As doenças inflamatórias intestinais (DII) são causadas por desequilíbrio entre as respostas imunes efetoras e reguladoras na mucosa intestinal e podem ser moduladas pelo eixo hipotálamo-hipófise-adrenal (HPA) por meio de interações neuroimunoendócrinas e secreção de cortisol. Embora os glicocorticóides (GC) sejam utilizados para tratar a DII, o cortisol produzido pelas glândulas supra-renais também está envolvido na resposta ao estresse, que pode levar a doenças inflamatórias descontroladas. Portanto, o objetivo deste trabalho é avaliar a participação do eixo HPA na modulação da resposta imune de mucosa intestinal. Para tal, camundongos C57BL/6 foram submetidos à remoção das glândulas adrenais seguida por indução de colite pela administração de água contendo 3% de dextran sulfato de sódio (DSS). Os resultados demonstraram que a ausência das adrenais levou à maior suscetibilidade à doença e mortalidade precoce, fenômeno que não foi prevenido pela reposição de GC. Os animais adrenalectomizados com colite apresentaram níveis significativamente menores de LPS, concomitantemente ao aumento de IL-6 no soro quando comparados aos camundongos não adrenalectomizados. Além disso, os animais adrenalectomizados apresentaram menor celularidade na lâmina própria (LP), menos áreas de erosão e menor escore histopatológico associado ao aumento de IFN-? e FasL, no intestino, sem produção local compensatória de corticosterona. Houve aumento na atividade das enzimas mieloperoxidase (MPO), N- acetilglicosaminidase (NAG) e eosinófilo-peroxidase (EPO) no intestino dos animais expostos ao DSS quando comparados ao grupo de camundongos controles saudáveis, independentemente da presença do eixo HPA intacto e o tratamento com GC nos animais adrenalectomizados levou à redução significativa da atividade de MPO. Também foi observado na LP dos camundongos adrenalectomizados aumento significativo na frequência de células dendríticas tolerogênicas CD11b+CD11c+CD103+, T auxiliares (CD3+CD4+), T citolíticas (CD3+CD8+) e NKT (CD3+CD49b+), além de redução significativa da população de células dendríticas pró-inflamatórias CD11b+CD11c+CD103-, leucócitos CD11b+ e linfócitos intra-epiteliais, de maneira dependente de GC. A ausência do eixo HPA intacto levou à diminuição de leucócitos totais no baço quando comparados ao grupo com colite, relacionada principalmente à redução significativa na frequência de células NKT (CD3+CD49b+), as quais foram restauradas nos camundongos tratados com GC exógenos. Durante a exposição ao DSS houve aumento de células Th2 e Th1 no baço dos camundongos não adrenalectomizados, enquanto que a remoção das adrenais levou a notável redução na população de células T CD4 produtoras de IL-4, IL-10, IFN-? ou IL-17, com aumento de células Th17 e diminuição significativa de células Th1 no baço dos camundongos adrenalectomizados e tratados com GC. De forma interessante, houve menor acúmulo de células T reguladoras juntamente à redução na intensidade média de fluorescência (MFI) de FOXP3 em células T CD4+CD25+ do baço dos camundongos adrenalectomizados expostos ao DSS, de maneira geral dependente de GC. Por fim, esta diminuição de mecanismos reguladores foi acompanhada de menor índice de proliferação e aumento de IL-10 no sobrenadante de cultura de esplenócitos de camundongos com o eixo HPA não ii funcional, indicando que a ausência de GC endógenos pode alterar significativamente a homeostase do sistema imunológico. Juntos, nossos resultados demonstram que o eixo HPA é importante na modulação da resposta imunológica durante a colite induzida experimentalmente / Inflammatory bowel diseases (IBD) are caused by imbalance between regulatory and effector immune responses in the intestinal mucosa and can be modulated by the hypothalamic-pituitary-adrenal (HPA) axis via neuroimmune endocrine interactions and secretion of cortisol. Although glucocorticoids (GC) are used to treat IBD, cortisol produced by the adrenals glands is also involved in the stress response, which can lead to uncontrolled inflammatory diseases. Therefore, the aim of this study was to evaluate the HPA axis in the modulation of the immune response of intestinal mucosa. C57BL/6 mice were subjected to removal of the adrenal glands followed by induction of colitis by administration of water containing 3% dextran sulfate sodium (DSS). The results showed that the absence of adrenals led to increased susceptibility to disease and early mortality, a phenomenon that was not prevented by GC replacement. Adrenalectomized animals exposed to DSS had significantly lower levels of LPS, concomitantly to increased IL-6 in the serum when compared to non-adrenalectomized mice. In