Characterising cardiometabolic health through inflammation and micronutrients

• Metabolic Diseases

The EHES-LUX Study provides valuable inputs 

Researchers from the LIH Department of Population Health (DoPH) recently investigated whether the concentration of micronutrients/secondary plant compounds, markers of oxidative stress/inflammation, as well as socioeconomic indicators can be associated with the risk of metabolic syndrome (MetS). Their study, which was published in the January 2021 issue of the international journal Nutrients, is part of the FNR-funded CORE project “Micronutrients, Pollutants and Cardiometabolic Health in Luxembourg” (IMPACT.lu). IMPACT.lu builds on data from the European Health Examination Survey in Luxembourg (EHES-LUX), a population-based survey conducted between February 2013 and January 2015 in the Grand Duchy. In this interview, Dr. Maria Ruiz-Castell, Scientist within the Public Health Research Unit and leader of IMPACT-LUX and EHES-LUX, and Dr. Torsten Bohn, Group Leader of the Nutrition and Health Research Group, share their findings.

Dr. Bohn, could you tell us more about metabolic syndrome (MetS) and its relevance?

TB: When we talk about MetS, we refer to a combination of different metabolic disorders, including abdominal obesity, insulin resistance, high cholesterol and high blood pressure. Together, these increase the patient’s risk of developing cardiometabolic diseases such as cardiovascular disease (CVD) or type 2 diabetes, which in turn are the leading cause of mortality worldwide. Indeed, MetS is a global health issue, affecting nearly 25% of the world’s adult population. From a molecular perspective, MetS is typically associated with chronic inflammation and high levels of oxidative stress caused by the excessive production of pro-inflammatory cytokines, which ultimately leads to cellular damage and may even result in organ failure – as is also the case for COVID-19. It is believed that factors such as a sedentary lifestyle, unbalanced diet, chronic exposure to environmental pollutants and genetic predisposition could be at the origin of MetS. Indeed, several studies have shown an association between a healthy diet rich in fruits and vegetables and a reduction in the risk of developing MetS, but also chronic diseases such as CVD, type 2 diabetes and even certain types of cancer. This could be explained by the antioxidant and anti-inflammatory properties of certain nutrients and secondary plant-compounds present in fruits and vegetables, including vitamins, minerals, carotenoids, polyphenols and fibres, which counteract the action of oxidative and pro-inflammatory agents, either directly via quenching effects, or via cellular transcription factors such as NF-κB and Nrf-2, so-called “master-switches” for inflammation and oxidative stress. Moreover, increased amounts of adipose tissue are frequently associated with lower circulating levels of antioxidants in individuals with MetS. Indeed, one explanation is that the lipophilic nature of certain antioxidants, such as carotenoids and fat-soluble vitamins (A, D, E, K), could promote their uptake from the bloodstream into fatty tissues, thereby reducing their circulating levels and potentially accounting for the heightened oxidative and inflammatory state that characterises MetS. Of course, a lower intake of such dietary constituents or an increased turnover could also be an explanation. However, the protective effects of antioxidant vitamins and secondary plant compounds and their role in influencing the risk of MetS are still under debate.

Dr. Ruiz-Castell, what about EHES-LUX and how did it feed into your research?

MRC: EHES-LUX is a cross-sectional population-based survey conducted between February 2013 and January 2015 in Luxembourg, aiming to establish baseline information on the general health status of Luxembourg residents aged 25 to 64. EHES-LUX sought to provide accurate estimates of the prevalence of major chronic conditions among the Luxembourg population. For each participant, trained nurses collected health questionnaires and performed a medical examination to record different measurement such as blood pressure, height, weight and waist circumference. Hair and blood samples were also collected to measure environmental pollutants such as pesticides, and biomarkers related to cardio-metabolic diseases, such as blood glucose, triglycerides and cholesterol. The purpose of our study was to assess possible associations between micronutrients/phytochemicals, inflammatory and oxidative stress markers and MetS and MetS components.  To do so, we required a large number of participants, and the population of EHES-LUX was crucial to support our work. We randomly selected 606 individuals (315 with MetS and 291 without) out of the 1529 EHES-LUX participants and carried out a series of biological analyses. We defined MetS as having a waist-circumference of 94 cm for men and 80 cm for women, and the presence of at least two additional factors such as high total plasma triglycerides, low plasma HDL-cholesterol, elevated blood pressure, elevated fasting plasma glucose or a previous diagnosis of diabetes.

Dr. Bohn, what type of analysis did you perform as part of the present study?

TB: We measured levels of different dietary constituents, hormones and markers  associated with oxidative stress and inflammation – including cortisol, folic acid, vitamins D, A and E, carotenoids, phenolics, leptin, adiponectin, C-reactive protein (CRP), malondialdehyde, F2-isoprostanes, oxidized LDL and insulin – in the blood samples of the 606 selected individuals. We also took into consideration several sociodemographic and socioeconomic variables, such as age, gender, country of birth, education level and employment status, as well as lifestyle characteristics, such as smoking, alcohol consumption and physical activity. We then performed a series of statistical analyses to assess whether there were significant associations between MetS and any of the aforementioned potential risk factors, and to select the most significant variables that can help us characterise the risk of developing MetS.

