Cork Centre for Vitamin D and Nutrition Research - Doctoral Theses

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    Innovative food design to support a healthier diet – exploring the effects of dietary fibre enrichment on functional characteristics, physiological and microbiome effects, and consumer acceptance of staple foods
    (University College Cork, 2026-04-30) Walsh, Sarah Kate; Lucey, Alice; Walter, Jens; Research Ireland
    Introduction: Inadequate dietary fibre intake is a public health concern and has been linked to increased risk of noncommunicable chronic diseases. Food reformulation using isolated fibres offers a practical tool to develop palatable fibre-rich foods with a lower glycaemic index, energy density, and increased microbiome accessibility. However, it is unclear whether isolated fibres can substitute high proportions of refined carbohydrates in foods without compromising functionality or acceptability. Additionally, to our knowledge, no randomised controlled trial (RCT) has evaluated the metabolic and microbiome effects of such foods within a fully controlled diet. The overarching aim of this thesis was to apply innovative food design to systematically replace refined carbohydrates with isolated fibres in three commonly consumed foods, test their techno-functional, nutritional and sensory qualities, and conduct a strictly controlled RCT to determine the effects of a fibre-rich diet including developed products on glycaemia, energy intake, satiety, and the gut microbiome. Methods: Chapters 2-3 present comprehensive reviews of fibre-based nutritional strategies and critically evaluate the evidence supporting the use of isolated fibres, including resistant starch (RS) for improving metabolic health and food functionality. Chapter 4 details the development and characterisation of reformulated bread, pasta, and scones produced by substituting digestible carbohydrates with diverse fibre blends, using two doses (high- and very-high) of dietary fibre. Their nutritional composition, techno-functional properties, and consumer acceptability were evaluated. These products were subsequently incorporated into whole-diet meal plans with matched controlled diets. Chapters 5-6 detail the design and conduct of The Fibre Full Study, a strictly controlled human feeding trial using a single-blinded, randomised crossover-controlled whole-diet approach among adults with excess body weight (BMI 25-35 kg/m2). The intervention comprised of two 8-day dietary periods including a fibre-rich diet and a control diet separated by a ≥13 day washout. The fibre-rich diet included a dose increase, beginning with a high-fibre phase (38-45 g/day) for the first 4-days followed by a very-high-fibre phase (57-67 g/day) for the last four intervention days, while the control diet provided 21-25 g/day of fibre. Ad libitum snacking was allowed at predefined times. The primary outcome was postprandial glycaemic response to study meals measured by incremental area under the curve (iAUC) using continuous glucose monitoring (CGM). Secondary outcomes included energy intake, perceived satiety, glycaemic variability, gastrointestinal symptoms, and microbiome composition and function. Results: Our literature reviews highlight the variability in function and efficacy of the different fibre sources across fibre-based nutritional strategies. Although intrinsic fibre from whole-plant foods demonstrated the most consistent clinical benefits, emerging research illustrates the use of isolated fibres such as RS to improve metabolic markers and support reformulation initiatives. In Chapter 4, very-high-fibre products were developed which substituted 52% (bread), 27% (pasta) and 47.5% (scones) of flour with isolated fibres, with high-fibre recipes using half of these replacement levels. Reformulation reduced the energy contents, in vitro digestibility, and increased the fibre contents of fibre-rich products in comparison to controls. While very-high-fibre products showed a decrease in quality characteristics and overall acceptability compared to controls, the high-fibre formulations showed consistent high overall consumer acceptability. Incorporating fibre-rich products into study meal plans led to decreases in daily energy content and increases in fibre content to 38-45 g/day and 57-67 g/day for the high and very-high-fibre diets respectively. The RCT demonstrated that the fibre-rich diet was well tolerated and accepted, with no overall increases in gastrointestinal symptoms. The fibre-rich diet significantly