Table 1.

Human skin metabolites: their primary source and functions

Substances	Functions
Metal and non-metal ions from SC and sweat
Sodium, chloride and potassium, calcium, copper, magnesium, zinc, iron, chromium, nickel, lead, manganese, arsenic, mercury, cobalt, molybdenum, strontium, titanium, aluminum, cadmium, lead, nitrogen, iodine, bicarbonate, and phosphorus (Consolazio et al. 1962, 1966; Sears et al. 2012; Minshall et al. 2014; Cohn and Emmett 1978)	Formation of the high-salt environment (Chen et al. 2018) pH of sweat (Sato 1977; Sato and Sato 1990) Regulation of electrolyte homeostasis (Müller et al. 2019) Microbial growth factors (Constante et al. 2017) NMF: potassium, sodium, magnesium, and calcium (Jokura et al. 1995)
Amino acid and its derivatives from SC and sweat glands
l-histidine, threonine, glycine, l-arginine, l-methionine, l-lysine, l-isoleucine, l-leucine, l-valine, l-phenylalanine, tryptophan, l-alanine, l-tyrosine, l-serine, N-acetyl-dl-serine, urocanic acid, uric acid, l-prolinamide, pyroglutamic acid, l-proline, l-carnitine, creatine, l-asparagine, l-glutamine, citrulline, l-glutamate, l-aspartic acid, l-pipecolic acid, ornithine, l-prolinamide, betaine, and taurine (Harshman et al. 2018; Craig et al. 2010)	NMF: l‐serine, Glycine, l‐alanine, histidine, ornithine, citrulline, arginine, and urocanic acid (Caspers et al. 2001; Burke et al. 1966) Skin barrier integrity and appearance (Solano 2020) Acid–base balance and water retention in SC: urocanic acid, serine, and taurine (Solano 2020; Kim et al. 2012, 2021b) Promote wound healing and restore impaired skin: serine, and arginine (Solano 2020; Badiu et al. 2010) UV protection: urocanic acid, phenylalanine, tyrosine, tryptophan, and taurine (Barresi et al. 2011; Wondrak et al. 2006; Kim et al. 2021b) Antioxidant: methionine, tryptophan (Solano 2020; Sardana and Garg 2010) Defense against pathogens: urocanic acid (Solano 2020) Inflammatory and allergic responses: taurine (Solano 2020; Kim et al. 2021b) Collagen synthesis: isoleucine, leucine, and valine (Yamane et al. 2018) Prevention of acne and cold sore: lysine (Solano 2020)
Peptides, proteins and their derivatives
Proteins from SC, viable epidermis and sweat gland
Urea (Caspers et al. 2001); loricrin (Nithya et al. 2015); keratins (Jokura et al. 1995); filaggrin (Arezki et al. 2017); prolactin-inducible protein, clusterin, apolipoprotein D, PIP (Csősz et al. 2015; Myal et al. 1991); serum albumin, cytokeratin I, Zn-α2-glycoprotein, cystatin A; lipophilin B, CatD (Baechle et al. 2006); protease: several members of the major skin desquamatory family of KLKs (such as KLK1, KLK6-11, KLK13) and cathepsins B, D, Z, F, S, L2, β-chain, MMP8 (Baechle et al. 2006; Yu et al. 2017; Baker 2019)	NMF: filaggrin, urea (Caspers et al. 2001; Arezki et al. 2017) Protect skin from various stresses: keratins, filaggrin, urea, loricrin, apolipoprotein D, and serum albumin (Solano 2020; Nithya et al. 2015; Fluhr et al. 2008; Bajo-Grañeras et al. 2011; Tözsér and Berta 1998) Skin maintenance and protection via desquamation of horny layer, hydrolysis of debris in the ductal lumen, allergen inhibition: proteolytic enzymes (Yokozeki et al. 1991) Tissue regeneration: apolipoprotein D (Bajo-Grañeras et al. 2011) Transport, binding, antioxidant and catalytic activity role: serum albumin, protease (Yu et al. 2017; Gum et al. 2004) Immunological functions: Prolactin-inducible protein bind to IgG, IgG-Fc, CD4-T cell receptor (Autiero et al. 1991; Lee et al. 2002) and also to different species of bacteria such as streptococci (Nistor et al. 2009; Hassan et al. 2009) Chaperone, modulator of MMP9 activity: clusterin (Schenkels et al. 1997; Jeong et al. 2012)
Neuropeptides from sweat gland
SP, CGRP (N'Diaye et al. 2017)	Sense microbes and critical for skin homeostasis (N'Diaye et al. 2017) Modulator of skin microbiome virulence (N'Diaye et al. 2017) Anti-inflammation (Choi et al. 2018): low concentrations of SP
Antimicrobial peptides (AMPs) from sweat, sebocytes and keratinocytes (KCs)