What did you find out, Dr. Ruiz-Castell?

MRC: We observed that in our sample, men generally presented higher levels of cardiometabolic risk factors compared to women, namely higher blood pressure, elevated concentrations of triglycerides, cholesterol and glucose, and lower concentrations of high-density lipoprotein (HDL) cholesterol, i.e. the “good” cholesterol. Indeed, out of the final 504 individuals included in our analysis, nearly 62% of men had MetS compared to 48% of women. Moreover, younger participants with a higher education level, employed and who did aerobic physical activity were less likely to have MetS. We also observed differences in the concentrations of various micronutrients/phytochemicals and inflammatory/oxidative stress markers between participants with and without MetS. Specifically and interestingly, levels of vitamin E and A, leptin, CRP and insulin were significantly higher in participants with MetS, while concentrations of beta-carotene and adiponectin  were lower in participants with MetS. Importantly, our statistical analysis selected leptin, adiponectin, CRP, vitamin A, age, gender and physical activity as the most significant factors associated with MetS.

What do these findings entail from a clinical perspective?

MRC: In practical terms, our findings indicate that changes in the levels of the above mentioned markers/micronutrients may affect the chances of developing MetS. Namely, a one-unit increase in log CRP (µg/dL) was associated with a 51% increase in the odds of having MetS, which actually soars to 71% in men but was only 38% in women. Conversely, a one-unit increase in log adiponectin (µg/dL) was associated with a 76% decrease in the odds of having MetS, a figure which reaches 82% in women. Similarly, a one-unit increment in log leptin (µg/dL) increases the odds of developing MetS by 3.1 times, without major gender differences. As for vitamin A, a one-unit increase (µg/dL) was associated with a 2% increase in the chance of having MetS, particularly so in women, for whom this figure reached 3%. Similarly, looking at the individual disorders that characterise MetS, our results indicate that higher levels of leptin were correlated with greater chances of abdominal obesity, hyperglycemia and blood pressure in both men and women, while CRP was directly linked to abdominal obesity in men only. Lower concentrations of adiponectin and high levels of vitamin A were also associated with higher odds of abdominal obesity, hypertriglyceridemia, low HDL, hyperglycemia and high blood pressure in women specifically.

Based on these observations, what can you conclude in terms of the main factors affecting MetS?

MRC: In summary, our study confirmed the significance of chronic inflammation as the hallmark of MetS, as demonstrated by the fact that the levels of inflammatory markers such as CRP, adiponectin and leptin were found to be the most representative MetS determinants. Indeed, levels of CRP are increased in response to inflammation and are traditionally considered an indicator of coronary risk and metabolic problems. Similarly, high concentrations of leptin are typically correlated with total body fat, explaining its strong association with MetS and abdominal obesity. As for adiponectin and its protective role, this has been mainly observed in women, possibly due to the fact that women had higher concentrations in the blood compared to men, which could in turn be explained by body composition and fat distribution, with women usually having less visceral adipose tissue and more subcutaneous adipose tissue than men.

On the contrary, our results indicate that micronutrients do not seem to significantly affect MetS, with the exception of vitamin A in women, although other studies did not necessarily find an association between vitamin A and MetS. Thus said, since vitamin A mainly comes from meat, dairy products, fish and associated oils, it could be an indicator of a diet rich in animal sources and low in fruit- and vegetable-derived carotenoids, possibly accounting for its higher concentrations in participants with MetS. This is in line with the lower carotenoid levels found in subjects with MetS. To conclude, although the role of certain micronutrients in influencing the onset of MetS is still under investigation, our study successfully integrated a large number of individual risk factors, leveraging advanced statistical methods to select the ones that can most likely be associated with this condition.

Could you tell us more about the collaborations in the context of the study?

TB: The study was conducted in close cooperation with different research groups both within DoPH and externally. Indeed, aside from Dr. Ruiz-Castell and myself, our work relied on the expertise of Gwenaëlle Le Coroller and Dr. Michel Vaillant from the LIH Competence Centre for Methodology and Statistics, on Dr. Guy Fagherazzi from the Deep Digital Phenotyping Research Unit and on Dr. Brice Appenzeller from the Human Biomonitoring Research Unit. In addition, it involved Laboratoires Réunis in Luxembourg and the University of Aix-Marseille in France. And of course, we are grateful to the EHES-LUX participants and to the EHES-LUX team, who have contributed to making this study possible. In terms of financial support, our research was funded by the Luxembourg National Research Fund, the Health Directorate and the Ministry of Health, as well as the Ministry of Higher Education and Research.

The open access paper was published in Nutrients, with the title “Micronutrients and Markers of Oxidative Stress and Inflammation Related to Cardiometabolic Health: Results from the EHES-LUX Study”.  It is available here.