. 2022 Feb 25;80(8):1856–1895. doi: 10.1093/nutrit/nuac009

Table 2.

Characteristics of included randomized controlled trials

Reference	Country	Trial name (if available)	Study design	Participants (sample size, mean age, % female (F), mean BMI)	Intervention	Control	Biomarkers	Statistical method, Technique
Mediterranean diet
Davis et al (2017)³³	Australia		Parallel	n = 152, 71 y, 56% F, 27.0 kg/m²	Intervention: 6 months Mediterranean diet: based on a traditional Mediterranean diet, with small adaptations to the Australian food supply Written guide, recipe book, checklists Key foods were provided (EVOO, nuts, Greek yogurt, canned legumes, and canned tuna).	Habitual diet: Written instructions detailing the conditions of the diet	Established biomarkers^a Serum Within-group differences, 24 wks—baseline =: no change within either group log₁₀-transformed β-cryptoxanthin (=) (P = 1.00 within both groups) Lycopene* (=) (P = 1.00 within both groups) α-carotene, ng/mL (46.5 ± 202.2, P < 0.01 within intervention group), (P = 0.50 within control group) β-carotene (=) (P = 0.10 within intervention group; P = 1.00 within control group) Lutein: zeaxanthin* (=) (P = 0.40 within intervention group; P = 1.00 within control group) Erythrocyte % SFAs (decreased from 43.3% ± 0.1% to 42.8% ± 0.1%, P < 0.001 within intervention group) (P = 1.00 within control group) % TFAs (–0.1 ± 0.1, P < 0.001 within intervention group) (P = 0.34 within control group) % MUFAs (increased from 18.4% ± 0.1% to 19.3% ± 0.1%, P < 0.001 within intervention group) (P = 1.00 within control group) % n–3 FAs (=) (P = 1.00 within intervention group; P = 0.30 within control group) % n–6 FA (=) (P = 0.07 within intervention group; P = 1.00 within control group) % DHA (increased from 5.8% ± 0.14% to 6.1% ± 0.13%, P = 0.01 within intervention group) n–6:n–3 (–0.1 ± 0.4, P = 0.05 within intervention group) (P = 0.15 within control group) n–3 index* (0.2 ± 0.9; P = 0.02 within intervention group) (P = 0.28 within control group) 24-h urinary (=) Sodium, potassium, calcium, and magnesium	Linear mixed-effects models (diet × visit interaction) Serum (HPLC) Erythrocyte (direct transesterification)
Diekmann et al (2019)³⁴	Germany		Crossover	n = 26, 70 y, 31% F, 30.3 kg/m²	Intervention: 4.5 h Washout: 2 wks Mediterranean diet Ciabatta, smoked salmon, muesli, fruit and vegetables, canola oil Food was provided.	Western diet high-fat meal Croissants, bread rolls, jam, butter, cold cuts, boiled eggs, cream yogurt	Established biomarkers^a Plasma α-tocopherol (+) (P = 0.032) Retinol (=) (P = 0.837) β-carotene (+) (P = 0.002) Vitamin C (+) (P < 0.001)	Linear mixed models α-tocopherol, retinol, β-carotene: Normal-phase HPLC Vitamin C: HPLC with ultraviolet detection
Djuric et al (2009)³⁵	USA		Parallel	n = 69, 44 y, 100% F, 24 kg/m²	Intervention: 24 wks Mediterranean diet n = 27 Dietary counseling was provided.	Habitual diet n = 33 Provided written materials (National Cancer Institute’s Action Guide to Healthy Eating) to correct nutritional deficiencies	Established biomarkers^a Plasma 18:1, n–9 (oleic acid) (+) (P < 0.05) 18:2, n–6 (linoleic acid) (–) (P < 0.05) 18:3, n–3 (α-linolenic acid) (=) NS 20:4, n–6 (arachidonic acid) (=) NS 20:5, n–3 (EPA) (=) NS 22:6, n–3 (DHA) (=) NS Lutein (=) NS Zeaxanthin (+) (P < 0.05) β-cryptoxanthin (+) (P < 0.05) α-carotene (+) (P < 0.05) β-carotene (+) (P < 0.05) Lycopene (=) NS Total carotenoids (+) (P < 0.05) Cyclolycopene (+) NS γ-tocopherol (+) (P < 0.05) α-tocopherol (=) NS Plasma Phospholipid SFA (=) NS MUFA (+) NS PUFA (=) NS 18:1, n–9 (oleic acid) (+) NS 18:2, n–6 (linoleic acid) (=) NS 18:3, n–3 (α-linolenic acid) (=) NS 20:4, n–6 (arachidonic acid) (=) NS 20:5, n–3 (EPA) (=) NS 22:6, n–3 (DHA) (=) NS	ANOVA GC-MS HPLC
Fitó et al (2014)²³	Spain	PREDIMED	Parallel	n = 930, 67 y, 55% F, 29.5 kg/m² 48% of participants had type 2 diabetes.	Intervention: 1 y Mediterranean diet + VOO OR Mediterranean diet + nuts Dietary recommendation Key foods were provided.	Low-fat diet (reduce all fat and American Heart Association guidelines)	Established biomarkers^a (n = 450) Urinary Tyrosol (concentration) (virgin olive oil) (increased in Mediterranean diet + VOO group vs baseline, and low-fat group, P < 0.05) Hydroxytyrosol (concentration) (VOO) (increased in Mediterranean diet + VOO group vs baseline, low-fat group, and Mediterranean diet + nuts group, P < 0.05) Plasma α-linolenic acid (%) (walnut) (increased in Mediterranean diet + nuts group vs baseline, P < 0.05) (no differences in other inter- or intragroup comparisons)	ANOVA GC-MS GC
