Effects of lifestyle and associated diseases on serum CC16 suggest complex interactions among metabolism, heart and lungs.

INTRODUCTION: Clara cell 16-kDa protein (CC16) is an anti-inflammatory, immunomodulatory secreted pulmonary protein with reduced serum concentrations in obesity according to recent data. OBJECTIVE: Studies focused solely on bodyweight, which does not properly reflect obesity-associated implications of the metabolic and reno-cardio-vascular system. The purpose of this study was therefore to examine CC16 in a broad physiological context considering cardio-metabolic comorbidities of primary pulmonary diseases. METHODS: CC16 was quantified in serum samples in a subset of the FoCus (N = 497) and two weight loss intervention cohorts (N = 99) using ELISA. Correlation and general linear regression analyses were applied to assess CC16 effects of lifestyle, gut microbiota, disease occurrence and treatment strategies. Importance and intercorrelation of determinants were validated using random forest algorithms. RESULTS: CC16 A38G gene mutation, smoking and low microbial diversity significantly decreased CC16. Pre-menopausal female displayed lower CC16 compared to post-menopausal female and male participants. Biological age and uricosuric medications increased CC16 (all p < 0.01). Adjusted linear regression revealed CC16 lowering effects of high waist-to-hip ratio (est. -11.19 [-19.4; -2.97], p = 7.99 × 10-3), severe obesity (est. -2.58 [-4.33; -0.82], p = 4.14 × 10-3) and hypertension (est. -4.31 [-7.5; -1.12], p = 8.48 × 10-3). ACEi/ARB medication (p = 2.5 × 10-2) and chronic heart failure (est. 4.69 [1.37; 8.02], p = 5.91 × 10-3) presented increasing effects on CC16. Mild associations of CC16 were observed with blood pressure, HOMA-IR and NT-proBNP, but not manifest hyperlipidemia, type 2 diabetes, diet quality and dietary weight loss intervention. CONCLUSION: A role of metabolic and cardiovascular abnormalities in the regulation of CC16 and its modifiability by behavioral and pharmacological interventions is indicated. Alterations by ACEi/ARB and uricosurics could point towards regulatory axes comprising the renin-angiotensin-aldosterone system and purine metabolism. Findings altogether strengthen the importance of interactions among metabolism, heart and lungs.

Cohort profile: the Food Chain Plus (FoCus) cohort.

The Food Chain Plus (FoCus) cohort was launched in 2011 for population-based research related to metabolic inflammation. To characterize this novel pathology in a comprehensive manner, data collection included multiple omics layers such as phenomics, microbiomics, metabolomics, genomics, and metagenomics as well as nutrition profiling, taste perception phenotyping and social network analysis. The cohort was set-up to represent a Northern German population of the Kiel region. Two-step recruitment included the randomised enrolment of participants via residents' registration offices and via the Obesity Outpatient Centre of the University Medical Center Schleswig-Holstein (UKSH). Hence, both a population- and metabolic inflammation- based cohort was created. In total, 1795 individuals were analysed at baseline. Baseline data collection took place between 2011 and 2014, including 63% females and 37% males with an age range of 18-83 years. The median age of all participants was 52.0 years [IQR: 42.5; 63.0 years] and the median baseline BMI in the study population was 27.7 kg/m2 [IQR: 23.7; 35.9 kg/m2]. In the baseline cohort, 14.1% of participants had type 2 diabetes mellitus, which was more prevalent in the subjects of the metabolic inflammation group (MIG; 31.8%). Follow-up for the assessment of disease progression, as well as the onset of new diseases with changes in subject's phenotype, diet or lifestyle factors is planned every 5 years. The first follow-up period was finished in 2020 and included 820 subjects.

Vitamin C and Omega-3 Fatty Acid Intake Is Associated with Human Periodontitis-A Nested Case-Control Study.

Vitamins and omega-3 fatty acids (Ω3FA) modulate periodontitis-associated inflammatory processes. The aim of the current investigation was to evaluate associations of oral nutrient intake and corresponding serum metabolites with clinical severity of human periodontitis. Within the Food Chain Plus cohort, 373 periodontitis patients­245 without (POL) and 128 with tooth loss (PWL)­were matched to 373 controls based on sex, smoking habit, age and body mass index in a nested case-control design. The amount of oral intake of vitamins and Ω3FAs was assessed from nutritional data using a Food Frequency Questionnaire. Oral intake and circulatory bioavailability of vitamins and Ω3FA serum metabolomics were compared, using ultra-high-resolution mass spectrometry. Periodontitis patients exhibited a significantly higher oral intake of vitamin C and Ω3FA Docosapentaenoic acid (p < 0.05) compared to controls. Nutritional intake of vitamin C was higher in PWL, while the intake of Docosapentaenoic acid was increased in POL (p < 0.05) compared to controls. In accordance, serum levels of Docosapentaenoic acid were also increased in POL (p < 0.01) compared to controls. Vitamin C and the Ω3FA Docosapentaenoic acid might play a role in the pathophysiology of human periodontitis. Further studies on individualized nutritional intake and periodontitis progression and therapy are necessary.

