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Metabolic footprint and intestinal microbial changes in response to dietary proteins in a pig model
(2019)
Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome. (C) 2019 Elsevier Inc. All rights reserved.
In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.
Frailty and sarcopenia share some underlying characteristics like loss of muscle mass, low muscle strength, and low physical performance. Imaging parameters and functional examinations mainly assess frailty and sarcopenia criteria; however, these measures can have limitations in clinical settings. Therefore, finding suitable biomarkers that reflect a catabolic muscle state e.g. an elevated muscle protein turnover as suggested in frailty, are becoming more relevant concerning frailty diagnosis and risk assessment.
3-Methylhistidine (3-MH) and its ratios 3-MH-to-creatinine (3-MH/Crea) and 3 MH-to-estimated glomerular filtration rate (3-MH/eGFR) are under discussion as possible biomarkers for muscle protein turnover and might support the diagnosis of frailty. However, there is some skepticism about the reliability of 3-MH measures since confounders such as meat and fish intake might influence 3-MH plasma concentrations. Therefore, the influence of dietary habits and an intervention with white meat on plasma 3-MH was determined in young and healthy individuals. In another study, the cross-sectional associations of plasma 3-MH, 3-MH/Crea and 3-MH/eGFR with the frailty status (robust, pre-frail and frail) were investigated.
Oxidative stress (OS) is a possible contributor to frailty development, and high OS levels as well as low micronutrient levels are associated with the frailty syndrome. However, data on simultaneous measures of OS biomarkers together with micronutrients are lacking in studies including frail, pre-frail and robust individuals. Therefore, cross-sectional associations of protein carbonyls (PrCarb), 3-nitrotyrosine (3-NT) and several micronutrients with the frailty status were determined.
A validated UPLC-MS/MS (ultra-performance liquid chromatography tandem mass spectrometry) method for the simultaneous quantification of 3-MH and 1-MH (1 methylhistidine, as marker for meat and fish consumption) was presented and used for further analyses. Omnivores showed higher plasma 3-MH and 1-MH concentrations than vegetarians and a white meat intervention resulted in an increase in plasma 3-MH, 3 MH/Crea, 1-MH and 1-MH/Crea in omnivores. Elevated 3-MH and 3-MH/Crea levels declined significantly within 24 hours after this white meat intervention. Thus, 3-MH and 3-MH/Crea might be used as biomarker for muscle protein turnover when subjects did not consume meat 24 hours prior to blood samplings.
Plasma 3-MH, 3-MH/Crea and 3-MH/eGFR were higher in frail individuals than in robust individuals. Additionally, these biomarkers were positively associated with frailty in linear regression models, and higher odds to be frail were found for every increase in 3 MH and 3-MH/eGFR quintile in multivariable logistic regression models adjusted for several confounders. This was the first study using 3-MH/eGFR and it is concluded that plasma 3-MH, 3-MH/Crea and 3-MH/eGFR might be used to identify frail individuals or individuals at higher risk to be frail, and that there might be threshold concentrations or ratios to support these diagnoses.
Higher vitamin D3, lutein/zeaxanthin, γ-tocopherol, α-carotene, β-carotene, lycopene and β-cryptoxanthin concentrations and additionally lower PrCarb concentrations were found in robust compared to frail individuals in multivariate linear models. Frail subjects had higher odds to be in the lowest than in the highest tertile for vitamin D3 α-tocopherol, α-carotene, β-carotene, lycopene, lutein/zeaxanthin, and β cryptoxanthin, and had higher odds to be in the highest than in the lowest tertile for PrCarb than robust individuals in multivariate logistic regression models. Thus, a low micronutrient together with a high PrCarb status is associated with pre-frailty and frailty.
Anthropogenic climate change alters the hydrological cycle. While certain areas experience more intense precipitation events, others will experience droughts and increased evaporation, affecting water storage in long-term reservoirs, groundwater, snow, and glaciers. High elevation environments are especially vulnerable to climate change, which will impact the water supply for people living downstream. The Himalaya has been identified as a particularly vulnerable system, with nearly one billion people depending on the runoff in this system as their main water resource. As such, a more refined understanding of spatial and temporal changes in the water cycle in high altitude systems is essential to assess variations in water budgets under different climate change scenarios.