reduced postprandial glycaemic responses. Postprandial iAUC significantly decreased at breakfast and lunch with greatest effects on the very-high-fibre phase. Average daily mealtime iAUC was lower on the very-high-fibre diet than on the control (p<0.05). Twenty-four-hour glycaemic variability (CV) also decreased across both fibre-rich phases versus control (all p<0.05). Total daily energy intake was lower on the fibre-rich diet (p<0.001), with no compensatory increase in snacking. Microbiome analyses showed a reduction of branched-chain fatty acid (BCFA) concentrations and the BCFA:SCFA ratio and increases in fibre-degrading taxa with the fibre-rich diet compared to the control. Regression analysis indicated that postprandial glycaemic response did not predict energy intake. Instead, greater abundances of fibre-degrading taxa, and lower BCFA:SCFA ratios predicted lower energy intake. Conclusions: This thesis highlights that innovative food design using isolated fibres offers a pragmatic strategy to produce palatable, nutritionally improved foods capable of altering metabolic and microbiome outcomes. When incorporated into a whole-diet, very-high-fibre reformulated foods reduced postprandial glycaemia, lowered energy intake, maintained satiety, and shifted microbial metabolism. These findings provide new mechanistic and clinical evidence supporting fibre-reformulation as a practical and scalable public health strategy to help close the population fibre gap and support metabolic health.
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    Iodine status in pregnancy and associations with infant neurodevelopmental outcomes
    (University College Cork, 2025) Kelliher, Lisa; Hennessy, Aine; Kiely, Mairead; Science Foundation Ireland
    Adequate iodine intake in pregnancy is crucial for foetal brain development. Although the effects of severe iodine deficiency are well established, data on the effects of mild-to-moderate deficiency are mixed. Pregnant women are vulnerable to iodine deficiency due to higher requirements and lower dietary intakes of key dietary sources, particularly cows’ milk. The overall aim of this thesis was to assess the iodine status of Irish women and to evaluate the relationship between maternal iodine status in early gestation, and child neurodevelopmental outcomes through a series of original research studies. Chapter 2 describes the development of an iodine food frequency questionnaire (I-FFQ), and its validation in a convenience sample of non-pregnant Irish women aged 18-50 years (n=100) using a 4-day Food Diary (FD) as the reference method. Due to the overlap in dietary sources of iodine and vitamin D, the I-FFQ was developed by refining an existing UCC Vitamin D questionnaire and validated using the method of triads, Bland-Altman analysis and classification of the tertiles of intake distribution. The I-FFQ demonstrated reasonable validity; coefficients for the I-FFQ and FD and UIC were 0.542, 0.800 and 0.228, respectively. Median (IQR) intakes were estimated at 161 (106, 217)µg/d and 133 (98, 182)µg/d for the I-FFQ and FD, respectively (P =0.001), and were moderately correlated (r=0.434). The I-FFQ classified 89% of participants into the same or adjacent tertile of intake as the FD. The median (IQR) UIC of Irish women of childbearing age was low [82 (49,139)]µg/d. The I-FFQ provides a reasonable estimate of habitual iodine intake in women and due to its simplicity and reproducibility may have applications in research for screening individuals at risk of iodine deficiency. Chapter 3 provides an account of dietary iodine intakes in two human nutrition intervention studies: the Cork Vitamin D requirements in pregnant women (DMAT) and the Trial to Assess Vitamin D Requirements in Lactating Women (DMUMs) pregnancy and breastfeeding RCTs. Participants (n=156) provided vitamin D intake at baseline (≤18 week’ gestation) using a quantitative FFQ, which was validated for vitamin D and calcium intakes. Iodine intakes in the current study were calculated by applying food composition data from COFIDs (7th edition) and the Food Safety Authority of Ireland to the food intake data. Thyroid hormones (TSH, FT3, FT4) were assessed longitudinally and Tg in the first trimester using existing maternal sera from the DMAT and DMUMs RCTs. Analytes were measured in duplicate by chemiluminescence immunoassay via the Beckman Coulter DXI900 at the Clinical Biochemistry Laboratory, Cork University Hospital. Associations between diet and thyroid function were explored, through