A dietary carbohydrate - gut Parasutterella - human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes.

Recent rodent microbiome experiments suggest that besides Akkermansia, Parasutterella sp. are important in type 2 diabetes and obesity development. In the present translational human study, we aimed to characterize Parasutterella in our European cross-sectional FoCus cohort (n = 1,544) followed by validation of the major results in an independent Canadian cohort (n = 438). In addition, we examined Parasutterella abundance in response to a weight loss intervention (n = 55). Parasutterella was positively associated with BMI and type 2 diabetes independently of the reduced microbiome α/ß diversity and low-grade inflammation commonly found in obesity. Nutritional analysis revealed a positive association with the dietary intake of carbohydrates but not with fat or protein consumption. Out of 126 serum metabolites differentially detectable by untargeted HPLC-based MS-metabolomics, L-cysteine showed the strongest reduction in subjects with high Parasutterella abundance. This is of interest, since Parasutterella is a known high L-cysteine consumer and L-cysteine is known to improve blood glucose levels in rodents. Furthermore, metabolic network enrichment analysis identified an association of high Parasutterella abundance with the activation of the human fatty acid biosynthesis pathway suggesting a mechanism for body weight gain. This is supported by a significant reduction of the Parasutterella abundance during our weight loss intervention. Together, these data indicate a role for Parasutterella in human type 2 diabetes and obesity, whereby the link to L-cysteine might be relevant in type 2 diabetes development and the link to the fatty acid biosynthesis pathway for body weight gain in response to a carbohydrate-rich diet in obesity development.

BMI, Alcohol Consumption and Gut Microbiome Species Richness Are Related to Structural and Functional Neurological Abnormalities.

Background: The incidence of neurological diseases is increasing throughout the world. The aim of the present study was to identify nutrition and microbiome factors related to structural and functional neurological abnormalities to optimize future preventive strategies. Methods: Two hundred thirty-eight patients suffering from (1) structural (neurodegeneration) or (2) functional (epilepsy) neurological abnormalities or (3) chronic pain (migraine) and 612 healthy control subjects were analyzed by validated 12-month food frequency questionnaire (FFQ) and 16S rRNA microbiome sequencing (from stool samples). A binomial logistic regression model was applied for risk calculation and functional pathway analysis to show which functional pathway could discriminate cases and healthy controls. Results: Detailed analysis of more than 60 macro- and micronutrients revealed no distinct significant difference between cases and controls, whereas BMI, insulin resistance and metabolic inflammation in addition to alcohol consumption were major drivers of an overall neurological disease risk. The gut microbiome analysis showed decreased alpha diversity (Shannon index: p = 9.1× 10-7) and species richness (p = 1.2 × 10-8) in the case group as well as significant differences in beta diversity between cases and controls (Bray-Curtis: p = 9.99 × 10-4; Jaccard: p = 9.99 × 10-4). The Shannon index showed a beneficial effect (OR = 0.59 (95%-CI (0.40, 0.87); p = 8 × 10-3). Cases were clearly discriminated from healthy controls by environmental information processing, signal transduction, two component system and membrane transport as significantly different functional pathways. Conclusions: In conclusion, our data indicate that an overall healthy lifestyle, in contrast to supplementation of single micro- or macronutrients, is most likely to reduce overall neurological abnormality risk and that the gut microbiome is an interesting target to develop novel preventive strategies.

Circulating sDPP-4 is Increased in Obesity and Insulin Resistance but Is Not Related to Systemic Metabolic Inflammation.

