Background
Methods
Literature search
Screening, inclusion and exclusion criteria
Selection of studies and data extraction
Quality assessment
Results
Overview of included papers
Author | Year | Country | Study design | CFS/ME/SEID diagnostic criteria | Metabolite | Sample size | |||
---|---|---|---|---|---|---|---|---|---|
Sample | Targeted/untargeted | Analysis method | CFS/ME/SEID | HC | |||||
Germain et al. | 2020 [21] | USA | Case control | Fukuda | Plasma | Untargeted | Metabolon mass spectrometry | 26 F | 26F |
Germain et al. | 2018 [22] | USA | Case control | Fukuda | Plasma | Untargeted | Metabolon mass spectrometry | 32 F | 19 F |
Nagy-Szakal et al. | 2018 [29] | USA | Case control | Fukuda CCC | Plasma | Targeted and untargeted | Gas chromatography time-of-flight and liquid chromatography–tandem mass spectrometry | 26 | 49 |
Germain et al. | 2017 [23] | USA | Case control | Fukuda | Plasma | Untargeted | Q-exactive mass spectrometry | 17 F | 15 F |
Yamano et al. | 2016 [24] | Japan | Case control | Fukuda | Plasma | Untargeted | Capillary electrophoresis mass spectrometry | 41 F 5 M | 41 F 6 M |
Fluge et al. | 2016 [25] | Norway | Case control | CCC | Serum | Targeted | Gas chromatography–tandem mass spectrometry | 162 F 38 M | 67 F 35 M |
Naviaux et al. | 2016 [30] | USA | Case control | Fukuda CCC IOM | Plasma | Targeted | Triple quadrupole mass spectrometry | 23 F 22 M | 21 F 18 M |
Armstrong et al. | 2015 [26] | Australia | Case control | CCC | Serum Urine | Untargeted | Nuclear magnetic resonance spectrometry | 34 F | 25 F |
Armstrong et al. | 2012 [18] | Australia | Case control | CCC | Serum | Untargeted | Nuclear magnetic resonance spectrometry | 6 F 5 M | 5 F 5 M |
Jones et al. | 2005 [27] | United Kingdom | Case control | Fukuda Oxford | Plasma Urine | Targeted | Reversed phase chromatography | 19 F 11 M | 19 F 11 M |
McGregor et al. | 1996 [28] | Australia | Case control | Fukuda Oxford | Urine | Untargeted | Capillary gas chromatography–mass spectrometry | 16 F 4 M | 32 F 13 M |
Participant and study characteristics
Blood metabolites—primary outcome
Author and year | Number of metabolites | Blood metabolite | ||
---|---|---|---|---|
Assessed | Significantly different in CFS/ME/SEID vs HC | Decreased in CFS/ME/SEID vs HC (p-value) | Increased in CFS/ME/SEID vs HC (p-value) | |
Germain et al. (2020) [21] | 786 | 41 | Cysteinylglycine (0.008) Hypotaurine (0.039) Indolelactate (0.006) Tryptophan betaine (0.035) Dehydroepiandrosterone sulfate (DHEA-S) (0.035) Epiandrosterone sulfate (0.035) Androstenediol (3alpha, 17alpha) monosulfate (2) (0.039) 5alpha-androstan-3beta,17alpha-diol disulfate (0.04) Androsterone sulfate (0.041) Androstenediol (3beta,17beta) disulfate (2) (0.044) Etiocholanolone glucuronide (0.049) Cortisone (0.004) Cortisol (0.02) Dihomo-linolenoyl-choline (0.019) Linoleoylcholine (0.036) Stearoylcholine (0.043) Docosahexaenoylcarnitine (C22:6) (0.025) Adrenoylcarnitine (C22:4) (0.029) Octanoylcarnitine (C8) (0.035) Decanoylcarnitine (C10) (0.049) Branched chain 14:0 dicarboxylic acid (0.049) 3-hydroxymyristate (0.013) 3-hydroxydecanoate (0.015) 3-hydroxylaurate (0.029) Cis-4-decenoate (10:1n6) (0.047) Valerate (5:0) (0.045) Phenylalanylalanine (0.007) Phenylalanylglycine (0.014) Valylleucine (0.046) Dimethyl sulfone (0.032) Piperine (0.027) Sulfate of piperine metabolite C16H19NO3 (3) (0.027) Stachydrine (0.044) | N-carbamoylalanine (0.049) 4-hydroxyglutamate (0.004) N-acetyl-1-methylhistidine (0.038) N,N,N-trimethyl-alanylproline betaine (TMAP) (0.039) Arachidoylcarnitine (0.025) Adipoylcarnitine (C6-DC) (0.042) Glycohyocholate (0.048) Gamma-glutamyltyrosine (0.045) |
Germain et al. (2018) [22] | 832 | 9 | Gamma-CEHC (0.005) Alpha-CEHC glucuronide (0.018) Gamma-CEHC glucuronide (0.019) Inosine 5′-monphosphate (0.003) 2′-O-methylcytidine (0.009) Adenosine 3′-5′-cyclicmonophosphate (0.012) | Haem (0.002) Alpha-ketoglutarate (0.03) Gamma-glutamyl-threonine (0.003) |
Nagy-Szakal et al. (2018) [29] | 562 | 2 | Carnitine-choline (0.017) Phosphatidylcholine (0.017) | None |
Germain et al. (2017) [23] | 361 | 65 | Acetylcarnosine (0.0014) ATP (0.0024) ADP (0.0034) Glycochenodeoxycholate (0.0044) C3H4O2.3 (0.0050) 2-Methylglutaconic acid (0.0097) C20H34O4.4 (0.0032) Taurine (0.0073) 13-carboxy-alpha-tocopherol (0.0027) 4-Imidazolone-5-propanoate (0.0023) Sulfoglycolithocholate (0.0058) C4H6O3.3 (0.0074) Acetamidopropanal (0.0164) l-proline (0.0164) d-glucose (0.0091) l-erythrulose (0.0093) 2,3-epoxy-alpha-tocopherylquinone,5,6-epoxy-alpha-tocopherylquinone (0.0082) l-glutonate (0.0091) d-glutonate (0.0091) C20H32O4.21 (0.0034) Glycolothocholate (0.0075) CDP-Choline (0.0141) Glycocholate (0.0110) 25-hydroxyvitamin D3-26,23-lactone (0.0075) Lithocholate (0.0182) Glyoxylate (0.0073) Choline phosphate(1-)(0.0085) Succinylcarnitine (0.0271) 5-guanidino-2-oxopentanoic acid (0.0050) Phosphoanto-oxy-phisphonate-UDP-d-galactose (0.0110) S-(2-Methylpropanoyl)-dihydrolipoamide (0.0064) Ethanolamine phosphate (0.0201) S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]-l-cysteine (0.0153) 3alpha,7alpha,12alpha,25-tetrahydroxy-5beta-cholestane-24-one/3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate (0.0136) l-kynurenine/Fromyl-5-hydroxykynurenamine (0.0201) Fructoseglycine (0.0332) Oxaloacetate (0.0396) C27H46O4.3 (0.0259) 5-hydroxyindoleacatate (0.0328) 2-Keto-3-deoxy-d-glycero-d-galacto-nonic acid (0.0430) l-isoleucine, l-Leucine (0.0482) 13-carboxy-gamma-tocopherol (0.0475) d-Glucuronate 1-phosphate (0.0195) Nicotinamide (0.0396) 3-oxo-8(R)-hydroxy-hexadeca-6E10Z-dienoate_3-oxo-8(S)-hydroxy-hexadeca-6E10Z-dienoate (0.0264) Biotin (0.0363) 3-Hydroxyisovalerylcarnitine (0.0460) UTP (0.0461) 5-amino-1-(5-phospho-d-ribosyl)imidazole-4-carboxamide (0.0357) | Cis-11-Eicosenate (0.0069) C20H30O2.4 (0.0041) Cervonic acid C22:6(n-3), docosahexaenoate (0.0042) 3-(methylthio)propionate (0.0299) (Trans-vaccenate-elaidate-oleate (0.0375) 5,6-Dihydrothymine (0.0259) Urocanate (0.0392) N2-Formyl-N1-(5-phospho-d-ribosyl)glycinamide (0.0361) 4-Hydroperoxy-2-nonenal (0.0264) Glycero-3-phosphate (0.0333) Arachidonate, Eicosatetranoic acid (0.0240) Pristanic acid, pristanate (0.0290) Deoxyuridine (0.0296) Clupanodonic acid docosa-4,7,10,13,16-pentaenoic acid (0.0341) 4-Hydroxyphenylacatate/2-Hydroxyphenylacetate/3,4-Dihydroxyphenylacetaldehyde (0.0430) Spermidine (0.0464) |