Spearman’s correlation and cross-classification of thyroid hormones across tertiles of intake. From our analysis, in euthyroid pregnant women (n=144) median (IQR) iodine intake was 293 (227, 371)μg/d and 13% had intakes below the IOM AR (200µg/d). There was a large differential in the prevalence below the IOM AR, between iodine containing supplement users and non-users (1.1% of and 34%, respectively). Milk made the largest contribution to iodine intake (42.7%). Nutritional supplements were the second highest contributor to iodine intake (30.1%). In breastfeeding mothers, (n=109) median (IQR) intakes were 197 (140, 280)µg/d and over half of women had intakes below the Institute of Medicine (IOM) Average Requirement (AR) (209µg/d). The prevalence of iodine containing supplement use was low (8% at first visit ). Cows’ milk made the largest contribution to iodine intake (62.6%), with fish coming second (8.0%). Associations between diet and thyroid hormones were assessed across the three trimesters and during breastfeeding. We did not observe any significant differences in thyroid function across thirds of the intake distribution, except for TSH in pregnant women at the midpoint visit. Isolated maternal hypothyroxinaemia was most prevalent in the third trimester (9.3%). Additionally, trimester specific normative reference ranges were determined for pregnant and breastfeeding women in the Irish population. Many women had low iodine intakes and although there were no associations between diet and thyroid function, the finding of 9% of women with isolated maternal hypothyroxinaemia in the third trimester is one with warrants further investigation of the long-term effects of inadequate iodine intake and thyroid function in this population. In chapter 4 we conducted the first large scale assessment (n=1350) of maternal iodine status using existing biobanked data from the Cork arm of the European funded IMproved PRegnancy Outcomes by Early Detection (IMPROvED) study. Urinary iodine concentration (UIC) at 11 and 15-weeks’ gestation was quantified by the Sandell-Kolthoff (S-K) microplate colorimetric method and creatinine was measured on the Randox Monaco analyser. The non-dietary determinants of maternal UIC and I:Cr were explored in multivariate linear and logistic regression models. Low maternal iodine status was observed at both timepoints, 128µg/L and 125µg/L at 11 and 15 weeks, respectively. In fully adjusted models, iodine-containing nutritional supplement use and winter season of sampling were significant predictors of UIC (µg/L and UIC <150µg/L) at 15 weeks’ gestation. After correction for urine volume, supplement use, education, BMI, winter UIC sampling and age were significant predictors of I:Cr < 150µg/g. This study showed that most Irish women had insufficient iodine status during early pregnancy and there is a need to further evaluate the implications of low maternal intake on infant neurodevelopment. The first assessment of maternal iodine status in pregnancy and its associations with child neurodevelopment was conducted in chapter 5. The Cork Nutrition and Development Maternal-Infant cohort (COMBINE), which was a follow up birth cohort to the IMPROvED study, assessed child neurodevelopment and behavioural outcomes up to 2 years, through psychologist led validated assessments: Bayley Scales of Infant and Toddler Development (3rd edition) (BSID-III) and the Child Behaviour Checklist (CBCL). Associations between maternal UIC/I:Cr and child neurodevelopment at 24 months was tested using multivariate linear and logistic regression. In fully adjusted multivariate linear regression models maternal UIC <100µg/L was negatively associated with child cognitive (β (95% CI): -3.97 (-7.70, -0.24), P = 0.037) and language (β (95% CI): -5.14 (-9.95, -0.34), P =0.036) composite scores, and with the combined cognitive and language scores (β (95% CI): -4.29 (-8.26, -0.32, P =0.034) (reflective of executive function). No significant observations were found between maternal urinary iodine status and child behaviour problem scores. Conclusion Overall, the results of this thesis indicate that iodine status is low among Irish pregnant and breastfeeding women, and in women of childbearing age. Low maternal iodine status in early pregnancy was associated with lower child language, cognition and executive functioning at 2 years, which is concerning as there are currently no policies for mandatory fortification or supplementation and awareness of the importance of the role of iodine in health is low.