Jennings et al (2020)³⁷	Europe (France, Italy, Netherlands, Poland, UK)	New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE)	Parallel	n = 1142, 71 y, 55% F, 26.6 kg/m²	Intervention: 1 y Mediterranean-style diet Key foods were provided.	Habitual Western diet Requested to continue with usual diet	Established biomarkers^a Serum Selenium (=) (P = 0.91) (n = 1076) Ferritin (=) (P = 0.41) (n = 1118) Iron (=) (P = 0.62) (n = 1118) Soluble transferrin receptor (+) (P = 0.06) (n = 1127)	Linear mixed-effect models (time × treatment interaction) Selenium: Inductively Coupled Plasma Mass Spectrometry (ICP-MS; Micro- mass), with a plasma gas (argon) nebulizer; Ferritin, iron: soluble transferrin receptor: COBAS system (Roche Diagnostics)
Marin et al (2011)³⁹	Spain		Crossover	n = 20, 67.1 y, 50% F, 31.9 kg/m² No evidence of chronic illness (eg, hepatic, renal, thyroid, or cardiac dysfunction) Six patients had high BP, 2 had hyperlipidemia, 3 had diabetes.	Intervention: 4 wks each diet Mediterranean diet, enriched in MUFAs, with virgin olive oil, containing 15% of energy as protein, 47% as carbohydrate, and 38% as fat Food was provided.	Low-fat, high-carbohydrate diet enriched in n–3 PUFAs (CHO-α-linolenic acid diet), with 15% of energy as protein, 55% as carbohydrate, and 30% as fat SFA-rich diet, with 15% of energy as protein, 47% as carbohydrate, and 38% as fat	Established biomarkers^a Plasma Mediterranean diet β-carotene, µmol/L·×·10^–3 (+) (compared with the other 2 diets) (58.2 ± 38.6, P = 0.003) α-tocopherol (=) (P = 0.360)	One-factor ANOVA with a post hoc Bonferroni test (P < 0.05) Adjustment Gender Reversed-phase HPLC
Meslier et al (2020)⁴⁰	Italy		Parallel	n = 82, 43 y, 52% F, 31.1 kg/m²	Run-in: 2 wks on habitual diet Intervention: 8 wks Mediterranean diet (n = 43) 7-day food diaries were completed every 2 wks.	Habitual (Western) diet (n = 39)	Metabolomics^b Targeted Plasma: TMAO (NS) Carnitine (meat) (–) (P < 0.001) Choline (NS) Creatinine (NS) Betaine (NS) Urinary: TMAO (NS) Carnitine (meat) (–) (P < 0.001) Choline (NS) Creatinine (NS) Betaine (NS) Untargeted Fecal: Oxindole-3-acetic acid (vegetables/berries) (+) Leucine (animal-based foods) (–) Isoleucine (animal-based foods) (–) Bile acids (meat products) (–) Urinary: 3-(3,5-dihydroxyphenyl) propanoic acid-glucuronide (whole grains) (+) Benzoxazinoids (whole grains) (+) Pipecolic acid betaine (whole grains) (+) Tryptophan betaine (legumes) (+) Pyrogallol-sulfate (legumes) (+) 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) (fish) (+) Urolithins (nuts) (+) Carnitine (meat) (–) Aromatic amino acids (–) N-acetylcadaverine p-cresol sulfate (proteolysis) (–) Indoxyl-sulfate (proteolysis) (–) Phenylacetylglutamine (proteolysis) (–) Short-chain and medium-chain acylcarnitines (complex CHO and protein metabolism) (–) TMAO (fish/meat-derived proteins) (=) Serum: TMAO (fish/meat-derived proteins) (=)	Unpaired Wilcoxon rank-sum test (targeted) PLS-DA (untargeted) Liquid Chromatography tandem MS (targeted) UPLC-MS (untargeted)
Michielsen et al (2019)⁴¹	Netherlands	FoodBALL	Parallel	n = 47, 56 y, 57% F, 27.4 kg/m²	Run-in: 2 wks on Western diet Intervention: 8 wks Mediterranean-type diet Higher in fatty fish, legumes, nuts, unrefined grain products, and red wine, and lower in dairy products and meat 90% of energy needs were provided; the remaining 10% was chosen from a list of low-fat and low-fiber products.	Western diet High in SFA MUFA diet Western-type diet in which part of the SFA was replaced by MUFA	Metabolomics^b Targeted Serum: Most important for the separation between the 3 diets: Mediterranean-type diet–associated DHA: total FA (fish) (P < 0.001) n–3 FA: total FA (fish) (P < 0.001) Western Diet–associated Conjugated linoleic acid (CLA) (butter) (P < 0.001) CLA: FA (butter) (P < 0.001) MUFA Diet–associated MUFA: FA (olive oil) (P < 0.002)	Sparse PLS-DA ANOVA false discovery rate–corrected P-values ¹H-NMR
Park et al (2019)⁴³	USA		Crossover	n = 18, 31 y, 35% F, 22.6 kg/m²	Intervention: 4 wks Washout: 4 wks Mediterranean diet (South Beach) 3-day food records were completed at completion of each dietary phase.	High-fat diet (Atkins) Very-low-fat diet (Ornish)	Metabolomics^b Targeted^c Plasma (n = 14): Not significant when compared with baseline in each dietary phase or compared with Atkins diet: Choline Betaine Carnitine Butyrobetaine Crotonobetaine Iso-leucine Phenylalanine Tyrosine; Significantly higher levels in Atkins phase when compared with Ornish phase: TMAO (P = 0.01) Leucine (P = 0.01) Valine (P = 0.005)	ANOVA LC-MS/MS