addition, adrenalectomized animals had lower cellularity in the lamina propria (LP), less erosion areas and less histopathologic score associated with increased IFN-? and FasL in the intestine, without compensatory local production of corticosterone. There was an increase in the activity of the myeloperoxidase (MPO) enzyme, N- acetilglicosaminidase (NAG) and eosinophil-peroxidase (EPO) in the intestines of DSS-exposed animals when compared to the healthy control group of mice, regardless of the presence of intact HPA axis, while treatment with GC led to significantly reduced MPO activity. It was also observed in the LP of adrenalectomized mice significant increase in the frequency of tolerogenic dendritic cells CD11b+CD11c+CD103+, helper T (CD3+ CD4+), cytolytic T (CD3+ CD8+) and NKT (CD3+ CD49b+) besides significant reduction in the population of pro-inflammatory dendritic cells CD11c+ CD11b+ CD103-, leukocyte CD11b+ and intraepithelial lymphocytes, GC-dependent manner. The absence HPA intact carried decrease in total leukocytes in spleen when compared to the group with colitis, related mainly to significant reduction in the frequency of NKT cells (CD3+CD49b+), which were restored in the GC treated mice. During exposure to DSS there was increased Th2 and Th1 cells in the spleen of non-adrenalectomized mice, while the removal of the adrenals was associated to a marked reduction in the population of CD4 T cells producing IL-4, IL-10, IFN-? or IL-17 with increased Th17 cells and significant decrease in Th1 cells in the spleen of adrenalectomized mice treated with GC. Interestingly there was less accumulation of regulatory T cells together to a reduction in mean fluorescence intensity (MFI) of FOXP3 in CD4+CD25+ T cells in the spleen of mice exposed to DSS after adrenalectomy, most dependent on GC. Finally, the decline of regulatory mechanisms was accompanied by lower rates of proliferation and increased IL-10 in the supernatant culture of splenocytes of mice with disrupted HPA axis, indicating that the absence of endogenous GC altered significantly the homeostasis of the immune system. Together, our results demonstrate that the HPA axis is important in modulating the immune response during experimentally induced colitis

Philosophiae Doctor - PhD / Background: A subtype of inflammatory bowel disease, Crohn' s disease is thought to represent a complex interaction between environmental factors, a defective immune system, the gastrointestinal microbiome and genetic' susceptibility; however; the-prevalence of different susceptibility mutations appears to vary between population groups, implying distinctions in disease pathogenesis or risk. Vitamin D, signaling through the vitamin D receptor, appears to have numerous effects on the immune system, and deficiency has been shown to playa role in both the pathogenesis and severity of experimental inflammatory bowel disease. However, the literature surrounding the association between vitamin D concentrations and disease severity in Crohn's disease is limited, and no such literature exists in South Africa. Furthermore, a paucity of data exists on the racial variability of Crohn' s disease phenotype in the Western Cape population of South Africa, as well as environmental factors in childhood associated with future Crohn's disease development. Aims: The three primary aims of the study were to investigate: 1) the racial variability of, Crohn's disease phenotype, defined by the Montreal classification scheme, as well as Crohn's disease behavior, using predefined definitions, stratified as 'complicated' or 'uncomplicated', based on a cross-sectional study design; 2) the association between childhood environmental exposures and the subsequent development of Crohn's disease, with specific emphasis on the timing of exposure, based on a case-control study design; and 3) the association between serum 25(OH)D concentration with Crohn's disease activity, measured by the Harvey Bradshaw Index, based on a cross-sectional study design; in this process, various vitamin D thresholds for predicting a high disease activity score were investigated, and the serum 25(OH)D concentrations were compared with those of the healthy controls to evaluate the prevalence of vitamin D deficiency. Design: This was a case control study, as well as two cross-sectional evaluations of the case control study data, of all consecutive Crohn's disease patients (ages 18-70 years) seen between September 2011 and January 2013 during their normally scheduled appointments at Schuur Hospital and Tygerberg Hospital. Control subjects for the study were identified from the same populations giving rise to the