German Institute of Human Nutrition

Mastering emotion regulation is crucial for social skills and mental health. Hormonal fluctuations, particularly in estradiol (E2) levels across the menstrual cycle, significantly impact emotion processing. E2 is known to influence emotion regulation, mental health, and the plasticity of limbic and striatal regions, which are involved in emotion processing and are rich in E2 receptors. Although research indicates that E2 levels may impact gray matter volume (GMV) of limbic and striatal areas, sufficient causal evidence is missing so far. Furthermore, because of the additional fluctuations of progesterone across the menstrual cycle, the sole impact of E2 on brain volume has been difficult to disentangle. To isolate the effects of E2 from other fluctuating sex hormones, we used a randomized, placebo-controlled, double-blind, crossover design and administered oral E2 to 27 naturally cycling females during their early follicular phase (low endogenous sex hormone levels). We analyzed emotion regulation strategies and E2 levels to assess their impact on regional GMV. Our data showed that a rapid increase of E2 was negatively associated with right striatal GMV. Moreover, greater use of reappraisal was associated with reduced GMV of the right striatum. Rapidly increased E2 did not influence GMV of other limbic regions. These results highlight that rapid increases in E2 and individual differences in emotion regulation dynamically modulate GMV. This offers important implications for female mental and brain health associated with hormonal fluctuations. Considering female endocrine profiles improves hormone-informed health care and therefore supports individualized medicine.

Polyphenols represent the largest and most diverse class of dietary antioxidants. Epidemiological evidence linking specific (poly)phenol classes, such as flavonoids and lignans, to breast cancer (BC) risk remains limited and largely inconclusive in prospective studies. The aim of this study is to examine the association between the intake of total (poly)phenols-and its classes and subclasses-and BC risk-overall and by subtypes (estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2))-in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The EPIC cohort includes 257,960 adult women from seven European countries. During a mean follow-up of 14 years, there were 10,722 incident overall BC cases. Associations were computed using Cox regression models adjusted for potential confounders. No significant associations were found between total (poly)phenol intake and overall BC risk (HRQ5 vs. Q1 = 1.02; 95% CI: 0.95-1.11). In addition, null associations were mostly found between classes and subclasses of (poly)phenols and BC subtypes. After stratifying by menopausal status, no significant associations were observed. In conclusion, this study found no evidence of associations between the intake of any class or subclass of (poly)phenols and BC risk in the European population.

Gut microbiota may contribute to the adiposity-associated disease risk, but human studies reported inconsistent associations of adiposity with gut microbiota composition. We examined associations of body mass index (BMI) with alpha diversity and relative microbial abundance at the phylum and genus taxonomic levels (based on 16S rRNA amplicon sequencing or metagenomics) among 7415 adults from eight European observational studies in a joint federated analysis of harmonized data using DataSHIELD. Higher BMI (per 5 kg/m2) was associated with lower alpha diversity (β: -0.05; 95% CI: -0.07, -0.03) and, on the phylum level, positively associated with Proteobacteria, but neither with Firmicutes nor Bacteroidetes nor their ratio, where high between-study heterogeneity was observed. On the genus level, BMI was inversely associated with the relative abundance of Faecalibacterium of the Firmicutes phylum (β: -0.11; 95% CI: -0.14, -0.07) but positively with the odds of detection of Dorea, Streptococcus, and Clostridium (all three Firmicutes) as well as Collinsella (Actinobacteria). This federated analysis of multiple studies found lower alpha diversity, alongside depleted Faecalibacterium, as well as higher odds of detection of Dorea, Streptococcus, Clostridium, and Collinsella with higher adiposity. By combining data from diverse study populations using harmonized data and statistical methods, our analysis partly overcomes sources of heterogeneity that may explain previously observed inconsistencies.