Vázquez-Fresno et al (2015)³²	Spain	PREDIMED (nondiabetic)	Parallel	n = 98, 66.6 y, 71.3% F, 30.2 kg/m² Participants had at least 3 cardiovascular risk factors (current smoking, hypertension, hypercholesterolemia, BMI ≥25, family history of premature CVD).	Intervention: 1 y and 3 y Mediterranean diet + EVOO n = 41 OR Mediterranean diet + nuts n = 27 Dietary recommendation Key foods were provided.	Low-fat diet n = 30 (reduce all fat and American Heart Association guidelines)	Metabolomics^b Untargeted^c Urinary: Significant at both 1 y and 3 y if not specified Mediterranean diet–associated 3-HB (+) Leucine (+) Isobutyric acid (+) 2-oxoisovaleric (+) (EVOO vs LFD at 3 y) 4-DTEA (4-deoxythreonic acid) (+) N-Ac (N-acetylglycoproteins) (+) (EVOO vs LFD) Glycine (+) (3 y) p-cresol (+) (EVOO vs LFD 1 y, Nuts vs LFD 3 y) Suberic acid (+) Oleic acid (+) Proline (+) Mediterranean diet + Nuts–associated PAGN (+) N-AGN (+) Creatine (3 y, Nuts vs EVOO, Nuts vs LFD) Mediterranean diet + EVOO–associated Creatinine (+) Citrate (+) (1 y and 3 y, EVOO vs Nuts, EVOO vs LFD; 3 y, EVOO vs LFD) Cis-aconitate (+) (y1, EVOO vs Nuts, Nuts vs LFD) Low-fat diet–associated Hippurate (+) TMAO (+) (3 y, LFD vs EVOO) Anserine (+) (1 y), (–) (3 y, LFD vs EVOO) Histidine (+) (1 y) 3-methylhistidine (+) (1 y, LFD vs EVOO) 1-methylhistidine (+) (1 y, LFD vs Nuts) Carnosine (+) (1 y, LFD vs Nuts; 3 y, LFD vs EVOO) Proline betaine (+) (3 y, LFD vs EVOO, LFD vs Nuts) Xanthosine (+) (1 y, LFD vs Nuts; 3 y, LFD vs EVOO)	OSC-PLS-DA (orthogonal signal correction) and 2-way Hierarchical Clustering Analysis VIP score threshold: >1.5 ANCOVA (P < 0.05) (controlled by baseline values: age, gender, BMI, smoking status, hypertension, hyper-cholesterolemia) ¹H-NMR
Zhu et al (2020)⁴⁹	USA		Crossover	n = 10, 22 y, 50% F, 24.4 kg/m²	Intervention: 4 d Washout: 4 d Mediterranean diet: rich in vegetables, whole grains, olive oil, nuts, and fish Food was provided.	Fast-food diet: Burgers and fries Exact dollar amounts were provided for purchase at a specific restaurant.	Metabolomics^b Untargeted Plasma: Increased after Mediterranean diet and decreased after Fast-food diet Indole-3-lactic acid (P = 0.003) Indole-3-propionic acid (P = 0.021) Indole-3-acetic acid (P = 0.021) Increased after Fast-food diet and decreased after Mediterranean diet Tryptophan (P = 0.014) Indole-6-carboxaldehyde (P = 0.014) 4-(1-piperazinyl)-1H-indole (P = 0.030) No change after either Mediterranean diet or Fast-food diet TMAO (=) Choline (=) Increased after Mediterranean diet but not after Fast-food diet Oleoylcarnitine (P = 0.038) Acetylcarnitine (P = 0.052) Betaine (P = 0.032) Hippuric acids (P = 0.04)	Differential abundance analyses using a linear mixed model. Multiple test adjustments were performed. LC-MS
Dietary approaches to stop hypertension
McClure et al (2019)²⁵	USA	DASH Trial	Parallel	n = 397, 45 y, 48% F, 28.2 kg/m²	Run-in: 3 wks on control diet Intervention: 8 wks DASH diet Food was provided.	Fruit and vegetables diet TAD	Established biomarkers^a 24-h Urinary: Fruit and vegetables vs TAD Phosphorus (=) (P = 0.74) All other pairwise comparisons Phosphorus (+) (P < 0.001)	ANOVA followed by pairwise comparisons with Tukey’s honest significant difference test only if ANOVA P < 0.05
Miller et al (2005)²⁷	USA		Parallel	n = 103, 52 y, 56% F, 29.6 kg/m² 14% current smokers 75% African American	Run-in: 2 wks on control diet Intervention: 3 months DASH diet: rich in fruits, vegetables, low-fat dairy products; included whole grains, poultry, fish, and nuts; and was reduced in red meat, sweets, sugar-containing beverages, saturated fat, total fat and cholesterol (n = 51) Food was provided. Alcoholic and caffeinated beverages were limited and monitored.	TAD, n = 52	Established biomarkers^a Serum: Lutein (+) (P < 0.001) Cryptoxanthin (+) (P < 0.001) Zeaxanthin (+) (P < 0.001) β-carotene (+) (P < 0.001) Lycopene (–) (P < 0.001) γ-tocopherol (–) (P < 0.001) Retinol (=) NS α-tocopherol (=) NS α-carotene (–) (P < 0.01)	Regression analysis Adjustments Baseline measurement (age, gender, ethnicity, smoking status, BMI) HPLC
Miller et al (1998)²⁶	USA	Ancillary study within the DASH trial	Parallel	n = 123, 48.5 y, 47% F, 27.5 kg/m²	Run-in: 3 wks on control diet Intervention: 8 wks Combination (DASH) diet n = 41 Emphasized fruit and vegetables (10 servings per day), low-fat dairy and other reduced-fat foods, rich in potassium, magnesium, fiber, calcium, and protein and reduced in saturated fat, total fat, and cholesterol	TAD, n = 40 Fruit and vegetable diet, n = 42 Nine servings of fruit and vegetables per day, rich in potassium, magnesium, and fiber; otherwise similar to control diet	Established biomarkers^a Serum (n = 34): Combination (DASH) diet (n = 12) AND Fruit and vegetable diet (n = 10) compared with TAD (n = 12) β-carotene (+) (P < 0.05) Cryptoxanthin (+) (P < 0.05) Zeaxanthin (+) (P < 0.05) Combination (DASH) diet compared with TAD Lutein (+) (P < 0.05) Among diets Lycopene (=) NS Retinol (=) NS α-tocopherol (=) NS	t-test (ANCOVA) with Bonferroni adjustment HPLC
