atherosclerotic plaques. CD36 also stimulates blood clotting by aggregating platelets and binds to thrombospondin 1 (TSP-1), advanced oxidation protein products (AOPPs), and S100 family proteins (S100-A8, S100-A9, and S100-A12) to transfer ox-LDL into arteries. The CD36-protein complex binds to Ca2+, growth hormone-releasing peptide (GHRP), cell-derived microparticles (MPs), and amyloids. If CD36 is compromised, as in damaged endothelia, plasma levels of Ca2+ and MPs (e.g., small vesicles that carry proteins and lipids) increase. The malfunctioning of GHRP disturbs the balance between growth hormone (GH) and insulin-like growth factor-1 (IGF-I). A modification of the GH/IGF-I axis may lead to the accumulation of lipids, an increase in body weight, and possibly also the development of AS. Further research on the regulation of the GH/IGF-I axis may provide a better understanding of AS and cardiovascular diseases (CVDs). CD36 may be developed into a reporter system for the early detection of AS. Further research on the regulation of genes encoding CD36 and transcription factors such as PPAR may lead to the development of a ligand to detect CD36 levels. This is a challenging task, as CD36 is a diverse protein that binds to low-chain fatty acids (LCFAs), ox-LDL, thrombospondins, amyloid proteins, collagen, and AGE. The binding of microbial lipopolysaccharides (LPS) to TLRs triggers several inflammatory reactions that may lead to CVD. One of the most important reactions is the stimulation of the pro-atherogenic metabolite trimethylamine N-oxide (TMAO). The latter promotes the expression of NLRP3, foam cells, and arterial plaque formation. TMAO, produced by gut microbiota from choline, phosphatidylcholine, and L-carnitine, causes vascular endothelial damage by activating nitric oxide dismutase (NOD), leucine-rich repeats (LRR), and pyrin domain-containing NLRP3 inflammatory bodies. An increase in intracellular calcium ions contributes to the aggregation of platelets, which may lead to thrombosis. TMAO also inhibits the sirtuin 3-superoxide dismutase2-mitochondrial ROS (reactive oxygen species) pathway, the ROS-thioredoxin interactive protein axis, and activates the protein kinase C/NF-κB (canonical NF-κB)/vascular cell adhesion molecule-1 pathway, all of which promote AS. TMAO also upregulates the expression of CD36. TMAO may thus be used as a reporter of AS, but serves as a target for the prevention and treatment of CVDs. Biomarkers that may be considered for the early detection of AS are: The epithelial cellular adhesion molecule (Ep-CAM), trefoil factor 3 (TF3), leptin, plasminogen activator inhibitor 1 (PAI1), alpha-1 acid glycoprotein 1 (AGP1), contactin 1 (CNTN1), butyrate, TMAO, NLRP3, and elastin. Butyrate regulates AS. It is thus sensible to focus on receptors, such as PPAR, TLR, AhR, and butyrate-influenced signal-generating pathways, such as MAPK, and ox-LDL transporters to find a cure for AS. Our knowledge of the interactions between butyrate and receptors on IECs and ECs, specifically GPCRs (free fatty acid receptors, FFARs), provides a solid basis for the intervention of AS and may lead to the design of novel GPCR-targeted drugs. A last thought: Are we getting old because of a changing (and aging) gut microbiome that struggles to maintain epithelial and endothelial membranes and loses the ability to generate “life-supporting” signals? In other words, do our organs fail us, and do we develop AS because of misbehaving gut microbiota that throw a tantrum if they are not fed correctly? Surely it is not this simple. AFRIKAANSE OPSOMMING: Die opname van mikro- en makro nutriënte deur die volwasse mens se ingewande word deur bakterieë van sewe Filums beheer (Bacillota, Bacteroidota, Pseudomonadota, Fusobacteriota, Verrucomicrobiota, Cyanobacteria en Actinomycetota). Ingewandsmikrobes oorleef saam in ‘n stroewe omgewing deur kommunikasie met behulp