Table 2.
Circulating ceramides with dietary pattern interventions
| Participants/region | Study design | Experimental design | Measurement/class | Sphingolipid outcomes |
|---|---|---|---|---|
| 980 participants from the PREDIMED Trial, 25% with incident cases of CVD, Spain (148) | Case-cohort | 1 year of Mediterranean diet supplemented with EVOO or nuts, with low-fat diet control | Untargeted LC-MS/MS metabolomics; plasma Cer(d18:1/16:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) | No change was detected in plasma ceramides. |
| 5,124 adults from the Framingham Offspring Study, United States (147) | Cross-sectional | Dietary pattern scores (DGAI, MDS) assessed from Harvard FFQ | Targeted LC-MS/MS; plasma Cer(d18:1/16:0), Cer(d18:1/22:0), and Cer(d18:1/24:0) | DGAI score was associated with lower Cer(d18:1/16:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/22:0)/Cer(d18:1/16:0) ratio; SFA intake was associated with Cer(d18:1/16:0); fat and sugar intake were inversely associated with Cer(d18:1/22:0)/Cer(d18:1/16:0) ratio; MDS was associated with lower Cer(d18:1/16:0) and Cer(d18:1/22:0) and higher Cer(d18:1/24:0) and Cer(d18:1/24:0)/Cer(d18:1/16:0) ratio; Cer(d18:1/24:0) was associated with nut intake and MUFA/SFA intake ratio and negatively associated with fruit intake; and Cer(d18:1/24:0)/Cer(d18:1/16:0) ratio was associated with nut intake, MUFA/SFA intake ratio, and vegetable intake. |
| 106 adults with metabolic syndrome, Finland (81) | Randomized controlled trial | 12-week parallel study of healthy diet with whole grain products, fatty fish (3 servings/week) and bilberries (300 g/day); whole grain enriched diet with whole grain products; or control diet with refined grain products | Targeted UPLC-MS; plasma ceramides | No change was present in plasma ceramides. |
| 200 adults with metabolic syndrome from the Systems Biology in Controlled Dietary Interventions and Cohort studies (SYSDIET) study, Finland, Denmark, Sweden, Iceland (80) | Randomized controlled trial | 18–24 week parallel study of healthy Nordic diet (whole grains, fruits, vegetables, berries, vegetable oils and margarines, fish, low-fat dairy, low-fat meat) and average Nordic diet control | Targeted UPLC-MS; plasma ceramides | Cer(d18:1/22:0), Cer(d18:1/23:0), and Cer(d18:1/24:0) decreased after 8 weeks in the Healthy Nordic diet group; differences normalized by 18 and 24 weeks. |
| 96 middle-aged adults, United States (26) | Cross-sectional | HEI-2015 assessed from 24-hour dietary recall | Targeted LC-MS; plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), and Cer(d18:1/24:0) | Higher HEI-2015 score and total vegetable and whole grain intake were inversely associated with Cer(d18:1/22:0); saturated fat and sugar intake were positively associated with Cer(d18:1/22:0). |
| 36 overweight young adults, United States (93) | Non-randomized, repeated measures | 8-week high-fruit, high-vegetable diet (FRUVED) according to USDA MyPlate, alone or with low-refined-carbohydrate (FRUVED+LRC) or low-fat (FRUVED+LF) guidelines | Targeted LC-MS/MS; serum ceramides, glucosylceramides, and lactosylceramides | Total ceramide, Cer(d18:1/22:0), Cer(d18:1/24:1), and Cer(d18:1/26:0) were significantly lower at 5 weeks in FRUVED+LRC and FRUVED+LF groups compared with baseline. GluCer(d18:1/22:0), GluCer(d18:1/24:0), GluCer(d18:1/24:1), LacCer(d18:1/22:0), and LacCer(d18:1/24:0) levels decreased with time in FRUVED+LRC and FRUVED+LF groups. Cer(d18:1/16:0) was higher in all study groups at 8 weeks compared with baseline. |
| 31 CAD patients previously treated with PCI, Sweden (24) | Cross-over randomized controlled trial | 4-week lacto-ovo-vegetarian diet (VD) or isocaloric diet with daily meat consumption (MD) separated by 4-week washout period | Targeted UPLC-MS/MS; plasma ceramides, hexosylceramides, lactosylceramides, and sphingomyelins | Cer(d18:1/16:0) and a WGCNA lipid cluster dominated by SM and ceramide species were lower in VD than MD. Cer(d18:1/16:0) and Cer(d18:1/22:0), HexCer(d18:1/22:0), and LacCer(d18:1/16:0) decreased in VD from baseline. |
| 5,124 adults from the Framingham Offspring Study, United States (147) | Cross-sectional | SSB intake assessed from Harvard FFQ | Targeted LC-MS/MS; plasma Cer(d18:1/16:0), Cer(d18:1/22:0), and Cer(d18:1/24:0) |
SSB intake was positively associated with Cer(d18:1/16:0) and Cer(d18:1/22:0). SSB intake was positively associated with Cer(d18:1/24:0) only in prediabetic or diabetic individuals. |