CONTEXT: Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. It exists in a membrane-bound form and a soluble form (sDPP-4). Initial human studies suggested sDPP-4 to be an adipokine involved in metabolic inflammation. However, recent mechanistic data in genetically modified mice has questioned these findings. OBJECTIVES: We examined circulating sDPP-4 in a cohort of n = 451 humans with different metabolic phenotypes and during 3 different weight loss interventions (n = 101) to further clarify its role in human physiology and metabolic diseases. DESIGN: sDPP-4 serum concentrations were measured by enzyme-linked immunosorbent assay and related to several phenotyping data including gut microbiome analysis. RESULTS: sDPP-4 increased with age and body weight and was positively associated with insulin resistance and hypertriglyceridemia but was reduced in manifest type 2 diabetes. In addition, we found reduced serum concentrations of sDPP-4 in subjects with arterial hypertension. In contrast to earlier reports, we did not identify an association with systemic markers of inflammation. Impaired kidney and liver functions significantly altered sDPP-4 concentrations while no relation to biomarkers for heart failure was observed. Having found increased levels of sDPP-4 in obesity, we studied surgical (gastric bypass and sleeve gastrectomy) and nonsurgical interventions, revealing a significant association of sDPP-4 with improvement of liver function tests but not with changes in body weight. CONCLUSIONS: Our data suggest that sDPP-4 is related to hepatic abnormalities in obesity rather than primarily functioning as an adipokine and that sDPP-4 is implicated both in glucose and in lipid metabolism, but not fundamentally in systemic inflammation.

Precision Nutrition in Chronic Inflammation.

The molecular foundation of chronic inflammatory diseases (CIDs) can differ markedly between individuals. As our understanding of the biochemical mechanisms underlying individual disease manifestations and progressions expands, new strategies to adjust treatments to the patient's characteristics will continue to profoundly transform clinical practice. Nutrition has long been recognized as an important determinant of inflammatory disease phenotypes and treatment response. Yet empirical work demonstrating the therapeutic effectiveness of patient-tailored nutrition remains scarce. This is mainly due to the challenges presented by long-term effects of nutrition, variations in inter-individual gastrointestinal microbiota, the multiplicity of human metabolic pathways potentially affected by food ingredients, nutrition behavior, and the complexity of food composition. Historically, these challenges have been addressed in both human studies and experimental model laboratory studies primarily by using individual nutrition data collection in tandem with large-scale biomolecular data acquisition (e.g. genomics, metabolomics, etc.). This review highlights recent findings in the field of precision nutrition and their potential implications for the development of personalized treatment strategies for CIDs. It emphasizes the importance of computational approaches to integrate nutritional information into multi-omics data analysis and to predict which molecular mechanisms may explain how nutrients intersect with disease pathways. We conclude that recent findings point towards the unexhausted potential of nutrition as part of personalized medicine in chronic inflammation.

Secreted frizzled-related protein 5 serum levels in human periodontitis-A nested case-control study.

AIM: Recombinant secreted frizzled-related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological approach. MATERIALS AND METHODS: sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex-, smoker-, age- and BMI-matched individuals in a nested case-control design. RESULTS: Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 [0.0-10.4] ng/ml, median [IQR]) compared to patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR], p = 0.04] and matched controls (7.0 [2.5-18.3] ng/ml, median [IQR], p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR]) and controls (3.1 [0.0-10.6] ng/ml, median [IQR], p = 0.06). CONCLUSIONS: sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies.

Role of wnt5a in Metabolic Inflammation in Humans.

Context: Common nutrition-associated diseases like obesity and type 2 diabetes are linked to chronic low-grade inflammation. The secreted glycopeptide wingless-type mouse mammary tumor virus integration site family member 5a (wnt5a) has been implicated in metabolic inflammation in rodent models, suggesting a potential treatment target. Data on the role of wnt5a in human physiology have yielded conflicting results. Objective: Serum concentrations of wnt5a were measured in a cross-sectional cohort of 896 people to gain deeper insights into wnt5a physiology. Design: Serum concentrations of wnt5a were measured by ELISA and related to several phenotyping and genotyping data. In vitro experiments were performed in THP-1 macrophages to examine potential molecular mechanisms. Results: Wnt5a levels were significantly positively correlated to IL-6 and triglyceride levels. In subjects with diabetes, wnt5a levels were elevated and significantly correlated with fasting plasma glucose concentrations. Although wnt5a levels were not influenced by common single-nucleotide polymorphisms in the human wnt5a gene, environmental factors significantly altered wnt5a concentrations, as follows: (1) wnt5a levels were reduced in subjects with high nutritional load of the long-chain eicosatetraenoic acid independent of the total caloric intake and overall composition of the macronutrients, and (2) wnt5a levels were lower in humans with a high gut microbiome α diversity. In vitro experiments revealed that stimulation of the IL-6 receptor or the long-chain fatty acid receptor GPR40 directly affected wnt5a expression in human macrophages. Conclusion: Our data suggest that wnt5a is important in linking inflammation to metabolism. The nutrition and the microbiome might be interesting targets to prevent and/or treat wnt5a-mediated metabolic inflammation.