Nowson et al (2009)⁴²	Australia		Parallel	n = 95, 59.2 y, 100% F, 29.6 kg/m² 36.8% of participants were using antihy-pertensives.	Run-in: 3–4 wks Intervention: 14 wks Vitality diet n = 46 Low dietary acid load; based on low-sodium DASH diet rich in fruits and vegetables and including lean red meat; lower in sodium, higher in potassium and magnesium Key foods were provided (red meat, low-sodium bread, no-added-salt baked beans, salt-free margarine, and low-sodium stock powder).	Reference healthy diet, n = 49 Based on general dietary guidelines to reduce fat intake, particularly saturated fat, and increase intake of cereals and breads with a high acid load (Regular-salt margarine and baked beans)	Established biomarkers^a 24-h Urinary: Sodium (–) (P < 0.001) Potassium (+) (P = 0.08) Calcium (–) (P = 0.02) Magnesium (=) (P = 0.89) Chloride (–) (P = 0.001) Phosphate (–) (P = 0.2) Urea (=) (P = 0.92) Sodium:potassium ratio (–) (P < 0.001)	Student’s t-test Photometry: Randox Daytona automated clinical chemistry analyzer (Antrim, United Kingdom)
Rebholz et al (2018)³⁰	USA	DASH Trial subset	Parallel	n = 329, Age category, % (n): 18–30 y, 11.9 (39); 31–55 y, 69.0 (227); ≥56 y, 19.2 (63) 47% F, 28 kg/m²	Run-in: 3 wks on control diet Intervention: 8 wks DASH diet (n = 110) Food was provided.	Fruit and vegetable diet, n = 111 (similar to DASH, high fiber; potassium and magnesium close to 75th percentile of US consumption; more fruit and vegetables, fewer CHO-rich sweet desserts and snacks. Otherwise, similar to control diet) TAD, n = 108 (macronutrient intake similar to average US consumption, potassium, magnesium, and calcium 25th percentile of US consumption)	Metabolomics^b Untargeted Serum: The 10 metabolites most able to distinguish the DASH diet from the Fruit and vegetable diet: 2-methylserine (+) (amino acid: glycine, serine, and threonine metabolism) S-allylcysteine (+) (Xenobiotics: Food component/plant) 4-allylphenol sulfate (+) (Xenobiotics: Food component/plant) Linoleoyl-linolenoyl-glycerol (18:2/18:3) [1] (+) (lipid: diacylglycerol) # Linoleoyl-linolenoyl-glycerol (18:2/18:3) [2] (+) (lipid: diacylglycerol) # Linoleoyl-docosahexaenoyl-glycerol (18:2/22:6) (+) (lipid: diacylglycerol) # Heptenedioate (C7:1-DC) (–) (lipid: fatty acid, dicarboxylate) # Suberoylcarnitine (C8-DC) (–) (lipid: fatty acid metabolism [acyl carnitine]) Adipoylcarnitine (C6-DC) (–) (lipid: fatty acid metabolism [acyl carnitine]) # 3-methylglutarylcarnitine (–) (amino acid: leucine, isoleucine, and valine metabolism) The 10 metabolites most able to distinguish the DASH diet from the TAD N-methylproline (+) (amino acid: urea cycle; arginine and proline metabolism) Stachydrine (+) (xenobiotics: Food component/plant) Tryptophan betaine (+) (amino acid: tryptophan metabolism) Chiro- inositol (+) (lipid: inositol metabolism) Methyl glucopyranoside (α + β) (+) (Xenobiotics: Food component/plant) β-cryptoxanthin (+) (cofactors and vitamins: Vit A metabolism) Theobromine (–) (xenobiotics: xanthine metabolism) 7-methylurate (–) (xenobiotics: xanthine metabolism) 3-methylxanthine (–) (xenobiotics: xanthine metabolism) 7-methylxanthine (–) (xenobiotics: xanthine metabolism) # significant for both DASH vs Fruit and vegetable and DASH vs TAD	PLS-DA GC-MS LC-MS
Healthy Nordic diet
Acar et al (2019)²⁰	Denmark	SHOPUS	Parallel	n = 146, age range 18–65 y, 68% F, BMI not reported Centrally obese	Run-in: 1 wk Intervention: 26 wks New Nordic diet (organic diet high in fruit and vegetables, whole grains and fish; based on Nordic Nutrition Recommendations 2004 but higher in protein) Food was provided from study shop, collected ad lib.	Average Danish diet (Higher in imported and processed foods, refined grains, meat, dairy, sugary products, convenience foods, low fiber vegetables, imported fruit)	Metabolomics^b Untargeted Plasma: New Nordic diet Prolyl hydroxyproline (fish collagen) Phosphatidylcholine (40:9) (lipid and fatty acid metabolism) Phosphatidylcholine (18:0/22:6) (Fish C [22:6]) Pipecolic acid betaine (whole grain) TMAO (fish) Hydroxydecanoic acid (unknown) Lysophosphatidylcholine (16:0) (fish) Phosphatidylcholine (P-38:4) (unknown) Average Danish diet Phosphatidylcholine (18:0/20:3) (lipid and fatty acid metabolism) Theobromine (chocolate) Butyryl carnitine (lipid metabolism) Cyclo-(pro-val) (food heating) Proline betaine (citrus fruits) Phosphatidylcholine (36:3) (lipid and fatty acid metabolism) Phosphatidylcholine (O-18:0/20:4) (fish C [20:4]) Phosphatidylcholine (36:3) (unknown) Threonine or allothreonine (animal protein) Phosphatidylcholine (P-18:0/20:3) (lipid and fatty acid metabolism) 2- or 3-hydroxy-3-methylbutyrate (amino acid metabolism) Phosphatidylcholine (18:0/20:3) (lipid and fatty acid metabolism) 3-indolelactic acid (tryptophan metabolite)	PLS-DA Ultra-performance liquid chromatography, coupled to quadruple time-of-flight mass spectrometer (UPLC-qTOF-MS)
