Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance.
ABSTRACT: Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1-/- mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1-/- only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.
Project description:BACKGROUND:Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established. OBJECTIVE:To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA. DESIGN:We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels. RESULTS:We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10-2). CONCLUSIONS:Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.
Project description:The transition from pregnancy to lactation is characterized by a progressive decrease in insulin sensitivity. Propionate increases with dietary fiber consumption and has been shown to improve insulin sensitivity. Recent studies suggest that plasma odd-chain fatty acids [OCFAs; pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0)] that inversely correlated with insulin resistance are synthesized endogenously from gut-derived propionate. The present study investigated the effects of soluble fiber during gestation on gut microbiota, plasma non-esterified fatty acids and insulin sensitivity in sows. Sows were allocated to either control or 2.0% guar gum plus pregelatinized waxy maize starch (SF) dietary treatment during gestation. The SF addition changes the structure and composition of gut microbiota in sows. Genus Eubacterium increased by SF addition may promote intestinal propionate production. Moreover, the dietary SF increased circulating levels of plasma OCFAs, especially C17:0. The SF-fed sows had a higher insulin sensitivity and a lower systemic inflammation level during perinatal period. Furthermore, the plasma C15:0 and C17:0 was negatively correlated with the area under curve of plasma glucose after meal and plasma interleukin-6. In conclusion, dietary SF improves insulin sensitivity and alleviates systemic inflammation in perinatal sows, potentially related to its stimulating effect on propionate and OCFAs production.
Project description:Pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) have been described as dietary biomarkers of dairy-fat consumption, with varying degrees of reliability between studies. It remains unclear how the total amount of dietary fat, representing one of the main confounding factors in these biomarker investigations, affects C15:0 and C17:0 circulating concentrations independent of their relative intake. Additionally, it is not clear how changes in the dietary total-fat affects other fatty acids in circulation. Through two dietary studies with different total-fat levels but maintaining identical fatty acid compositions, we were able to see how the dietary total-fat affects the fatty acids in circulation. We saw that there was a statistically significant, proportionate, and robust decrease in the endogenous C15:0 levels with an increase in dietary total-fat. However, there was no significant change in the circulating C17:0 concentrations as the total-fat increased. To conclude, the dietary total-fat content and fat-type have a very complex influence on the relative compositions of circulating fatty acids, which are independent of the actual dietary fatty acid composition. Knowing how to manipulate circulating C15:0 and C17:0 concentrations is far-reaching in nutritional/pathological research as they highlight a dietary route to attenuate the development of metabolic disease (both by reducing risk and improving prognosis).
Project description:Dietary odd-chain saturated fatty acids (OCFAs) are present in trace levels in dairy fat and some fish and plants. Higher circulating concentrations of OCFAs, pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0), are associated with lower risks of cardiometabolic diseases, and higher dietary intake of OCFAs is associated with lower mortality. Population-wide circulating OCFA levels, however, have been declining over recent years. Here, we show C15:0 as an active dietary fatty acid that attenuates inflammation, anemia, dyslipidemia, and fibrosis in vivo, potentially by binding to key metabolic regulators and repairing mitochondrial function. This is the first demonstration of C15:0's direct role in attenuating multiple comorbidities using relevant physiological mechanisms at established circulating concentrations. Pairing our findings with evidence that (1) C15:0 is not readily made endogenously, (2) lower C15:0 dietary intake and blood concentrations are associated with higher mortality and a poorer physiological state, and (3) C15:0 has demonstrated activities and efficacy that parallel associated health benefits in humans, we propose C15:0 as a potential essential fatty acid. Further studies are needed to evaluate the potential impact of decades of reduced intake of OCFA-containing foods as contributors to C15:0 deficiencies and susceptibilities to chronic disease.