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    Impact of a transition to diets from sustainable sources on micronutrient intakes and status
    (University College Cork, 2024) Leonard, Ursula; Kiely, Mairead; Arranz, Elena; Department of Agriculture, Food and the Marine, Ireland; Food Institutional Research Measure
    Background: A global transition to diets from sustainable sources is required for planetary health. This transition will result in greater reliance on plant-based protein sources coupled with reductions in animal source foods. The evidence base underpinning the formulation of nutrition policy lacks data on the feasibility, safety and effectiveness of translating sustainable dietary guidelines into practice in the population, which could pose risks to nutrition for large sectors, including females of reproductive age and children. Objective: The aim of this thesis was to explore of the impact of a transition to diets from sustainable sources on micronutrient (MN) intakes and status. Objectives were to systematically review the existing evidence assessing the impact of following environmentally protective diets on MN intakes and status (Chapter 2); design and conduct a first-of-its-kind dietary intervention trial of an environmentally protective diet (Chapter 3); assess the impact of the intervention on MN intakes (Chapter 4) and status (Chapter 5); and explore the potential for dietary modelling to assist the development of MN adequate diets from sustainable sources (Chapter 6). Methods: PRISMA guidelines were followed to conduct a systematic literature review (SLR) of studies reporting MN and environmental outcomes, searching seven databases from January 2011 to October 2022 (Chapter 2). Chapters 3 to 5 describe a 12-week, three-centre, single-blind, parallel, randomised controlled trial (RCT) among 355 healthy participants aged 18-64 years, known as MyPlanetDiet. The intervention provided participants with personalised dietary advice based on their dietary habits, in line with sustainable healthy principles (intervention arm) or dietary guidance based on the Irish and Northern Irish healthy eating guidelines (control arm). Outcomes included changes in dietary environmental impacts, energy, protein, MN intakes, the prevalence of inadequate intakes and changes in MN status throughout the intervention. Chapter 6 describes a narrative review of diet optimisation studies that design diets considering nutritional, environmental and context-specific constraints. Results: The SLR (Leonard et al., 2024) included 56 studies; one RCT which provided the only biomarker data; 10 dietary intake studies, and 45 dietary modelling studies, including 29 diet optimisation studies. Most studies suggested that intakes of zinc, calcium, iodine, and vitamins A, B12 and D would decrease, and total iron and folate would increase in a dietary transition to reduce environmental impacts, with similar findings for the prevalence of inadequate intakes, reported in only 10 studies. In the MyPlanetDiet RCT, dietary GHGE decreased from baseline to endpoint in both arms and was lower in the intervention arm at endpoint. There were changes in MN intakes in both arms over the 12-weeks, and at endpoint, the intervention arm had lower intakes of energy, protein, thiamin, riboflavin, niacin, vitamins D, B6, B12 and C, calcium, zinc, potassium, selenium and iodine, and higher intakes of vitamins A, E and K1 (P < 0.05) compared with controls. The prevalence of inadequate intakes of riboflavin, calcium, zinc, vitamins B6, B12 and C was higher, and of vitamin E and copper was lower (P < 0.05) among females in the intervention arm than controls. Among males, the prevalence of inadequate intakes of riboflavin, selenium and iodine was higher in the intervention arm than controls (P < 0.05). Changes in biomarkers of nutritional status analysed for this thesis were minimal over the 12 weeks. Our narrative review of diet optimisation studies (Leonard & Kiely, 2024) identified a range of diets that meet individual MN requirements, have reduced environmental impacts, and minimise deviation from culturally acceptable dietary practices. Although these are theoretical solutions, opportunities arising from the results of diet optimisation studies include supporting the development of food-based dietary guidelines and exploring food-based strategies to increase nutrient supply, such as fortification. Conclusions: The findings from our SLR, mainly based on observational data, and the MyPlanetDiet RCT aligned, identifying several key MNs that are at risk in the transition to diets from sustainable sources, particularly among females. Greater emphasis on meeting diverse MN requirements from appropriate dietary sources is required in the global discussion around developing diets from sustainable sources. Dietary modelling techniques, such as diet optimisation, can be a useful tool in the generation of hypotheses and diet solutions for testing in further intervention studies among diverse populations.