Anderson et al (2014)²¹	Denmark	SHOPUS	Parallel	n = 107, 42.9 y, 74% F, 29.7 kg/m² Centrally obese	Run-in: 1 wk Intervention: 26 wks New Nordic diet	Average Danish diet	Metabolomics^b Untargeted Urinary: New Nordic diet Hydroquinone glucuronide (no info) TMAO (fish) Hippuric acid (no info) (2-oxo-2,3-dihydro-1H-indol-3-yl) acetic acid (no info) 3,4,5,6-tetrahydrohippurate (no info) Average Danish diet Pyrraline (heat treatment) Theobromine (chocolate) 7-methyluric acid (chocolate) 6-amino-5-[N-methylformylamino]-1-methyluracil (chocolate) 3,7-dimethyluric acid (chocolate) 7-methylcanthine (chocolate) Proline betaine (citrus cluster) Pyroglutamyl proline (no info) P-menth-1-ene-6,8,9-triol (limonene) Perillic acid-8,9-diol-glucuronide (limonene) Limonene-8,9-diol-glucuronide (limonene) Dihydroperillic acid glucuronide (limonene) Limonene-1,2-diol glucuronide (limonene) Octanoyl-glucuronide (no info) 3-indoleacetyl-glucuronide (no info)	PLS-DA (with feature selection) Ultra-performance liquid chromatography, coupled to quadruple time-of-flight mass spectrometer (UPLC-qTOF-MS)
Khakimov et al (2016)²⁴	Denmark	SHOPUS	Parallel	n = 145, age range 18–65 y, 69% F, BMI not reported Centrally obese	Run-in: 1 wk Intervention: 26 wks New Nordic diet	Average Danish diet	Metabolomics^b Untargeted Plasma: New Nordic diet 3-hydroxybutanoic acid Erythritol (fruit and vegetables) 2-hydroxybenzoic acid (fruit and vegetables) Aspartic acid 2,3,4-trihydroxybutanoic acid Xylitol (fruit and vegetables) N-acetylaspartic acid 2,5-dimethoxyphenylpropionic acid Palmitoleic acid; Average Danish diet Lactic acid Oxalic acid Alanine Threonine (grains, mushrooms) Diethyl phthalate 2,6-diisopropylnaphthalene Citric acid Cholesterol	PLS-DA GC-MS
Poulsen et al (2014)²⁹	Denmark	SHOPUS	Parallel	n = 181, 42 y, 71% F, 30.2 kg/m² Centrally obese	Run-in: 1 wk Intervention: 26 wks New Nordic diet	Average Danish diet	Established biomarkers^a 24-h urinary (n = 143) Nitrogen (+) (P = 0.12) Sodium (=) (P = 0.33) Whole blood (n = 145) % SFAs (–) (P = 0.14) % MUFAs (=) (P = 0.56) % PUFAs (+) (P = 0.79) % n–6 FA (=) (P = 0.17) % n–3 FA (+) (P < 0.001) % EPA + DHA (+) (P < 0.001) % n–6/n–3 ratio (–) (P < 0.001) % n–3 HUFA in total HUFA (+) (P < 0.001)	Student’s t-test
Trimigno et al (2020)³¹	Denmark	OPUS	Parallel	n = 181, 42 y, 48% F, BMI not reported Centrally obese	New Nordic diet	Average Danish diet	Metabolomics^b Untargeted Urinary (n = 142): Acetate (+) (q = 0.203) Acetone (unbalanced diet) (–) (q = 0.808) Alanine (low-protein, high-carbohydrate diet; average Danish diet) (–) (q = 0.279) Glycine betaine (fish; cereals and fibers) (+) (q = 0.001) Carnitine (red meat; protein) (–) (q = 0.094) Creatine (meat; game meat; fish) (+) (q = 0.719) Dimethyl sulfone (onions; grains and fibers; cabbage and asparagus; meat, egg, dairy and fish) (–) (q = 2.34 × 10⁻⁸) Dimethylamine (fish; red meat, eggs and dairy) (+) (q = 0.167) Fumarate (+) (q = 0.268) Glucose (fruits, honey and sugar) (+) (q = 1.34 × 10⁻⁴) Glucose, lactose, maltose (+) (q = 6.85 × 10⁻⁴) Glycine (protein-rich foods; NND) (+) (q = 0.336) Guanidinoacetate (amino acids) (+) (q = 0.427) Hippurate (vegetarian diet; plant-based foods; green and black tea; dairy products) (+) (q = 0.013) Isoleucine, leucine (cheese) (–) (q = 0.314) Lysine (+) (q = 0.418) Methanol (alcohol; pectins in fruit and fruit juices) (–) (q = 0.380) Phenylalanine (protein-rich foods; fish, pulses and nuts) (+) (q = 0.026) Propylene glycol (lacto-ovo vegetarian breakfast; diet of people at risk for poverty) (–) (q = 0.004) Succinate (low-protein diet) (–) (q = 0.554) Tartrate (red wine; grapes) (–) (q = 5.73 × 10⁻⁵) Taurine (omnivorous diet; high-protein diet) (+) (q = 0.013) TMA (fish; red meat, eggs and dairy; pulses) (+) (q = 0.0841) TMAO (fish) (+) (q = 8.75 × 10⁻⁵) Tyrosine (cheese) (–) (q = 0.474)	PLS-DA with false discovery rate-corrected ANOVA q values ¹H NMR
Tuomainen et al (2019)⁴⁷	Nordic countries (Finland, Sweden, Denmark, Iceland)	SYSDIET	Parallel	n = 164, 55 y, 66% F, 31.7 kg/m²	Intervention: 18 or 24 wks (depending on the study center) Healthy Nordic diet Increased whole grains, canola oil, berries, and fish. Nordic nutrition recommendations used. Key foods were provided.	Control group (typical Nordic diet) Low-fiber cereal, milk fat, restricted amounts of fish and berries	Metabolomics^b Targeted^c Plasma: 4-aminovaleric acid betaine (P-value NA) (n = 5) 5-aminovaleric acid betaine (=) (P = 0.920) (n = 163) Acetyl L-carnitine (=) (P = 0.651) (n = 163) Alanine betaine (=) (P = 0.193) (n = 140) Choline (=) (P = 0.420) (n = 163) Glycine betaine (=) (P = 0.198) (n = 163) γ -Butyrobetaine (=) (P = 0.097) (n = 163) Hydroxyproline betaine (=) (P = 0.906) (n = 71) L-carnitine (=) (P = 0.890) (n = 163) Pipecolic acid betaine (coffee; citrus fruits) (+) (P = 0.00032) (n = 130) Phenylalanine betaine (=) (P = 0.419) (n = 97) Proline betaine (=) (P = 0.234) (n = 162) TMAO (=) (P = 0.027) (n = 162) Trigonelline (=) (P = 0.505) (n = 157) Tryptophan betaine (=) (P = 0.261) (n = 154)	ANOVA (significant at P < 0.0036) LC with triple quadrupole MS