Project description:Dairy fat intake, reflected by the biomarkers C14:0, C15:0, C17:0, trans-C16:1 (n-7), trans-C18:1 (n-7) and CLA, may have beneficial effects on cardiovascular health. It has, however, been questioned whether this association is genuine, since C15:0 and C17:0 are also biomarkers from fish. We investigated whether the above biomarkers are reliable markers for dairy fat intake in 864 healthy subjects. Subsequently, we explored the association between these biomarkers and cardiovascular risk factors. Intakes of dairy and fish were determined by Food Frequency Questionnaires FFQs. Fatty acids were analyzed in plasma triglycerides (TG) and phospholipids (PL). Median intakes of dairy and fish fat were 12.3 (8.4-17.4) g/day and 1.14 (0.53-1.75) g/day. All fatty acids, except TG C17:0, were associated with dairy fat (std.β range TG: 0.12 for C14:0 till 0.25 for C15:0 and Trans-C18:1 (n-7); and std.β range PL: 0.12 for C17:0 and Trans-C16:1 (n-7) till 0.24 for Trans-C18:1 (n-7) and CLA; p < 0.001). TG C17:0 was associated with fish fat (std.β = 0.08; p = 0.03), whereas PL C17:0 was not. Associations remained after adjustment for fish/dairy fat intake. Strongest inverse associations with biological variables were found with PL C17:0 and Trans-C18:1 (n-7) (Std.βs: waist circumference: -0.18, p < 0.001 and -0.10, p < 0.05; BMI: -0.17, p < 0.001, -0.11, p < 0.01; glucose: -0.10, p <0.01 and -0.08, p <0.05; high sensitive C-reactive protein (hs-CRP): -0.22, p < 0.001 and -0.16, p < 0.01; uric acid: -0.27, p < 0.001 and -0.24, p < 0.001). In conclusion, fatty acid biomarkers, except plasma TG C17:0, were associated with dairy fat intake, independent of fish fat intake. PL C17:0 and trans-C18:1 (n-7) were inversely associated with adiposity, diabetes, inflammation and uric acid.
Project description:The gut microbiota plays a critical role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Increased fructose consumption and inadequate copper intake are two critical risk factors in the development of NAFLD. To gain insight into the role of gut microbiota, fecal metabolites, obtained from rats exposed to different dietary levels of copper with and without high fructose intake for 4 weeks, were analyzed by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC × GC-TOF MS). In parallel, liver tissues were assessed by histology and triglyceride assay. Our data showed that high fructose feeding led to obvious hepatic steatosis in both marginal copper deficient rats and copper supplementation rats. Among the 38 metabolites detected with significant abundance alteration between groups, short chain fatty acids were markedly decreased with excessive fructose intake irrespective of copper levels. C15:0 and C17:0 long chain fatty acids, produced only by bacteria, were increased by either high copper level or high fructose intake. In addition, increased fecal urea and malic acid paralleled the increased hepatic fat accumulation. Collectively, GC × GC-TOF MS analysis of rat fecal samples revealed distinct fecal metabolome profiles associated with the dietary high fructose and copper level, with some metabolites possibly serving as potential noninvasive biomarkers of fructose induced-NAFLD.
Project description:The SCFA acetate (Ac) and propionate (Pr) are major fermentation products of dietary fibers and provide additional energy to the host. We investigated short- and long-term effects of dietary Ac and Pr supplementation on diet-induced obesity and hepatic lipid metabolism.C3H/HeOuJ mice received high-fat (HF) diets supplemented with 5% SCFA in different Ac:Pr ratios, a high acetate (HF-HAc; 2.5:1 Ac:Pr) or high Pr ratio (HF-HPr; 1:2.5 Ac:Pr) for 6 or 22 weeks. Control diets (low-fat (LF), HF) contained no SCFA. SCFA did not affect body composition but reduced hepatic gene and protein expression of lipogenic enzymes leading to a reduced hepatic triglyceride concentration after 22 weeks in HF-HPr mice. Analysis of long-chain fatty acid composition (liver and plasma phospholipids) showed that supplementation of both ratios led to a lower ?6:?3 ratio. Pr directly led to increased odd-chain fatty acid (C15:0, C17:0) formation as confirmed in vitro using HepG2 cells. Remarkably, plasma C15:0 was correlated with the attenuation of HF diet-induced insulin resistance.Dependent on the Ac:Pr ratio, especially odd-chain fatty acid formation and insulin sensitivity are differentially affected, indicating the importance of Pr.