However, not only anthropogenic influences have an impact on the hydrological cycle, but changes to the hydrological cycle can occur over geological timescales, which are connected to the interplay between orogenic uplift and climate change. However, their temporal evolution and causes are often difficult to constrain. Using proxies that reflect hydrological changes with an increase in elevation, we can unravel the history of orogenic uplift in mountain ranges and its effect on the climate.
In this thesis, stable isotope ratios (expressed as δ2H and δ18O values) of meteoric waters and organic material are combined as tracers of atmospheric and hydrologic processes with remote sensing products to better understand water sources in the Himalayas. In addition, the record of modern climatological conditions based on the compound specific stable isotopes of leaf waxes (δ2Hwax) and brGDGTs (branched Glycerol dialkyl glycerol tetraethers) in modern soils in four Himalayan river catchments was assessed as proxies of the paleoclimate and (paleo-) elevation. Ultimately, hydrological variations over geological timescales were examined using δ13C and δ18O values of soil carbonates and bulk organic matter originating from sedimentological sections from the pre-Siwalik and Siwalik groups to track the response of vegetation and monsoon intensity and seasonality on a timescale of 20 Myr.
I find that Rayleigh distillation, with an ISM moisture source, mainly controls the isotopic composition of surface waters in the studied Himalayan catchments. An increase in d-excess in the spring, verified by remote sensing data products, shows the significant impact of runoff from snow-covered and glaciated areas on the surface water isotopic values in the timeseries.
In addition, I show that biomarker records such as brGDGTs and δ2Hwax have the potential to record (paleo-) elevation by yielding a significant correlation with the temperature and surface water δ2H values, respectively, as well as with elevation. Comparing the elevation inferred from both brGDGT and δ2Hwax, large differences were found in arid sections of the elevation transects due to an additional effect of evapotranspiration on δ2Hwax. A combined study of these proxies can improve paleoelevation estimates and provide recommendations based on the results found in this study.
Ultimately, I infer that the expansion of C4 vegetation between 20 and 1 Myr was not solely dependent on atmospheric pCO2, but also on regional changes in aridity and seasonality from to the stable isotopic signature of the two sedimentary sections in the Himalaya (east and west).
This thesis shows that the stable isotope chemistry of surface waters can be applied as a tool to monitor the changing Himalayan water budget under projected increasing temperatures. Minimizing the uncertainties associated with the paleo-elevation reconstructions were assessed by the combination of organic proxies (δ2Hwax and brGDGTs) in Himalayan soil. Stable isotope ratios in bulk soil and soil carbonates showed the evolution of vegetation influenced by the monsoon during the late Miocene, proving that these proxies can be used to record monsoon intensity, seasonality, and the response of vegetation. In conclusion, the use of organic proxies and stable isotope chemistry in the Himalayas has proven to successfully record changes in climate with increasing elevation. The combination of δ2Hwax and brGDGTs as a new proxy provides a more refined understanding of (paleo-)elevation and the influence of climate.
Background
Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet.
Methods
The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release.
Results
While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity.
Conclusion(s)
Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research.
Background
Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet.
Methods
The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release.
Results
While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity.
Conclusion(s)
Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research.
Background: The role of fatty acid (FA) intake and metabolism in type 2 diabetes (T2D) incidence is controversial. Some FAs are not synthesised endogenously and, therefore, these circulating FAs reflect dietary intake, for example, the trans fatty acids (TFAs), saturated odd chain fatty acids (OCFAs), and linoleic acid, an n-6 polyunsaturated fatty acids (PUFA). It remains unclear if intake of TFA influence T2D risk and whether industrial TFAs (iTFAs) and ruminant TFAs (rTFAs) exert the same effect. Unlike even chain saturated FAs, the OCFAs have been inversely associated with T2D risk, but this association is poorly understood. Furthermore, the associations of n-6 PUFAs intake with T2D risk are still debated, while delta-5 desaturase (D5D), a key enzyme in the metabolism of PUFAs, has been consistently related to T2D risk. To better understand these relationships, the FA composition in circulating lipid fractions can be used as biomarkers of dietary intake and metabolism. The exploration of TFAs subtypes in plasma phospholipids and OCFAs and n-6 PUFAs within a wide range of lipid classes may give insights into the pathophysiology of T2D.