Diet based on dietary guidelines
Garcia-Perez et al (2017)³⁶	UK		Crossover	n = 19, 55.8 y, 47% F, 25.6 kg/m²	Intervention: 72 h inpatient period on 4 occasions Washout: ≥5 d WHO healthy eating guidelines (increased fruits, vegetables, whole grains, and dietary fiber; decreased fats, sugars, and salt) Four diets with a stepwise variance in concordance with WHO healthy eating guidelines: Diet 1: most concordant, Diet 4: least concordant The diets had a range of energy densities. DASH scores were calculated based on 4-day dietary records. Food was provided.	Diet 4: least concordant with WHO healthy eating guidelines.	Metabolomics^b Untargeted Urinary: Diet 1 (higher concentration compared with diet 4) 3-aminoisobutyrate (unknown) (P = 6.22 × 10^–25) Rhamnitol (Fruits) (P = 6.81 × 10^–11) Lysine (unknown) (P = 1.92 × 10^–3) Acetate (unknown) (P = 2.97 × 10^–3) N-acetyl-S-(1Z)-propenyl-cysteine-sulfoxide (vegetables) (P = 6.85 × 10^–26) Dimethylamine (fish) (P = 5.90 × 10^–4) N-acetyl-S-methyl-cysteine-sulfoxide (cruciferous vegetables) (P = 5.75 × 10^–21) S-methyl-cysteine-sulfoxide (cruciferous vegetables) (P = 2.03 × 10^–23) Creatine ([Red] meats) (P = 2.38 × 10^–5) 1-methylhistidine (lean [white] meats) (P = 1.26 × 10^–27) 3-methylhistidine (lean [white] meats) (P = 7.31 × 10^–25) TMAO (fish, meats) (P = 6.64 × 10^–16) N-methyl-2-pyridine-5- carboxamide (Niacin [Vit B3]) (P = 2.80 × 10^–10) 4-hydroxyhippurate (Fruits) (P = 3.58 × 10^–6) Hippurate (fruits, vegetables) (P = 2.81 × 10^–14) Tartrate (grapes) (P = 1.62 × 10^–19) N-methylnicotinate (Niacin [Vit B3]) (P = 1.09 × 10^–12) N-methylnicotinamide (Niacin [Vit B3]) (P = 4.23 × 10^–16) Urea (protein) (P = 8.87 × 10^–28); Diet 4 (higher concentration compared with diet 1) Fatty acids (C5–C10) (fats) (P = 7·34 × 10^–5) Alanine (unknown) (P = 6·95 × 10^–19) N–acetyl neuraminate (unknown) (P = 7·87 × 10^–5) Phenylacetylglutamine (unknown) (P = 4.34 × 10^–26) O-acetylcarnitine ([Red] meats) (P = 7.50 × 10^–16) Carnitine ([Red] meats) (P = 2.48 × 10^–14) Glucose (sugars) (P = 6.38 × 10^–22) Glycine (unknown) (P = 3.87 × 10^–10) Glycolate (unknown) (P = 6.04 × 10^–13) Applied model developed to confirm the association between urinary metabolic and dietary profiles in two cohorts: INTERMAP UK (n = 225) (P < 0.0001) (24-h urinary) Danish (n = 66) (P < 0.001) (spot urinary) Single metabolites quantified in INTERMAP: (+): higher concentration with high DASH score compared with low DASH score, P ≤ 0·05) (Kruskal-Wallis test and Wilcoxon rank sum post hoc tests) Hippurate (fruits and vegetables) (+) (no difference between high and intermediate DASH score, P = 0.051; no difference between intermediate and low DASH score, P = 0.096) 4-hydroxyhippurate (fruits) (+) (no difference between intermediate and low DASH score, P = 0.15) S-methyl-L-cysteine-sulfoxide (cruciferous vegetables) (+) (no difference between high and intermediate DASH score, P = 0.19) Proline betaine (citrus fruits) (+) (P < 0.05 in all pair-wise comparisons)	PLS-DA 1H-NMR spectroscopy
Reidlinger et al (2015)⁴⁵	UK	CRESSIDA	Parallel	n = 162, 52 y, 60% F, 26.2 kg/m² Nonsmoking healthy individuals	Intervention: 12 wks UK dietary guidelines Reduced intake of sodium, total fat, saturated fatty acids, and nonmilk extrinsic sugars Increased consumption of oily fish, and whole grains Key foods were provided (low-SFA and -TFA margarine, liquid vegetable oil).	Traditional British diet Refined cereals, meats, full-fat dairy, no restriction on salt/sugar intake, but limited confectionery and snack foods (butter-based spread and unhydrogenated vegetable oil)	Established biomarkers^a 24-h urinary: Sodium (salt) (–) (P < 0.01) Potassium (fruit and vegetables) (+) (P < 0.01) Sucrose and fructose (added sugars) (–) (P < 0.01) Erythrocyte lipids: n–3 index (oily fish) (+) (P < 0.01) Plasma: Alkylresorcinol (whole grains) (+) (P < 0.01) Serum: 25-hydroxyvitamin D (higher intake of oily fish) (+) (P < 0.001) Folate (avoidance of folic acid-fortified breakfast cereals) (–) (P = 0.001) Ferritin (iron status index) (=) (P = 0.43) Homocysteine (folate status index) (=) (P = 0.206)	ANCOVA (P < 0.01) Regressed against baseline value, age group, sex, ethnicity, and BMI category
Low-glycemic-load diet