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    Quantifying minor vitamin D metabolites using liquid chromatography-tandem mass spectrometry and determining their contribution to vitamin D nutritional status
    (University College Cork, 2019) Dowling, Kirsten G.; Cashman, Kevin; Kiely, Mairead; European Commission; Seventh Framework Programme; Department of Agriculture, Food and the Marine; Nordisk Ministerråd
    Adequate vitamin D status is necessary throughout life in terms of maintaining bone strength, calcium and phosphorus balance, as well as prevention of rickets in children and osteomalacia in adults. The accepted biomarker used for the assessment of vitamin D status is circulating total 25-hydroxyvitamin D (25(OH)D) concentration, which is comprised of the sum of 25-hydroxyvitamin D3 (25(OH)D3) and 25-hydroxvitamin D2 (25(OH)D2) The use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the analysis of total 25(OH)D has also enabled the detection of low concentration, minor vitamin D metabolites in serum. The aims of this work were to examine the impact of three such minor vitamin D metabolites, 25(OH)D2, 24,25-dihydroxyvitamin D (24,25(OH)2D), and 3 epimer of 25(OH)D3 (3-epi-25(OH)D3) on the assessment of vitamin D nutritional status and also to provide further insight and refinement of our understanding of the vitamin D metabolic pathway. This required the development and validation of LC-MS/MS methods for measuring these three metabolites in multiple matrices (serum/plasma, meat, milk). Serum 25(OH)D2, not only contributes to the total 25(OH)D estimate, but also serves as a marker for vitamin D2 intake. Its presence in sera from a diverse collection of European populations, as part of this work, suggests that vitamin D2 is present in the food chain. Preliminary analysis of Irish milk and beef, as prioritized candidate food sources, for 25(OH)D2 and vitamin D2 were unable to pinpoint the primary dietary contributors to vitamin D2 intake. In the present work, an improved method for LC-MS/MS analysis was developed which produced accurate results for both total 25(OH)D and the metabolite 24,25(OH)2D. Application of this method allowed us to demonstrate that the presence of 24,25(OH)2D in serum led to an overestimated measurement of serum total 25(OH)D when employing an exemplar immunoassay technique. 24,25(OH)2D is the first metabolite in the vitamin D catabolic cascade, and thus considered a marker of vitamin D catabolism. The new LC-MS/MS method for 24,25(OH)2D was applied as a means to determine differential catabolic rates between 25(OH)D2 and 25(OH)D3 in multiple species. This analysis also highlighted novel inter-species differences in the ratio of 24,25(OH)2D to 25(OH)D. The availability of a large sample set of age-stratified population studies across Europe revealed that serum 3-epi-25(OH)D3 was primarily dependent on age, with concentrations highest at birth and decreasing steadily up until adolescence. While some 3-epi-25(OH)D3 was detected in pork and beef, as potential exogenous sources of the epimer, the majority of circulating 3-epi-25(OH)D3 is produced endogenously via an enzyme distinct from 25-hydroxlase. Overall, this work highlights the potential of using LC-MS/MS to analyse minor vitamin D metabolites which can help add new information to the research area of vitamin D metabolism and status, and potentially better inform clinical interpretations of vitamin D status.