Pleural mesothelioma (PM) is a rare, asbestos-linked cancer with a long asymptomatic latency, delaying diagnosis and limiting treatment options. Identifying blood‐based biomarkers that signal disease before symptoms onset could improve surveillance of at‐risk individuals. In our work, we conducted a prospective proteomic study of pre-diagnostic serum from 21 PM cases (< 5 years before diagnosis) and 21 asbestos‐exposed controls in the EPIC cohort using SWATH‐MS, followed by ELISA validation. Findings were tested in an independent MoMar cohort of 32 pre‐diagnostic plasma samples (< 1 year before diagnosis) and 32 matched controls. SWATH-MS identified 12 differentially expressed proteins (nominal p < 0.05, fold change > 1.3 or < 0.75). Transferrin and complement C4A were elevated, while beta‐2‐microglobulin and dermcidin were reduced in pre‐diagnostic cases. ELISA confirmed a borderline significant rise in beta‐2‐microglobulin within two years of diagnosis in EPIC. Calretinin and mesothelin were also detected in both cohorts, with the five‐marker panel achieving an AUC of 0.91 (p = 0.001) in MoMar but not reaching significance in EPIC (AUC = 0.88, p = 0.17). Integrating novel proteomic biomarker candidates with established markers enhances early PM detection in high-risk populations. Larger, multi‐cohort validation is warranted to refine this biomarker panel for clinical surveillance.

The relationship between childhood maltreatment (CM) and obesity is nuanced, and recent evidence suggests stronger associations between CM and obesity-related traits in females compared to males. This study aims to validate and extend these findings in a large sample from the German National Cohort (NAKO). The NAKO is a population-based cohort study including 204,744 adults. For the present analyses, 151,143 individuals (74,596 female) were included. CM was assessed using the Childhood Trauma Screener (CTS). From the CTS, an overall severity score (CTS sum score), a cumulative CM score (number of CM subtypes with at least moderate severity), and five CTS subtypes were considered as exposures. Obesity-related traits included anthropometric (height, weight, body mass index [BMI], waist circumference [WC]) and body fat markers (relative fat mass [rFM], subcutaneous [SAT], visceral adipose tissue [VAT]). Sex-stratified linear and logistic regression models were adjusted for age, education, and examination center to associate CTS-based scores with obesity-related traits. Associations of the CTS sum score with weight, BMI, WC, rFM, and SAT were stronger in females compared to males, while similar associations were observed for VAT. In both sexes, most obesity-related traits exhibited dose-response relationships with increasing numbers of CM subtypes. Compared to unexposed females, females with exposure to ≥3 CM subtypes had a higher risk for obesity (i.e., BMI ≥ 30 kg/m2; OR = 1.56; 95% CI: 1.43, 1.71) and high WC (i.e., WC ≥ 88 cm; OR = 1.39; 95% CI: 1.29, 1.50). In males, exposure to ≥3 CM subtypes was also associated with increased obesity risk (OR = 1.51; 95% CI: 1.32, 1.72) and high WC (i.e., WC ≥ 102 cm; OR = 1.31; 95% CI: 1.18, 1.44). Physical and emotional abuse exhibited the strongest average associations and were associated with the most outcomes. Associations of CM exposure with adult anthropometric and body fat markers are stronger in females compared to males.

The liver continuously adjusts its metabolic activity to synchronize the nutrient supply with the body's demands. This synchronization involves the complex coordination of acute metabolic needs, nutrient availability, and activity levels, which is orchestrated according to cyclic internal rhythms governed by the circadian clock. This study aimed to decipher the role of circadian rhythms in liver metabolic functions, including mitochondrial activities that are critical for energy production and metabolic adaptation. We investigated rhythmic changes in liver metabolism via comprehensive multiomics and kinetic mathematical modeling. The liver proteome of male mice was analyzed and modeled, and complementary serum lipidomic and metabolomic analyses were performed. Mitochondrial proteins were examined to evaluate the role of mitochondria in the oscillating regulation of energy production. Most metabolic functions, particularly those related to carbohydrate and fatty acid metabolism, exhibit rhythmic patterns on a 12-hour rather than a 24-hour cycle. The importance of this rhythmicity is function-dependent and can account for 25% to 50% of the overall variability. Mitochondrial activities also exhibit temporal fluctuations that are closely linked to nutrient availability. The strong correlation between metabolic functions and serum metabolites highlights the precise alignment between physiological demand and metabolic performance. Hepatic metabolic functions follow a 12-hour cycle rather than a 24-hour cycle, significantly contributing to the liver's ability to meet nutrient demands throughout the day. Mitochondrial dynamics, which are influenced by nutrient availability, play a central role in adapting energy production to the body's metabolic needs.