Crohn's disease cases. An investigator-administrated questionnaire was used to identify numerous demographic and lifestyle variables, as well as childhood environmental exposures during three age intervals; 0-5, 6-10 and 11-18 years. Clinical variables at diagnosis and time of study enrolment were determined via a review of medical and pharmacy records, as well as clinical examination by the consulting gastroenterologist. Serum 25(OH)D was measured using the SIEMENS ADIVA Centaur® XP Vitamin D Immunoassay [Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA]. Vitamin D status was classified as either 'deficient' or 'sufficient', and was analyzed in 2 ways: ~20 ng/mL versus ~21 ng/mL; and ~29 ng/mL versus ~30 ng/mL, respectively. One year after study completion, a total of 40 (10%) randomly selected participants from the cohort completed the interviewer-administered questionnaire for a second time. A kappa statistic was used in order to measure the agreement between repeated data for the questionnaire. Only data pertaining to the three age intervals (0-5, 6-10 and 11-18 years) was extracted in this process. Results: One hundred and ninety four Crohn's disease patients and 213 controls meeting our inclusion criteria were identified; 35 (18%) and 19 (9%) were White, 152 (78%) and 177 (83%) were Coloured, and 7(4%) and 17 (8%) were South African Black, respectively. No subjects reported being of Asian or Indian ethnicity. Overall, 125 (31%) of the cohort were male. On multiple logistic regression analysis, Coloured Crohn's disease patients were significantly more likely to develop 'complicated' Crohn's disease (60% versus 9%, P = 0.023) during the disease course when compared to White Crohn's disease patients. In addition, significantly more White subjects had successfully discontinued cigarette smoking at study enrolment (31% versus 7% reduction, P = 0.02). No additional interracial differences were found. A low proportion inflammatory bowel diseases family history was observed among the Coloured and Black subjects. When evaluating childhood environmental exposures, multiple logistic regression analysis showed that during the age interval 6-10 years, never having consumed unpasteurized milk [(OR = 6.43; 95% Cl, 3.02-14.81), (K =0.79; 95% Cl, 0.39-1.00)] and never having a donkey, horse, sheep or cow on the property [(OR = 3.10; 95% Cl, 1.42-7.21), (K = 0.84; 95% Cl, 0.12-1.00)], significantly increased the risk of developing future Crohn's disease. During the age interval 11-18 years, an independent risk-association was identified for; never having consumed unpasteurized milk (OR = 2.60; 95% Cl, 1.17-6.10) and second-hand cigarette smoke exposure (OR = 1.93; 95% Cl, 1.13-3.35). For the vitamin Danalysis, 186 Crohn's disease patients and 199 control subjects met the study inclusion criteria. Overall, 113 (29%) of the cohort were male. Forty four percent of the cohort had a deficient vitamin D concentration (::;20 ng/ml.), no participants had severely deficient vitamin D concentrations, and 26% of the cohort had sufficient vitamin D concentrations (:::30 ng/mL). Fifty-three percent of the controls and 34% of the cases had vitamin D concentrations ::;20 ng/mL (P < 0.001). On multiple logistic regression analysis, higher Harvey Bradshaw Index scores and not having taken vitamin D supplementation in the six months prior to enrolment were identified as independent predictors of vitamin D deficiency in Crohn's disease patients; defined either as ::;20 ng/mL, or as ::;29 ng/mL (P < 0.001). Compared to patients with Harvey Bradshaw Index <5, those with Harvey Bradshaw Index 2:8 were 2.5-times more likely to have vitamin D concentrations ::;21 ng/mL (PR = 2.5; 95% Cl, 1.30-6.30). The risk was similar, though not as high, if deficiency was defined as ::;29ng/ml. (PR = 2.0; 95% Cl, 1.20-3.50). Conclusions: Coloured Crohn's disease patients were significantly more likely to develop 'complicated' Crohn's disease over time when compared to White Crohn's disease patients. Limited microbial exposures and exposure to second-hand cigarette smoke during childhood is associated with future development Crohn's diseases. However the inconsistencies between each age interval with regards to the identified risk factors may imply that the effect of different viruses or bacteria on the development of immune structures varies according to the timing of exposure. The finding that lower serum 25(OH)D was associated with moderate to severe Crohn's disease activity suggests that this patient population may benefit from vitamin D supplementation in order to achieve, or maintain a serum 25(OH)D concentration of at least 30 ng/mL.