Aim: This thesis aimed mainly to analyse the association of TFAs, OCFAs and n-6 PUFAs with self-reported dietary intake and prospective T2D risk, using seven types of TFAs in plasma phospholipids and deep lipidomics profiling data from fifteen lipid classes.
Methods: A prospective case-cohort study was designed within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, including all the participants who developed T2D (median follow-up 6.5 years) and a random subsample of the full cohort (subcohort: n=1248; T2D cases: n=820). The main analyses included two lipid profiles. The first was an assessment of seven TFA in plasma phospholipids, with a modified method for analysis of FA with very low abundances. The second lipid profile was derived from a high-throughout lipid profiling technology, which identified 940 distinct molecular species and allowed to quantify OCFAs and PUFAs composition across 15 lipid classes. Delta-5 desaturase (D5D) activity was estimated as 20:4/20:3-ratio. Using multivariable Cox regression models, we examined the associations of TFA subtypes with incident T2D and class-specific associations of OCFA and n-6 PUFAs with T2D risk.
Results: 16:1n-7t, 18:1n-7t, and c9t11-CLA were positively correlated with the intake of fat-rich dairy foods. iTFA 18:1 isomers were positively correlated with margarine. After adjustment for confounders and other TFAs, higher plasma phospholipid concentrations of two rTFAs were associated with a lower incidence of T2D: 18:1n-7t and t10c12-CLA. In contrast, the rTFA c9t11-CLA was associated with a higher incidence of T2D. rTFA 16:1n-7t and iTFAs (18:1n-6t, 18:1n-9t, 18:2n-6,9t) were not statistically significantly associated with T2D risk.
We observed heterogeneous integration of OCFA in different lipid classes, and the contribution of 15:0 versus 17:0 to the total OCFA abundance differed across lipid classes. Consumption of fat-rich dairy and fiber-rich foods were positively and red meat inversely correlated to OCFA abundance in plasma phospholipid classes. In women only, higher abundances of 15:0 in phosphatidylcholines (PC) and diacylglycerols (DG), and 17:0 in PC, lysophosphatidylcholines (LPC), and cholesterol esters (CE) were inversely associated with T2D risk. In men and women, a higher abundance of 15:0 in monoacylglycerols (MG) was also inversely associated with T2D. Conversely, a higher 15:0 concentration in LPC and triacylglycerols (TG) was associated with higher T2D risk in men. Women with a higher concentration of 17:0 as free fatty acids (FFA) also had higher T2D incidence.
The integration of n-6 PUFAs in lipid classes was also heterogeneous. 18:2 was highly abundant in phospholipids (particularly PC), CE, and TG; 20:3 represented a small fraction of FA in most lipid classes, and 20:4 accounted for a large proportion of circulating phosphatidylinositol (PI) and phosphatidylethanolamines (PE). Higher concentrations of 18:2 were inversely associated with T2D risk, especially within DG, TG, and LPC. However, 18:2 as part of MG was positively associated with T2D risk. Higher concentrations of 20:3 in phospholipids (PC, PE, PI), FFA, CE, and MG were linked to higher T2D incidence. 20:4 was unrelated to risk in most lipid classes, except positive associations were observed for 20:4 enriched in FFA and PE. The estimated D5D activities in PC, PE, PI, LPC, and CE were inversely associated with T2D and explained variance of estimated D5D activity by genomic variation in the FADS locus was only substantial in those lipid classes.
Conclusion: The TFAs' conformation is essential in their relationship to diabetes risk, as indicated by plasma rTFA subtypes concentrations having opposite directions of associations with diabetes risk. Plasma OCFA concentration is linked to T2D risk in a lipid class and sex-specific manner. Plasma n-6 PUFA concentrations are associated differently with T2D incidence depending on the specific FA and the lipid class. Overall, these results highlight the complexity of circulating FAs and their heterogeneous association with T2D risk depending on the specific FA structure, lipid class, and sex. My results extend the evidence of the relationship between diet, lipid metabolism, and subsequent T2D risk. In addition, my work generated several potential new biomarkers of dietary intake and prospective T2D risk.