Yamano et al. (2016) [24] | 144 | 6 | Citrate (< 0.05) Isocitrate (< 0.05) Malate (< 0.05) Urea (< 0.01) Citrulline (< 0.01) | Ornithine (< 0.05) |
Fluge et al. (2016) [25] | 20 | 14 | Lys (0.001) Leu (< 0.001) Phe (< 0.001) Tyr (< 0.001) Ile (< 0.001) Trp (0.009) Ala (0.027) Val (< 0.001) Met (0.017) Asx (< 0.001) His (< 0.001) Pro (< 0.001) Glx (0.029) SDMA (0.001) | None |
Naviaux et al. (2016) [30] | 612 | 61-Females | Ceramide(d18:1/25:0) (< 0.001) THC 18:1/24:0 (< 0.001) PC(16:0/16:0) (< 0.001) Lathosterol (< 0.001) PI(16:0/16:0) (< 0.001) Ceramide(d18:1/22:2) (< 0.001) Adenosine (< 0.001) Ceramide(d18:1/24:2) (< 0.001) THC 18:1/16:0 (< 0.001) 2-Octenoylcarnitine (< 0.001) GC(18:1/16:0) (< 0.001) Phenyllactic acid (< 0.001) Ceramide(d18:1/26:0) (< 0.001) Ceramide(d18:1/24:0) (< 0.001) DHC(18:1/16:0) (< 0.001) Ceramide(d18:1/26:2) (< 0.001) FAD (< 0.001) Ceramide(d18:1/16:0) (< 0.001) SM(d18:1/22:2) (< 0.001) Adenosine monophosphate (< 0.001) PI(38:3) (< 0.001) Chenodeoxycholic acid (0.007) Ceramide(d18:1/20:0) (0.007) Ceramide(d18:1/22:1 OH) (0.009) Ceramide(d18:1/18:2 OH) (0.009) Ceramide(d18:1/22:0) (0.010) Ceramide(d18:1/18:0) (0.010) Ceramide(d18:1/16:1 OH) (0.010) Ceramide(d18:1/24:2 OH) (0.012) SM(d18:1/16:0) (0.012) Ceramide(d18:1/24:1) (0.013) PI(34:1) (0.014) PI(36:0) (0.016) SM(d18:1/20:1) (0.016) 2-Arachidonylglycerol (0.018) THC 18:1/18:0 (0.018) Ceramide(d18:1/22:1) (0.019) PI(34:0) (0.020) Ceramide(d18:1/26:1 OH) (0.020) PI(38:4) (0.021) Hydroxyisocaproic acid (0.022) PC(30:0) (0.025) Cobalamin (0.026) Ceramide(d18:1/20:1 OH) (0.026) dAMP (0.027) PG(32:2) (0.032) PC(16:0/18:2) (0.033) PI(36:1) (0.034) | Hydroxyproline (< 0.001) 1-Pyrroline-5-carboxylic acid (< 0.001) PC(18:1/22:5) (< 0.001) PC(22:6/P-18:0) (< 0.001) PC(36:0) (0.006) PC(18:1/22:6) (0.008) Adipoylcarnitine (0.017) PC(16:0/22:6) (0.025) Arginine (0.030) PC(38:5) (0.031) Gluconic acid (0.032) Vitamin K2 (0.033) Glucosamine 6-phosphate (0.034) |
612 | 61-Males | PC(16:0/16:0) (< 0.001) GC(18:1/16:0) (< 0.001) Ceramide(d18:1/16:0) (< 0.001) THC 18:1/24:0 (< 0.001) Ceramide(d18:1/24:2) (< 0.001) PI(38:4) (< 0.001) DHC(18:1/16:0) (< 0.001) PA(16:0/16:0) (< 0.001) SM(d18:1/22:1 OH) (< 0.001) SM(d18:1/24:2 OH) (< 0.001) Ceramide(d18:1/16:1 OH) (< 0.001) SM(d18:1/22:0) (< 0.001) Ethanolamine (< 0.001) FAD (< 0.001) 4-Hydroxyphenyllactic (< 0.001) Ceramide(d18:1/16:1) (< 0.001) Ceramide(d18:1/18:0) (< 0.001) SM(d18:1/16:0) (< 0.001) SM(d18:1/18:2 OH) (< 0.001) Ceramide(d18:1/24:1) (< 0.001) Ceramide(d18:1/26:2) (< 0.001) Ceramide(d18:1/25:0) (0.005) Ceramide(d18:1/22:2) (0.005) Ceramide(d18:1/22:1) (0.005) Behenic acid (0.008) Hydroxyisocaproic acid (0.010) Uric acid (0.010) Pyroglutamic acid (0.012) SM(d18:1/24:0) (0.012) Lathosterol (0.011) PC(16:0/20:4) (0.011) SM(d18:1/22:1) (0.013) Ceramide(d18:1/22:0) (0.014) SM(d18:1/16:0 OH) (0.015) Ceramide(d18:1/24:0) (0.016) SM(d18:1/20:2 OH) (0.016) PC(18:1/18:1) (0.017) Ceramide(d18:1/16:2 OH) (0.018) PI(38:3) (0.021) 2-Methylcitric acid (0.021) SM(d18:1/22:0 OH) (0.022) 24,25-Epoxycholesterol (0.022) Cholesterol (0.023) SM(d18:1/18:0) (0.024) Ceramide(d18:1/24:0 OH) (0.026) SM(d18:1/22:2) (0.026) 2-Hydroxy-3-methylbutyrate (0.027) Ceramide(d18:1/16:0 OH) (0.028) Deoxyguanosine (0.028) Tiglylcarnitine (0.033) SM(d18:1/16:1 OH) (0.032) Ceramide(d18:1/18:1 OH) (0.031) SM(d18:1/25:0) (0.032) | 1-Pyrroline-5-carboxylic acid (< 0.001) l-Serine (< 0.001) Arginine (< 0.001) Methionine sulfoxide (< 0.001) PC(18:1/22:6) (0.012) PC(20:5/P-16:0) (0.019) l-Threonine (0.021) Gamma-Aminobutyric acid (0.028) | |
Armstrong et al. (2015) [26] | 29 | 6 | Acetate (0.040) Glutamate (0.029) Hypoxanthine (0.001) Lactate (0.006) Phenylalaine (0.001) | Glucose (0.011) |
Armstrong et al. (2012) [18] | 22 | 2 | Glutamine (0.002) Ornithine (0.045) | None |
Jones et al. (2005) [27] | 26 | 4 | Taurine (< 0.001) Histidine (< 0.001) Tyrosine (< 0.01) Alpha-amino-n-butyric acid (< 0.05) | None |
Author and year | Major biochemical pathways |
---|---|
Germain et al. (2020) [21] | Energy metabolism Amino acid metabolism Lipids Fatty acid metabolism Androgenic steroids Corticosteroids Secondary bile acid metabolism Xenobiotics Chemical Food component/plant |
Germain et al. (2018) [22] | Energy metabolism Tricarboxylic acid cycle Amino acid metabolism Nucleotides Pyrimidine metabolism Purine metabolism Peptides Protein degradation Cofactors and vitamins Haeme Vitamin E pathway |
Nagy-Szakal et al. (2018) [29] | Energy metabolism Transport of activated residues between cellular organelles Lipid metabolism Cell membrane phospholipid |
Germain et al. (2017) [23] | Energy metabolism ATP and ADP perturbations Amino acid metabolism Pentose phosphate pathway Ascorbate and aldarate metabolism Glycolysis pathway Gluconeogenesis pathway Citrate cycle Starch and sucrose metabolism Galactose metabolism Pyruvate metabolism Nucleotides Purine metabolism Lipids metabolism Biological membrane composition |
Yamano et al. (2016) [24] | Energy metabolism Tricarboxylic acid cycle Urea cycle |
Fluge et al. (2016) [25] | Energy metabolism Amino acid metabolism |
Naviaux et al. (2016) [30] | Energy metabolism Redox regulation NADPH availability |
Armstrong et al. (2015) [26] | Energy metabolism Glycolysis pathway amino acid metabolism |
Armstrong et al. (2012) [18] | Energy metabolism Amino acid metabolism (urea pathway) Nitrogen metabolism (urea pathway) |
Jones et al. (2005) [27] | Energy metabolism Amino acid metabolism |
Urine metabolites—secondary outcome
Author | Number of metabolites | Urinary metabolite | ||
---|---|---|---|---|
Assessed | Significantly different in CFS/ME/SEID vs HC | Decreased in CFS/ME/SEID vs HC (p-value) | Increased in CFS/ME/SEID vs HC (p-value) | |
Armstrong et al. [26] | 30 | 5 | Acetate (0.003) Alanine (0.049) Formate (0.002) Pyruvate (0.034) Serine (0.034) | None |
Jones et al. [27] | 26 | 6 | Beta-alanine (< 0.05) Hydroxyproline (< 0.001) Histidine (< 0.05) Methionine (< 0.01) Cystine (< 0.01) Phenylalanine (< 0.01) | None |
McGregor et al. [28] | 28 | 8 | CFSUM2 (< 0.001) Alanine (< 0.005) Glutamic acid (< 0.02) | Aminohydroxy-N-methylpyrrolidine (< 0.001) Tyrosine (0.02) Beta-Alanine (< 0.02) Succinic acid (< 0.05) Aconitic acid (< 0.05) |