Project description:Poison ivy (Toxicodendron radicans (L.) Kuntze) shows accession-level differentiation in a variety of morphometric traits, suggesting local adaptation. To investigate whether the presumed defense compound urushiol also demonstrates accession-level accumulation differences, in vitro nascent germinated poison ivy seedlings from geographically isolated populations were germinated in vitro and then assayed for known urushiol congener accumulation levels. Significant accession-level differences in the accumulation levels of total C15- and C17-, total C15-, total C17-, specific C15 congeners, and specific C17 congeners of urushiol were identified. In addition, hereto novel C15- and C17-urushiol isomers were identified as well. Cardanols are assumed to be the penultimate metabolites giving rise to urushiols, but this assumption was not previously empirically validated. C15-cardanol congeners and isomers corresponding to expected substrates needed to produce the observed C15-urushiol congeners and isomers were identified in the same poison ivy seedling extracts. Total C15-cardanol and C15-cardanol congeners also showed significant accession-level differences. Based on the observed C15-cardanol congeners in poison ivy, the penultimate step in urushiol biosynthesis was proposed to be a cardanol-specific hydroxylase activity.
Project description:The aim of this experiment was to investigate the gene expression profile of two xenografted nasopharyngeal carcinoma tumors - C15 and C17 which are international reference tools for biological investigations of this type of disease. C15 and C17 transcriptome was profiled by comparison with human untransformed diploid fibroblasts, MRC5. These fibroblasts are very sensitive to contact inhibition and were collected after 3 days of confluence, therefore in a quiescent state. We acknowledge that malignant nasopharyngeal carcinoma cells and MRC5 cells do not belong to the same lineage (epithelial cells versus fibroblasts). However this combination was expected to highlight genes involved in proliferation of NPC cells. Competitive hybridisation of cDNA for each pair C15 and MRC5, C17 and MRC5 was performed on Agilent microarrays containing 22 000 60mer oligonucleotides related to 16 000 human transcripts. The analysis was focused mainly on genes overexpressed in both C15 and C17 by comparison with MRC5
Project description:The aim of this study was to evaluate the relationship of milk odd- and branched-chain fatty acids (OBCFA) with urinary purine derivates and estimated ruminal microbial crude protein (MCP) synthesis. Forty-four lactating Holstein cows were used in a 4 × 4 Latin square design with 21-day periods comprised of a 13-day adaptation phase to diet followed by an 8-day sampling phase. Differences in estimated MCP yield and milk OBCFA composition were found by feeding total mixed rations containing forage (maize silage, MS; red clover silage, RCS) and concentrates (0.75:0.25) with targeted proportions of RCS to MS of 0.15:0.60, 0.30:0.45, 0.45:0.30, and 0.60:0.15 on a dry matter basis. The MCP was estimated from the total urinary purine derivate (PD) excretion (MCPPD) and intakes of metabolizable energy (MCPME) or digestible organic matter (MCPdOM). The Pearson correlations of individual OBCFA with urinary parameters (uric acid, allantoin, PD and nitrogen) were generally weak (r = -0.37 to 0.55). Yields of individual OBCFA correlated positively with MCPME and MCPdOM (r = 0.21 to 0.55). The prediction of urinary PD concentration was moderate (R2 = 0.64) when including the proportion of iso-C17:0. The prediction of total PD excretion was low (R2 = 0.21) with yields of iso-C15:0, anteiso-C17:0, and iso-C16:0. The prediction of MCPPD was high (R2 = 0.99) when including the iso-C16:0 and cis-9 C17:1 concentrations, while those of MCPME and MCPdOM were low (R2 = 0.37 and 0.36, respectively) when including yields of iso-C15:0, cis-9 C17:1, and iso-C18:0. The correlations and regression analyses demonstrate that the estimated MCP synthesis and urinary PD excretion can be only moderately predicted by yields and concentrations of individual or total OBCFA in cow's milk. However, milk OBCFA can still be seen as a promising, non-invasive method for predicting rumen function and microbial protein supply in dairy cows because MCP flow was not directly measured in this study but instead indirectly estimated probably comprising considerable deviations of the assumed values from the true ones.