Bakgrund: Inflammatorisk tarmsjukdom (IBD) är samlingsnamn för kroniska mag-och tarmsjukdomar och innefattar Crohns sjukdom (CD) samt Ulcerös kolit (UK). Båda sjukdomar löper i skov med återkommande, långvariga diarréer med förbättrings-och försämringsperioder och kan relateras till fysiska, psykiska samt sociala faktorer. Då uppenbara orsaker eller symtom ej finns är det på många sätt en dold sjukdom och kan skapa otillräcklig förståelse för patientens specifika behov. För att patienten ska få rätt stöd i hanteringen av sjukdomen samt få en god omvårdnad, bör sjuksköterskan att ha gott bemötande, tillräcklig kunskap där vården ges på ett personcentrerat, evidensbaserat sätt. Syfte: Syftet var att beskriva patienters upplevelse av att leva med inflammatorisk tarmsjukdom, IBD. Metod: En litteraturöversikt valdes som metod och baserades på tio kvalitativa artiklar. Databassökningar gjordes från CINAHL Complete och Medline with full text. Artiklarna analyserades enligt Fribergs fem steg. Resultat: I resultatet framkom sex teman utifrån patienternas upplevelse; påverkan av IBD på självbilden, påverkan av IBD i relationer och sociala sammanhang, patienters upplevelse av hälso- och sjukvården, känslomässig påverkan, utveckling och acceptans samt påverkan av IBD i arbetslivet. Diskussion: Resultatdiskussionen diskuterades av författarna utifrån Katie Erikssons caritativa teori om att lindra lidande och utifrån centrala fynd utifrån temaområden i resultatet. / Background: Inflammatory bowel disease (IBD) is the collective name for chronic gastrointestinal disorders and includes Crohn's disease (CD) and Ulcerative colitis (UK). Both diseases relapses with recurring, long-term diarrhea with improvement and deterioration periods and can be related to physical, mental and social factors. In the absence of obvious causes or symptoms, it is in many ways a hidden disease and can create scarce understanding of the patient's specific needs. In order for the patient to receive the right support in the management of the disease and to receive good nursing care, the nurse have to give good care, have sufficient knowledge and care for the patient in a person-centered, evidence-based way. Aim: The purpose was to describe the patient’s experiences of living with inflammatory bowel disease, IBD. Method: A literature review was chosen as the method and was based on ten qualitative articles. Database searches were performed from CINAHL Complete and Medline with full text. The articles were analyzed according to Friberg's five steps. Results: In the result, six themes emerged from the patients' experience; the influence of IBD on the self-image, the influence of IBD in relationships and social contexts, patients' experience of health care, emotional impact, development and acceptance, and the influence of IBD in working life. Discussion: The results discussion was discussed by the authors on the basis of Katie Eriksson's charitable theory of alleviating suffering and on the basis of central findings based on thematic areas in the result.

The effect of serum 25-hydroxycholekalciferol levels on musculoskeletal system in children with inflammatory bowel disease Background: Low bone mineral density and osteoporosis represent severe secondary complications that can be a result of childhood chronic disease. According to Frost's mechanostat theory impaired muscle functions may contribute to the changes observed on the skeleton. Aims: The aim of this study was to: 1) evaluate parameters of bone mineral density, bone geometry and dynamic muscle functions in children and adolescent with chronic disease - inflammatory bowel disease (IBD) and type 1 diabetes (T1D); 2) evaluate a possible effect of vitamin D deficiency and vitamin D supplementation or duration of the disease on the musculoskeletal unit; 3) determine clinical or laboratory predictors of muscle and bone parameters. Methods: The study was divided into two substudies according to the diagnosis. Seventy patients with IBD (median age 13.8 years) were included in one study, fifty-five of which completed all of the planned procedures. During the study, IBD patients were supplemented with 2000 IU/d of vitamin D. In the second study 95 patients with T1D were included (median age 16.4 years). BMD and bone geometry of non-dominant tibia was evaluated using peripheral quantitative computed...