| 30 adolescent and overweight male habitual SSB consumers, United States (14) | Cross-over randomized controlled trial | 3 weeks of daily consumption of 24 oz soda or 22 oz 2% milk separated by a 2-week washout period | Targeted UPLC-MS/MS; plasma sphingoid bases, ceramides, hexosylceramides, and spingomyelins | GluCer(d18:1/16:0), LacCer(d18:1/16:0), and LacCer(d18:1/18:0) significantly decreased during the milk consumption period. |
| 1,099 participants in the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study, United States (92) | Cross-sectional | Frequency of nut intake assessed from FFQs | Untargeted LC-MS; plasma sphingolipids | Nut consumption was positively correlated with Cer(d18:1/24:0), SM(d18:1/22:0), and SM(d18:1/24:0) and negatively associated with SM(d18:1/18:0). |
| 10 obese adults, United States (140) | Cross-over, double-blinded, randomized controlled trial | 5-day inpatient study with daily ingestion of 48 g walnuts or placebo with a 1-month washout period | Untargeted LC-MS; plasma sphingolipids | Walnut feeding was inversely associated with total ceramide, SM, and mono- and di-hexosylceramide. |
| 20 healthy adults, United States (139) | Cross-over, double-blinded, randomized controlled trial | 2 weeks of daily consumption of chocolate spread enriched with EVOO or palm oil | Targeted LC-MS/MS; 25 plasma sphingolipids | Cer(d18:1/16:0), Cer(d18:1/16:0)/Cer(d18:1/22:0)+Cer(d18:1/24:0) ratio, and SM(d18:1/18:0) were higher with palm oil feeding than EVOO. |
| 61 overweight adults, Sweden (115) | Double-blinded, randomized controlled trial | 8-week parallel feeding study of overconsumption with muffins enriched in sunflower oil (PUFA) or palm oil (SFA) followed by a 4-week caloric restriction period | Targeted UPLC-MS; serum and adipose dihydroceramides, ceramides, hexosylceramides, sphingoid bases, and sphingomyelin | SFA overfeeding led to an increase in the majority of serum sphingolipids, whereas PUFA overfeeding was associated with a decrease in all serum sphingolipids excepting Cer(d18:1/24:0) and Cer(d18:0/24:0). Serum sphingolipids normalized following caloric restriction period. Differences in adipose sphingolipids were not specified. |
| 18 healthy adults, United States (73) | Cross-over, randomized controlled trial | 3-week high-palmitate (HPA) or low-PA, high-oleic acid (HOA) diet separated by a 1-week washout period | Targeted LC-MS/MS; serum ceramides | Serum ceramides were significantly higher with HPA versus HOA feeding. |
| 2,860 Chinese Singaporeans from the Singapore Prospective Study Program, Singapore (120) | Cross-sectional | Dietary fat and protein intake estimated from FFQs | Targeted UPLC-MS; plasma ceramides, hexosylceramides, sphingoid bases, and sphingomyelins | SFA intake was associated with total SM; long chain SM; and ceramides, hexosylceramides, SM, and phosphorylated sphingoid bases with a 16:1 backbone. PUFA intake was negatively associated with Cer(d18:1/16:0), HexCer(d18:1/16:0), Cer(d18:1/18:0), and HexCer(d18:1/18:0). No associations were present between MUFA intake and plasma sphingolipids. Protein intake was negatively associated with all sphingolipid classes and individual species with 18:1 and 18:2 backbones, excepting Cer(d18:1/16:0) and Cer(d18:1/18:0) ceramides; protein intake was positively associated with 16:1 backbone SMs. |
| 33 subjects with recent acute myocardial infarction or unstable ischemic attack, Finland (79) | Randomized controlled trial | 8-week parallel study of fatty fish, lean fish, or control diet | Targeted UPLC-MS; plasma sphingolipids | Total ceramides decreased from the baseline in the fatty fish group. |
| 33 healthy adults, Norway (105) | Double-blinded, randomized controlled trial | 7-week parallel study of supplementation with 8 g/day fish oil or sunflower oil | Targeted UPLC-QTOFMS; plasma ceramides and sphingomyelins | Very-long-chain SM species significantly increased in the fish oil group. No change was reported in ceramides. |
| 58 postmenopausal women in the Milk Polar Lipids Consumption, Lipid Metabolism, and Inflammation in Menopausal Women cohort (VALOBAB-C) and 4 ileostomy patients (VALOBAB-D), France (83) | Double-blinded, randomized controlled trial | VALOBAB-C: 4-week parallel study of daily supplementation with milk polar lipid (PL)-enriched cream cheese (0, 3, or 5 g PL); VALOBAB-D: Cross-over study with acute milk PL-enriched cream cheese intake (0, 3, or 5 g PL) separated by 4–6 week washout periods |