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    An exploration of the calcium metabolic system in pregnancy and public health programmes to improve early nutrition in maternal-infant cohorts
    (University College Cork, 2019) Hemmingway, Andrea; Kiely, Mairead; Science Foundation Ireland
    Although pregnancy and infancy represent periods of particular nutritional vulnerability, many gaps in the evidence base remain during these life-stages. The research in this thesis was conducted in two phases across three studies in pregnant women and infants. The aim of the first phase was to examine the vitamin D-calcium metabolic system in pregnancy. In the largest clinical study to date, serum 25- hydroxyvitamin D [25(OH)D] and parathyroid hormone [PTH] were analysed in 1754 women in the SCOPE pregnancy cohort. While 25% of participants had a 25(OH)D concentration > 75 nmol/L, 17% were < 30 nmol/L. Functional vitamin D deficiency, defined as 25(OH)D < 30 nmol/L plus elevated PTH (> 80th percentile), occurred in 5.5% of participants. The prevalence of elevated mean arterial pressure (19.1 vs. 9.7%) and small-for-gestational-age (16.0 vs. 6.7%) were highest in those with functional vitamin D deficiency (P < 0.05), compared with the reference group [25(OH)D ≥ 75 nmol/L and normal PTH]. The adjusted prevalence ratio and risk ratio (95% CIs) were 1.83 (1.02, 3.27) and 1.53 (0.80, 2.93) for elevated mean arterial pressure and small-for-gestational-age, respectively. These data indicate the need to consider the broader calcium metabolic system in future studies of vitamin D and perinatal health. Following this, the relative impact of serum 25(OH)D and calcium intake on PTH was explored using baseline data from a vitamin D dose-response trial (n = 142). PTH was inversely correlated with 25(OH)D (r = -0.311, P < 0.001), but not calcium intake (r = -0.087, P = 0.306). In categorical analyses, there was no 25(OH)D-calcium interaction effect on PTH (P = 0.941) and 25(OH)D < 50 nmol/L, but not stratified calcium intake, significantly affected PTH concentration (P = 0.025 and 0.822, respectively). In this group of white-skinned pregnant women, who generally had sufficient calcium intakes, serum 25(OH)D was important for maintaining PTH concentration. The background nutritional status and participant population appear to be critical factors. The second research phase explored early life nutrition in the COMBINE birth cohort. COMBINE, a prospective, nutrition-led study, recruited 456 participants between 2015 and 2017 and has 9 study visits over the first 2 years of life. Examination of infant feeding practices indicated that 44% gave breastmilk as the main milk source at hospital discharge, 36% at 2 months, 24% at 6 months and 19% at 9 months. The rate of infant formula only feeding increased from 25% at discharge to 49% at 2 months and 74% at 9 months of age. Combination feeding of breastmilk and infant formula was common at discharge (31%) and 1 month (20%); these mothers were more likely to stop breastfeeding altogether than those who breastfed (all P< 0.05). The median (IQR) age of introduction to solid foods was 21 (18, 24) weeks; 9% introduced solids before 17 weeks of age. While these data provide evidence of some progress towards longer breastfeeding durations, there remains much scope to improve infant feeding practices in Ireland. Adherence to the national infant vitamin D supplementation policy, implemented in 2010, is not monitored nationally and the policy has not been formally evaluated; policy adherence was examined in the COMBINE cohort (n = 365). Most parents initiated supplementation at birth (92%), used a vitamin D3 only product (94%), and gave the recommended 5 µg dose (88%). Half (51%) administered vitamin D daily and a further 33% supplemented at least 3-6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. Given high levels of maternal and infant deficiency and the current lack of a maternal supplementation policy in Ireland, the infant vitamin D supplementation policy should remain a public health priority. With two research foci, the data generated in this thesis provides much-needed advancement of knowledge regarding the vitamin D-calcium metabolic system in pregnancy and public health nutrition in the first year of life.