Inflammatory bowel disease is a serious condition with an incomplete etiology and pathogenesis. In this thesis, a mouse model of sodium dextran sulfate-induced inflammation was used to study different changes in the metabolism of germ-free and conventionally raised mice due to the development of the inflammatory process. NMR metabolomics of fecal, urine and serum samples, combined with uni- and multivariate statistical analysis, were used to characterize the changes. It was shown that the metabolic signature differs between germ-free and conventional mice. In germ-free mice, significant amounts of carbohydrates were found in feces. Their levels decreased during inflammation as they were excreted in urine. In contrast to conventional mice, germ-free mice also excreted large amounts of amino acids in feces during the developing inflammation. Disorders of sugar and protein metabolism found in germ-free mice indicate severe malnutrition caused by inflammation. The results show that the presence of a microbiome represents a protective mechanism against significant disruption in the body. A stability study of fecal extracts of healthy conventionally colonized mice confirmed that none of the identified and quantified metabolites showed significant systemic changes in several consecutively collected...

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Tesis por compendio / [ES] La presente tesis doctoral titulada "Sistemas de liberacio'n controlada de fa'rmacos diseñados para mejorar el tratamiento de Enfermedad Inflamatoria Intestinal" se centra en el diseño, preparación, caracterización y evaluación in vivo de distintos sistemas de liberación controlada de fármacos en colon (CDDS, por sus siglas en inglés) utilizando como soporte micropartículas de silice mesoporosa, funcionalizadas con puertas moleculares. En conclusión, los estudios realizados demuestran que los materiales de silice mesoporosa, en combinación con puertas moleculares sensibles a estímulos específicos, tienen un gran potencial para el desarrollo de nuevos sistemas de liberación controlada de fármacos en el colon, dirigidos a mejorar el arsenal terapéutico disponible para el tratamiento de EII. La posibilidad de adaptar o personalizar la carga y las puertas moleculares hace que estos soportes de sílice mesoporosa sean una opción interesante para el desarrollo de nuevos sistemas de liberación controlada de fármacos en diferentes aplicaciones biomédicas. Finalmente, esperamos que los resultados obtenidos en esta tesis doctoral sirvan de inspiración para el desarrollo de sistemas de liberación controlada de fármacos innovadores y cada vez más inteligentes, para su aplicación tanto en medicina como en otras áreas. / [CA] La present tesi doctoral titulada "Sistemes d'alliberament controlat de farmacs dissenyats per a millorar el tractament de Malaltia Inflamatoria Intestinal" se centra en el disseny, preparacio, caracteritzacio i avaluacio in vivo de diferents sistemes d'alliberament controlat de farmacs en colon (*CDDS, per les seues sigles en angles) utilitzant com a suport microparticules de si'lice mesoporosa, funcionalitzades amb portes moleculars. En conclusio, els estudis realitzats demostren que els materials de si'lice mesoporosa, en combinacio amb portes moleculars sensibles a estimuls especifics, tenen un gran potencial per al desenvolupament de nous sistemes d'alliberament controlat de farmacs en el colon, dirigits a millorar l'arsenal terapeutic disponible per al tractament de MII. La possibilitat d'adaptar o personalitzar la carrega i les portes moleculars, fa que aquests suports de silice mesoporosa siguen una opcio interessant per al desenvolupament de nous sistemes d'alliberacio controlada de farmacs en diferents aplicacions biomediques. Finalment, esperem que els resultats obtinguts en aquesta tesi doctoral servisquen d'inspiracio per al desenvolupament de sistemes d'alliberament controlat de farmacs innovadors i cada vegada mes intel·ligents, per a la seua aplicacio tant en medicina com en altres arees. / [EN] This PhD thesis entitled "Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy" is focused on the design, synthesis, characterization and in vivo evaluation of several Colon Drug Delivery Systems (CDDS) using hybrid mesoporous silica microparticles as scaffolds containing molecular gates. In conclusion, the studies shown in this Thesis demonstrate that mesoporous silica materials in combination with responsive molecular gates have great potential in the design and preparation of new CDDS to improve the therapeutic options available for IBD. The possibility to adapt the cargo and the molecular gate makes mesoporous silica support especially appealing for similar controlled drug delivery applications in the biomedical field. We hope that the obtained results could inspire the development of new innovative smart drug delivery systems in this or other fields. / We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. AHT thanks to the Spanish MEC for his FPU grant. We thank the Generalitat Valenciana (Project PROMETEO2018/024) / Hernández Teruel, A. (2019). Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129863 / TESIS / Compendio