Targeted HPLC-MS/MS; serum, chylomicron, ileal efflux, and fecal ceramides and SM | Milk PL intake decreased serum SM(d18:1/16:1), SM(d18:1/18:1), SM(d18:1/20:1), and Cer(d18:1/24:1); serum Cer(d18:1/20:0), SM(d18:1/20:0), and SM(d18:1/22:1) increased with PL feeding. Milk PL intake decreased intestinally derived chylomicron ceramide and SM content. Milk PL intake increased ceramide and SM levels in ileal efflux and feces. |
| 105 healthy adults from the DESIR cohort, France (36) | Observational | Cheese and noncheese dairy consumption was assessed with FFQs | Shotgun lipidomics; plasma dihydroceramides and ceramides | Noncheese dairy intake was inversely correlated with total dihydroceramide, Cer(d18:0/16:0), Cer(d18:0/22:0), Cer(d18:0/23:0), Cer(d18:0/24:0), Cer(d18:0/24:1), Cer(d18:1/26:0), and Cer(d18:1/26:1) levels in women. |
| 16 healthy adult men, Australia (94) | Cross-over, randomized controlled trial | Breakfast meals consisting of dairy fat or soy oil were consumed 4–6 weeks apart | Targeted ESI-MS/MS; plasma dihydroceramide, ceramide, hexosylceramide, and sphingomyelin | Total dihydroceramide and sphingomyelin levels increased postprandially 4 h following the dairy fat meal. Total dihydroceramide, ceramide, GM3, and sphingomyelin decreased postprandially 1 h following the soy oil meal. |
| 29 adult men, United States (19) | Prospective cohort | 8-week period of overfeeding: 140% of kcal to maintain body weight, 44% of kcal from fat | Targeted LC-MS/MS; muscle ceramides | Muscle Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/18:1), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:1/24:1), and total ceramides increased post-overfeeding compared with baseline. |
| 40 healthy adults, Australia (52) | Prospective cohort | 4-week period of overfeeding: 1,250 kcal above baseline, 45% kcal from fat | Targeted HPLC-MS; serum sphingosine, dihydroceramides, ceramides, hexosylceramides, GM3, and sphingomyelins | Total ceramides increased with overfeeding. Cer(d18:1/22:0), Cer(d18:0/22:0), HexCer(d18:1/22:0), GM3(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:0/24:0), HexCer(d18:1/24:0), and GM3(d18:1/24:0) increased with overfeeding. Cer(d18:1/18:0), Cer(d18:0/18:0), GM3(18:1/18:0), Cer(d18:1/24:1), HexCer(d18:1/24:1), and GM3(d18:1/24:1) decreased with overfeeding. |
| 38 overweight adults, Finland (90) | Randomized controlled trial | 3-week parallel study of 1,000 kcal/day overfeeding with saturated fat (SAT), unsaturated fat (UNSAT), or simple sugars (CARB) | UPLC-QTOFMS; plasma ceramides, and dihydroceramides | Total ceramide, total dihydroceramide, Cer(d18:1/24:0), Cer(d18:1/24:1), Cer(d18:0/24:0), and Cer(d18:2/23:0) increased in the SAT overfeeding group. No changes were reported in sphingolipids in the UNSAT or CARB groups. |
| 50 adults with active rheumatoid arthritis, Sweden (88) | Cross-over, randomized controlled trial | 10-week Mediterranean-style diet intervention or Western-style diet control separated by a 2–5 month washout | Targeted LC-MS/MS; serum ceramides, lactosylceramide, glucosyl/galactosylceramide, globoceramide, and sphingomyelin | CERT2 risk score and total serum ceramides increased during control diet feeding period but did not decrease after Mediterranean diet intervention. |
Abbreviations: BMI, body mass index; CAD, coronary artery disease; Cer, ceramide; CERT2, Cardiac Event Risk Test 2; CVD, cardiovascular disease; DGAI, Dietary Guidelines for American Adherence Index; EVOO, extra-virgin olive oil; ESI-MS, electrospray ionization mass spectrometry; FFQ, food frequency questionnaire; GluCer, glucosylceramide; GM3, monosialodihexosylganglioside; HEI-2015, healthy eating index-2015; HexCer, hexosylceramide; LacCer, lactosylceramide; LC-MS, liquid chromatography tandem mass spectrometry; MDS, Mediterranean Diet Score; MUFA, mono-unsaturated fatty acid; PA, palmitic acid; PCI, percutaneous coronary intervention; PUFA, poly-unsaturated fatty acid; SFA, saturated fatty acid; SM, sphingomyelin; SSB, sugar sweetened beverages; UPLC-MS, ultra-performance liquid chromatography tandem mass spectrometry; UPLC-QTOFMS, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry; USDA, United States Department of Agriculture; WGCNA, weighted correlation network analysis.