Barton et al (2015)²²	USA	Carbohydrates And Related Biomarkers (CARB) study	Crossover	n = 19, 31.6 y, 53% F, BMI not reported 58% overweight/obese	Intervention: 4 wks Washout: 4 wks habitual diet Low-GL diet: 125 GL/d, 55 g fiber/d Food was provided.	High-GL diet: 250 GL/d, 28 g fiber/d Identical distribution of macronutrients compared with low-GI diet	Metabolomics^b Targeted Plasma: Kynurenate (tryptophan metabolism) (+) (P = 0.0002) Methyl succinate (dicarboxylic acids and derivatives) (+) (0.004) Cystamine (taurine and hypotaurine metabolism) (–) (P = 0.004) Proline (arginine and proline metabolism) (+) (P = 0.010) Acetylcholine (glycerophospholipid metabolism) (–) (P = 0.014) Hydroxyproline (arginine and proline metabolism) (–) (P = 0.016) Creatine (glycine, serine, threonine metabolism; arginine and proline metabolism) (–) (P = 0.016) TMAO (gut bacterial metabolite) (+) (P = 0.025) Carnitine (fatty acid metabolism) (+) (P = 0.030) Homovanillate (tyrosine metabolism) (+) (P = 0.036) Lysine (biotin metabolism; carnitine synthesis) (+) (P = 0.039) Nitrotyrosine (product of reactive nitrogen species) (+) (P = 0.042) Niacinamide (vitamin B3) (–) (P = 0.046) Dimethylguanosine (nucleoside) (+) (P = 0.047)	PLS-DA (VIP Score > 2) P-value calculated using paired t-test Adjustments Weight change Body fat % Fat distribution LC-MS/MS
Navarro et al (2019)²⁸	USA	Carbohydrates And Related Biomarkers (CARB) study	Crossover	n = 80, 30 y, 50% F, BMI not reported	Intervention: 4 wks Washout: 4 wks Low-GL diet Whole grains, legumes, fruits, vegetables, nuts, and seeds Food was provided.	High-GL diet High in refined grains and added sugars	Metabolomics^b Targeted Plasma: Inositol (+) (P = 1.46 × 10⁻²³)* Melatonin (–) (P = 3.58 × 10⁻²²)* Hydroxyphenylpyruvate (+) (P = 3.02 × 10⁻¹²)* Betaine (–) (P = 1.75 × 10⁻¹⁰)* Creatine (–) (P = 1.19 × 10⁻⁷)* Acetylcholine (–) (P = 8.54 × 10⁻⁷)* Citrulline (+) (P = 1.34 × 10⁻⁴)* Ornithine (+) (P = 3.83 × 10⁻⁴)* 13-Hydroxyoctadecadienoic acid (+) (P = 4.32 × 10⁻⁴)* Aspartic acid (–) (P = 7.25 × 10⁻⁴)* Hydroxyproline (–) (P = 7.77 × 10⁻⁴)* Methylhistidine (–) (P = 8.18 × 10⁻⁴)* Tryptophan (–) (P = 9.19 × 10⁻⁴)* Cystamine (–) (P = 0.002)* Glutamine (+) (P = 0.003)* Carnitine (–) (P = 0.004)* Trimethylamine (–) (P = 0.007)* Oxaloacetate (+) (P = 0.007)* Xanthurenic acid (–) (P = 0.03) Shikimic acid (+) (P = 0.06) *Significant with Benjamini-Hochberg False Discovery Rate < 0.05	Linear mixed model LC-MS/MS
Vegetarian diet
Lederer et al (2019)³⁸	Germany		Parallel	n = 53, 32 y, 62% F, 23.1 kg/m²	Run-in: 1 wk on a balanced mixed diet Intervention: 4 wks Vegan diet Strict Extensive training on assigned diet; detailed information material; recipe book; free meals offered	Meat-rich diet >150 g of meat daily	Established biomarkers^a Serum: Vitamin B₁₂ (–) (P < 0.001) Holotranscobalamin (–) (P < 0.001) Methylmalonic acid (+) (P = 0.090) Homocysteine (+) (P = 0.140) Arachidonic acid (–) (P = 0.046) DHA (–) (P = 0.298) Eicosanoic acid (=) (P = 0.211) Eicosenoic acid (+) (P = 0.906) Linoleic acid (+) (P = 0.532) Linolenic acid (+) (P = 0.705) Oleic acid (–) (P = 0.602) 25-hydroxyvitamin D₂/D₃ (=) (P = 0.903) Urinary: Creatinine (=) (P = 0.158) Plasma: Nitrite and nitrate (+) (P = 0.003)	ANCOVA adjusted for baseline values Serum biomarkers LC-Electrospray Ionization (ESI)-MS/MS FA profiles GC-MS
Raådjursöga et al (2018)⁴⁴	Sweden		Crossover	n = 32, 29 y, 50% F, 22.1 kg/m²	Intervention: 3 h Breakfast meal crossed over during 3 consecutive days Vegan diet Lacto-ovo vegetarian diet Food was provided.	Omnivore diet	Metabolomics^b Untargeted^c Serum: Lacto-ovo vegetarian vs Vegan Increased in concentration after lacto-ovo vegetarian diet: 3-hydroxyisobutyrate (P < 0.0001) Acetoacetate (P < 0.0001) Carnitine & acetoacetate (P < 0.0001) Creatinine & creatine & creatine phosphate (P < 0.0001) Isoleucine (P < 0.0001) Leucine (P < 0.0001) Leucine & arginine (P < 0.0001) Lysine (P < 0.0001) Methionine (P < 0.0001) N-acetylcysteine & proline & glutamate (P < 0.0001) Proline (P < 0.0001) Proline & glutamate & unknown (P < 0.0001) Propylene glycol (P = 0.004) Threonine (P < 0.0001) Tyrosine (P < 0.0001) Valine (P < 0.0001) Increased in concentration after vegan diet Lipids/FFA (P < 0.0001) Lacto-ovo vegetarian vs Omnivore diets Increased in concentration after lacto-ovo vegetarian diet: 3-hydroxyisobutyrate (P = 0.004) Alanine (P = 0.03) Carnitine + acetoacetate (P = 0.007) Lactate (P = 0.06) N-acetylcysteine & proline & glutamate (P = 0.005) Proline (P = 0.003) Proline & glutamate & unknown (P = 0.003) Propylene glycol (P = 0.02) Pyruvate (P = 0.2) Succinic acid (P = 0.2) Tyrosine (P = 0.005) Increased in concentration after omnivore diet: Ascorbate (P = 0.02) Betaine (P = 0.02) Choline (P = 0.003) Creatinine & Creatine & Creatine phosphate (P = 0.003) Isoleucine (P = 0.08) Lipids/FFA (P = 0.003) Lysine (P = 0.3) Serine & tyrosine (P = 0.001)	Orthogonal projections to Latent Structures with Effect Projection (OPLS-EP) P-value calculated using Wilcoxon signed ranked test ¹H-NMR