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In the present investigation peripheral blood lymphocytes from patients with inflammatory bowel disease (IBD) and different cancer states were treated with various agents and compared with lymphocytes from healthy control individuals (HCI) treated in the same way and measured in the Comet assay. For inflammatory bowel disease, patient¿s responses in IBD patients treated with H2O2 were higher than in HCI and crohn¿s patients (CD) were found to have higher responses than Ulcerative colitis (UC) patients. The responses for all IBD and HCI were all reduced in the presence of chaga mushroom extract which behaved in an antioxidant manner. A second group of IBD patients were treated with the heterocyclic amine (food mutagen), IQ and H2O2 and responses were reduced in the presence of the flavonoids, quercetin and epicatechin and compared with HCI similarity treated. In all cells responses were reduced with flavonoids and again CD had higher responses than the UC patients and IBD patients higher than HCI. The responses with CD and UC were that confirmed in two independent studies with IBD, one with chaga mushroom extract and the other with flavonoids. Peripheral lymphocytes from malignant melanoma and suspected melanoma patients and colon cancer and polyposis patients were compared to the lymphocytes from HCI and treated with UVA. There were differential sensitivities when measured in the micronucleus and Comet assays. The cancer patients had higher responses than those in the precancerous states and they in turn were higher than responses in HCI. In all the studies, untreated baseline DNA damage values were also higher in IBD and cancer patients and pre-cancerous patients than HCIs. This would suggest that baseline frequencies of different diseases compared to controls could be an important biomarker in the diagnosis of pre-cancers and early stage cancers. Also peripheral lymphocytes are a useful surrogate for cancers and pre-cancerous disease states since, blood is present in all organs and tissues and DNA is basically the same in all cells.

<p>Intestinal microbiota are key determinants of gut homeostasis and affect various gut physiological and immune processes. Co-evolution has enabled the host and intestinal microbes to exist in a mutualistic relationship. However, interactions between the host and its intestinal microbiota exist in a delicate balance between mutualism and pathogenicity. Maintenance or disruption of this balance depends on a complex interplay between the microbiota and the host, as well as other gut luminal factors, including diet, that are poorly understood. The main goal of this thesis has been to study the host-gut luminal interactions that regulate gut physiology and immunity. In particular, <strong>Chapter 2</strong> centers on investigating the effect of perturbing the intestinal barrier using a non-steroidal inflammatory drug on host-microbial and dietary interactions in a mouse model of gluten sensitivity. I demonstrated that indomethacin-induced increase in intestinal permeability is associated with altered intestinal microbiota composition, systemic antibody development against intestinal bacteria and a shift in immune responses to the dietary antigen, gluten. <strong>Chapter 3</strong> focuses on investigating whether modulation of the intestinal microbiota can affect the host’s susceptibility to intestinal injury. I used mice with defective intracellular bacterial receptor signaling because discrimination between commensals and pathogens is, in part, achieved by a family of receptors that recognize conserved bacterial components. I demonstrated that the microbiota with which these mice are colonized influences the expression of RegIII-γ, a type of antimicrobial peptide, and susceptibility to intestinal injury. To gain further insight on the effect of microbiota on antimicrobial peptides, in <strong>Chapter 4</strong> we conducted a combination of gnotobiotic and <em>in-vitro</em> experiments where we identified that specific components of the microbiota differentially regulate RegIII expression. Further examination showed that <em>MyD88 a</em>nd <em>Ticam1 </em>genes, which are signaling adaptor proteins of pattern recognition receptors, are essential regulators of microbial–induced RegIII expression by intestinal epithelial cells. Collectively, the work presented in this thesis provides novel insight on the bi-directional interaction between the host and the gut luminal content as well as of potential beneficial effects of microbiota-modulating strategies in maintaining homeostasis and preventing disease.</p> / Doctor of Philosophy (Medical Science)