van kworumwaarneming (quorum sensing “QS”). Die molekulêre seine wat hulle genereer kommunikeer met die gasheer deur interaksie met reseptore (bv. G-proteïngekoppelde reseptore, “GPCRs”) ingebed in die intestinale epiteel. Die butiraatvlakke en ander seinmolekules wat geproduseer word is afhanklik van die samestelling van die ingewandsmikrobioom, dieët en eksterne faktore soos angs, geestelike toestand, medikasie en sosiale gewoontes. Butiraat voorsien 70% van die energie benodig deur die dikdermepiteel en hou die epiteelselle in kontak om te voorkom dat die inhoud van die ingewande uitlek en die immuunsisteem oorstimuleer. Die binding van butiraat aan “GPCRs” in the ingewandsepiteel onderdruk die produksie van interferon γ (IFN-γ), Toll-tipe reseptor-2 (“TLR2”) en Nod-tipe reseptor pirien domein-3 (“NLRP3”), en dereguleer die produksie van vaskulêre sel aanhegtingsmolekule-1 (“VCAM-1”) asook E-selektien. Dit onderdruk die werwing van leukosiete en die produksie van pro-inflammatoriese sitokene. Deur “IFN-γ” en and “TLR2” te onderdruk, verhoog die vlakke van isoleukien (IL)- 10. Butiraat bind aan “GPCR” en inisieer die onderdrukking van transmembraan glikoproteïen CD36 (“cluster of differentiation 36”). Dit verlaag die opname van geoksideerde laedigtheid lipoproteïen (“ox-LDL”) deur makrofage en die omskakeling daarvan na lipiedryke makrofage (“foam cells”). Die afname in lipiedryke makrofage verhoed die deponering van “ox-LDL” op die intima en dus plaakvorming. Butiraat wat in die bloedstroom vrygestel word, bind aan “TLR4” en verhoog NADPH vlakke, maar aktiveer ook die mitogeen-geaktiveerde proteïen MAPK en nukliêre faktor kappa B (NF-κB) padweë. Die toename in NF-κB aktiveer endoteel niktriet-oksied sintase (“eNOS”) en verhoog die produksie van nitriet (stikstof)-oksied (NO), ‘n belangrike bloedvatverwydingsmiddel. Die interaksie tussen butiraat en peroksisoom proliferator-geaktiveerde reseptor gamma (“PPARγ”) stimuleer die aktiwiteit van IkBα, ‘n inhibitor van die NF-κB padweg. Die deaktivering van NF-κB verhoog IL-10 vlakke. “PPARγ” stimuleer adipogenese en voorkom dus plaakvorming in are. Wanregulering van “PPARγ” lei tot hipertensie, oorgewig, verhoogde bloedsuiker en serum trigliseriede, en verlaagde hoëdightheid lipoprotein (“HDL”). CD36 versamel “ox-LDL” en verhoed dus die oordrag van vetsure na die wande van are. CD36 op die oppervlak van lipiedryke makrofage, akkumuleer gevorderde glikasie eindprodukte (“advanced glycation end products”, “AGEs”) en versnel die vorming van aterosklerotiese plaak. CD36 stimuleer ook bloedstolling deur die versameling van bloedplaatjies en bind aan trombospondien-1 (“TSP-1”), gevorderde oksidasie protein-produkte (“advanced oxidation protein products”, “AOPPs”) en S1-familie proteïene (S100-A8, S100-A9 en S100-A12) om “ox-LDL” na are te vervoer. Die CD36-proteinkompleks bind aan Ca²⁺, groeihormoonvrystellende peptied (“GHRP”), sel-afgeleide mikropartikels (“MPs”), en amiloïede. Indien CD36 in gedrang kom, soos met beskadigde endoteel, verhoog die plasmavlakke van Ca²⁺ en “MPs” (d.i. klein protein en lipiedvesikels). Die wanfunksionering van “GHRP” veroorsaak ‘n wanbalans in groeihormone (“GH”) en insulientipe groeifaktor-1 (“IGF-I”). ‘n Modifikasie van die “GH/IGF-I”-aksel mag aanleiding gee tot die akkumulering van lipiede, liggaamsmassa, en moontlik die ontwikkeling van AS. Verdere navorsing op die regulering van die “GH/IGF-I”-aksel mag meer inligting verskaf oor “AS” en kardiovaskulêre siektes (“CVDs”). CD36 mag dalk in ‘n verklikkersisteem ontwikkel word vir die vroeë opsporing van “AS”. Verdere navorsing op die regulering van gene wat kodeer vir CD36 en transkripsiefaktore soos “PPAR” moet gedoen word om ‘n ligand te ontwikkel wat as verklikker van CD36 kan dien. Dit is ‘n uitdagende opdrag, aangesien CD36 ‘n diverse protein is wat aan laeketting vetsure (“LCFAs”), “ox-LDL”, trombospondiene, amiloïede, kollageen