We aimed to 1) investigate associations between leisure time physical activity level cumulated over 20 years and multiple plasma proteins and 2) explore if proteins significantly associated with physical activity are also associated with risk of imminent myocardial infarction (MI), long-term MI and mortality. In the cohort Uppsala Longitudinal Study of Adult Men (ULSAM), leisure time physical activity was self-reported at ages 50, 60, and 70. At age 70, 720 plasma proteins were analyzed in 782 participants with up to 19.3 years of follow-up for MI and 26.3 years follow-up for mortality. In the nested case-cohort study Markers of Imminent Myocardial Infarction (MIMI), plasma proteins were measured in disease-free individuals from six European cohorts. Cases (n=420) were those with acute MI within 6 months of a blood draw, with up to four cohort representatives per case (n=1,598). A higher level of leisure time physical activity level was inversely associated with 12 plasma proteins after adjusting for age, education, smoking and established cardiovascular risk factors (Bonferroni corrected p<0.000069). Of these 12 proteins, IL-6 was associated with increased incidence of imminent MI (HR 1.22 95%CI [1.09-1.37]), TNFRSF11A was associated with increased long-term MI incidence (HR 1.22 [1.01-1.48]) and 11 proteins were associated with increased mortality (HR 1.14-1.30 [1.01-1.42]). These findings confirm and extend our understanding of how physical activity could assert its beneficial effect on cardiovascular health through proteins involved with modulating inflammatory, immune and metabolic pathways. Further research is needed to explore the causal mechanisms behind these associations.

Abstract Primary cilia are tiny cellular protrusions of nearly every vertebrate cell controlling multiple cellular processes, such as proliferation, differentiation, migration etc. Their dysfunction results in severe human diseases collectively referred to as ciliopathies. Remarkably, many ciliopathies are associated with increased programmed cell death (PCD). However, it is largely unknown how primary cilia regulate PCD. In in vitro (murine and human cells) and in vivo ( Xenopus laevis and mouse) models, we observed elevated PCD in the absence of the ciliopathy protein RPGRIP1L. Mechanistically, our data elucidated that RPGRIP1L controls PCD by governing the activity of the ciliary proteasome. By using super-resolution microscopy, we first showed that the apoptosis inducer MOAP1 localises to primary cilia. Furthermore, our investigations revealed that RPGRIP1L controls PCD via the degradation of MOAP1 by the ciliary proteasome. Based on our finding that two more ciliopathy proteins, TCTN1 and CEP290, modulate PCD via regulating the activity of the ciliary proteasome, we suggest that the proteasomal degradation of MOAP1 represents a general mechanism by which primary cilia control PCD.

BackgroundProcessed meat (PM) consumption is an established risk factor for colorectal cancer (CRC). It has been hypothesized that nitrosyl-heme, formed by the addition of nitrites during meat processing, may enhance the carcinogenic effects of PMs. This study aims to investigate the association between nitrosyl-heme intake and CRC risk within the European Prospective Investigation into Cancer and Nutrition(EPIC) study.MethodsThis prospective study included 367,463 participants(70.3% women) from seven countries from the EPIC-study. Dietary data were collected via baseline questionnaires, and nitrosyl-heme exposure was estimated using biochemical data from 52 Spanish PMs, extrapolated to country-specific items. Sex-specific multivariable-adjusted hazard ratios(HRs) and 95% confidence intervals(CIs) were calculated using Cox proportional hazards models.ResultsOver a 15-year median follow-up, 5,115 incident CRC cases were identified. Comparing the highest vs. the lowest sex-specific tertile of nitrosyl-heme intake we found no significant association with CRC risk (HRT3vsT1:1.01;95%CI:0.93–1.09). Subgroup analyses by tumor subtype and interactions with lifestyle factors also showed no associations.ConclusionsThis study offers insights into nitrosyl-heme exposure in European populations but found no link to CRC risk. Further research is needed to understand nitrosyl-heme's role in CRC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12937-025-01266-7.