Prudent diet
Wellington et al (2019)⁴⁸	Canada	Subset of Diet and Gene Intervention (DIGEST) pilot study	Parallel	n = 42, 47 y, 64% F, 27 kg/m²	Intervention: 2 wks Prudent diet Based around minimally processed foods including lean protein and whole grains, and high in fresh fruits and vegetables Food was provided: allotment picked up at store, or delivered to home;	Western diet Reflecting a typical Canadian macronutrient profile with higher intake of processed foods	Metabolomics^b Untargeted Plasma: Proline betaine (+) (P = 0.007) 3-methylhistidine (+) (P = 0.001) Proline (–) (P = 0.02) Carnitine (–) (P = 0.005) Deoxycarnitine or γ-butyrobetaine (–) (P = 0.008) Linoelaidic acid (–) (P < 0.001) Pentadecanoic acid (–) (P < 0.001) Alanine (–) (P = 0.018) Ketoleucine or 4-methyl-2-oxopentanoic (+) (P = 0.043) 3-hydroxybutyric (+) (P = 0.097) α-linoleic acid (–) (P = 0.002) Ketovaline or α-isovaleric acid (+) (P = 0.125) Myristic acid (+) (P < 0.001) Linoleic acid (–) (P < 0.001) Urinary: 3-methylhistidine (+) (P = 0.008) 5-hydroxypipecolic acid (+) (P = 0.293) Imidazole propionic acid (+) (P = 0.002) Proline betaine (+) (P = 0.002) Valinyl-valine (+) (P = 0.06) Enterolactone glucuronide (+) (P = 0.01) Dihydroxybenzoic acid (+) (P = 0.01) Dimethylglycine (+) (P = 0.065) Acesulfame K (–) (P < 0.05)	Paired orthogonal PLS-DA Mixed ANOVA High-resolution MS/MS
Korean diet
Shin et al (2019)⁴⁶	Korea		Crossover	n = 54, 41 y, 48% F, 27.5 kg/m²	Intervention: 4 wks Washout: 2 wks Typical Korean Diet Based on the Korean Food Guide of the Dietary Reference Intakes for Koreans Comprised of 5 food groups: grains (mix of whole and refined); meat, fish, eggs, and beans; vegetables; fruits; milk and dairy products Traditional Korean preparation techniques used Food was provided.	Recommended American diet (RAD) Sample menus from the 2010 Dietary Guidelines for Americans developed by the US Department of Agriculture TAD What We Eat in America dietary survey from NHANES 2001–2004	Metabolomics^b Targeted (+) increased compared with baseline (–) decreased compared with baseline Serum: Significantly altered after (P < 0.01): Typical Korean diet: Acetate (+) Isoleucine (–) Leucine (–) Lactate (–) Proline (–) Valine (–) RAD: 2-aminobutyrate (+) 3-hydroxybutyrate (+) Acetate (+) Ascorbate (+) Mannose (+) Myo-inositol (+) TAD: Ethanol (–) Glutamine (+) Glycine (–) Proline (–) Pyruvate (–) Tyrosine (+) Urinary: Significantly altered after: All diets: Glycolate (–) P = 0.001 in Typical Korean diet and RAD, P = 0.003 in TAD Taurine (+) in Typical Korean diet and RAD, P < 0.001; (–) in TAD, P < 0.001 RAD: 3-hydroxy-3-methylglutarate (3-HMGA) (–) (P = 0.004) Citrate (–) (P < 0.001) Dimethylamine (–) (P = 0.007) Hippurate (–) (P < 0.001) Homovanillate (–) (P < 0.001) TAD: 1-methylnicotinamide (+) (P = 0.001) Carnitine (+) (P = 0.001) Pyruvate (–) (P = 0.003)	Univariate statistical analysis (Wilcoxon Signed-Rank test) ¹H-NMR

Values are means ± SDs; +, higher in intervention group; –, lower in intervention group; =, no difference between groups, unless otherwise indicated. Use of established dietary biomarkers of specific foods or nutrients.

Use of metabolomics to study biomarkers and biomarker profiles; targeted metabolomics focused on defined subsets of metabolites within specific metabolic pathways, and untargeted metabolomics quantified all metabolites globally (including known and unknown) in a biospecimen.

Metabolomics type (targeted or untargeted) was ascertained from the reported methodology as this information was not specified in the article.Abbreviations: ¹H-NMR, hydrogen-1 proton nuclear magnetic resonance; 3-HB, 3-hydroxybutyrate; ANCOVA, analysis of covariance; ANOVA, analysis of variance; BMI, body mass index; BP, blood pressure; CHO, carbohydrate; CVD, cardiovascular disease; DASH, dietary approaches to stop hypertension; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EVOO, extra virgin olive oil; FAs, fatty acids; FFA, free fatty acid; GC-MS, Gas Chromatography–Mass Spectrometry; GL, glycemic load; HPLC, high-performance liquid chromatography; HUFA, highly unsaturated fatty acid; LC-MS, liquid chromatography–mass spectrometry; LFD, low-fat diet; MUFAs, monounsaturated fatty acids; n–3, omega 3; n–6, omega 6; N-AGN, n-acetylglutamine; NHANES, National Health and Nutrition Examination Survey; NS, not significant; PAGN, phenylacetylglutamine; PLS-DA, partial least-squares discriminant analysis; PUFAs, polyunsaturated fatty acids; RAD, recommended American diet; SFAs, saturated fatty acids; TAD, typical American diet; TFAs, trans fatty acids; TMAO, trimethylamine N-oxide; VOO, virgin olive oil.