en “AGE” bind. Die binding van mikrobiese lipopolisakkariede (“LPS”) aan “TLRs”, prikkel verskeie inflammatoriese faktore wat tot “CVD” aanleiding kan gee. Een van die belangrikste reaksies is die stimulasie van die pro-aterogeniese metaboliet trimetielamien N-oksied (“TMAO”). Laasgenoemde bevorder die uitdrukking van “NLRP3”, die vorming van lipiedryke makrofage en plaakvorming. “TMAO”, geproduseer deur ingewandsmikrobes vanaf kolien, fosfatidielkolien, en L-karnitien, beskadig vaskulêre endoteel deur die aktivering van nitriet-oksied dismutase (“NOD”), leusienryke herhalings (“LRR”) en piriendomein bevattende “NLRP3” inflammatoriese liggaampies. ‘n Verhoging in intrasellulre kalsiumione dra by tot die versameling van bloedplaatjies en kan trombose veroorsaak. “TMAO” inhibeer ook die sirtuin3-superoksied dismutase2-mitokondriale “ROS” (reaktiewe suurstofspesie) padweg, die ROS-tioredoksien interaktiewe proteïenaksel en aktiveer die proteïenkinase C/NF-κB (kanoniese NF-κB)/vaskulêre sel adhesie molekule-1 padweg, wat aanleiding gee tot “AS”. “TMAO” verhoog ook die uitdrukking van CD36. “TMAO” mag dus as verklikker van “AS” gebruik word, maar kan ook dien as teiken vir die voorkoming en behandeling van “CVDs”. Biomerkers wat moontlik oorweeg kan word vir die vroeë opsporing van “AS” is: Die epiteelsel-aanhegtingsmolekule (“Ep-CAM”), trefoilfaktor 3 (TF3), leptien, plasminogeen aktiveerder inhibitor-1 (“PAI1”), alfa-1 suur glikoprotein-1 (“AGP1”), kontaktien-1 (“CNTN1”), butiraat, “TMAO”, “NLRP3” en elastien. Butiraat reguleer “AS”. Dit is dus sinvol om op reseptore soos “PPAR”, “TLR”, “AhR” en butiraat-beinvloede seingenererende padweë soos “MAPK” en “ox-LDL” vervoerders te fokus om “AS” te genees. Ons kennis van die interaksies tussen butiraat en reseptore op “IECs” en “ECs”, veral “GPCRs” (vry vetsuur reseptore, “FFARs”), dien as ‘n soliede grondslag vir die intervensie van “AS” en mag lei tot unieke “GPCR”-geteikende medikasie. ‘n Laaste gedagte: Word ons oud omdat ‘n veranderde (en ouerwordende) ingewandsmikrobioom sukkel om die epiteel- en endoteelmembrane instand te hou, asook die vermoë om “lewensondersteunende seine” te genereer verloor? In ander woorde, faal ons organe ons en ontwikkel ons “AS” as gevolg van die wangedrag van ingewandsmikrobes wat ‘n vloermoer gooi as hulle nie reg gevoer word nie? Dit is sekerlik nie so eenvoudig nie. Doctoral 2025-12-18T07:47:05Z 2025-12-18T07:47:05Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134601 en Stellenbosch University 13 unnumbered, 182 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Intestines -- Microbiology Gastrointestinal tract -- Diseases Cardiovascular system -- Diseases Atherosclerosis Diet -- Health aspects Nutrition -- Physiological effect Lipoproteins -- Metabolism UCTD Dicks, Leon Milner Theodore Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis |
| title | Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis |
| title_full | Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis |
| title_fullStr | Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis |
| title_full_unstemmed | Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis |
| title_short | Gut microbiota and cardiovascular disease: exploring microbial metabolites, inflammation, and arterial specificity in atherosclerosis |
| title_sort | gut microbiota and cardiovascular disease exploring microbial metabolites inflammation and arterial specificity in atherosclerosis |
| topic | Intestines -- Microbiology Gastrointestinal tract -- Diseases Cardiovascular system -- Diseases Atherosclerosis Diet -- Health aspects Nutrition -- Physiological effect Lipoproteins -- Metabolism UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/134601 |
| work_keys_str_mv | AT dicksleonmilnertheodore gutmicrobiotaandcardiovasculardiseaseexploringmicrobialmetabolitesinflammationandarterialspecificityinatherosclerosis |