RNAse7, S100 proteins (S100A7, S100A8, S100A9, S100A12 and S100A15), hBD-1-3, cathelicidins (Büchau and Gallo 2007); active form of cathelicidin (NL-8, LR-10, KR-10, IK-14, LL-17, LL-23, KR-20, KS-27, KS-30, and LL-37) (Yamasaki et al. 2006; Murakami et al. 2002); DCD (Lousada et al. 2021; Reithmayer et al. 2009); DCD-1L and DCD-1L derived peptides (Schittek et al. 2001); cathelicidin hCAP-18 (Sørensen et al. 2001; Baechle et al. 2006); histone H4 (Lee et al. 2009); LF (Park et al. 2011); sIgA (Imayama et al. 1994); Lcn2 (Takahashi and Yamasaki 2020)	Participation in epithelial innate defense and defense against pathogens (Serag et al. 2021; Gläser et al. 2005; Nizet et al. 2001; Park et al. 2011) Enhance the antimicrobial action of FFAs in human sebum: histone H4 (Lee et al. 2009)
Cytokines/chemokines/antibodies from KCs and sweat
IL-1α, 1β, 6, 8, 25, 31, 36, TNF-α, IFN-β and CXCL10, IgG, IgA (Takahashi and Yamasaki 2020; Dai et al. 2013; Baker 2019)	Prime and amplify epidermal innate immune signals with the dermal adaptive immune system (Takahashi and Yamasaki 2020; Li et al. 2018b; Xu et al. 2018) Defense against pathogens (Baker 2019; Li et al. 2018b)
Sugar from sweat, cosmetics and extracellular matrix
Lactate (Caspers et al. 2001); glucose, fructose, mannose, and galactose (Roux et al. 2022); β-glucans (Du et al. 2014); hyaluronic acid (Lew and Liong 2013)	NMF: lactate (Caspers et al. 2001) The elevated glucose level promotes itching and delay the recovery of skin barrier (Ono et al. 2018) Anti-wrinkle, wound healing, antioxidant activity, anti-UV effect, and moisturizing effect: β-Glucans (Du et al. 2014) Epidermal barrier regulation: hyaluronic acid (Lew and Liong 2013) Enhance self-defense of the skin for infection: low molecular weight hyaluronic acid (Gariboldi et al. 2008)
Lipid and its metabolites
Sweat-derived lipids
Over 150 lipid mediators, including prostanoids, alcohols, diols, epoxides, ketones, nitrolipids, N-acylethanolamides, monoacylglycerols, and ceramides (Agrawal et al. 2018); lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), oleic acid (C18:1), and stearic acid (C18:0) (Nunome et al. 2010); lactic acid; pyrrolidone-5-carboxylic acid (Caspers et al. 2001); 5-aminopentanoic acid, and l-pipecolic acid (Harshman et al. 2018)	Extracellular stimuli response: lipid mediators (Murakami 2011) Antimicrobial, anti-inflammatory effect: lauric acid, oleic acid, and lactic acid (Drake et al. 2008; Fischer et al. 2012; Clayton et al. 2019; Lew and Liong 2013) NMF: lactic acid, pyrrolidone-5-carboxylic acid (McGrath 2008; Caspers et al. 2001)
Epidermal (SC) Lipids
Ceramides (Unique to epidermis) (Pappas 2009); FAs: saturated FFAs, monounsaturated FAs, polyunsaturated FAs (PUFAs), and hydroxyl FFAs (Ansari et al. 1970); cholesterol (Cui et al. 2016)	Barrier against the chemical, physical, and microorganism insults (Feingold 2009)
Sebaceous lipids from sebum (sebaceous glands)
TG and FAs (Greene et al. 1970); diglycerides, wax esters (Pappas 2009); squalene (Thiboutot 2004; Nicolaides 1974; Thody and Shuster 1989); cholesterol, cholesterol esters (Greene et al. 1970); sapienic acid (C16:1Δ6) (Pappas 2009; Nicolaides 1974); sebaleic acid (18:2Δ5, 8) (Picardo et al. 2009); oleic acid (18:1Δ9) (Lovászi et al. 2017)	Maintain skin surface moisture permeability: wax ester, FFAs, and squalene (Cui et al. 2016; Pappas 2009) Antimicrobial, antioxidant, anti-inflammatory effect: squalene, wax esters, FFAs, cholesterol ester, sapienic acid, and oleic acid (Nakatsuji et al. 2010; Pappas 2009; Kim and Karadeniz 2012; Cui et al. 2016) Mediate immune responses: FFAs (Cui et al. 2016) UV protection: squalene (Ohsawa et al. 1984)
Plasma lipids
Cholesterol, plant sterols, β-sitosterol, campesterol, and stigmasterol (Bhattacharyya et al. 1972); lathosterol and lanosterol (Bhattacharyya et al. 1972); itaconic acid, crotonic acid and heptadecanoic acid, xanthine, d-ribose 5-phosphate, and uric acid (Chen et al. 2021)	Participation in lipid metabolism: itaconic acid, crotonic acid, and heptadecanoic acid (Chen et al. 2021) Positive correlated with specific skin bacteria: itaconic acid, crotonic acid, and heptadecanoic acid (Chen et al. 2021) Participation in nucleotide metabolism: xanthine, d-ribose 5-phosphate, and uric acid (Chen et al. 2021)
Lipids in cosmetic products/personal care products
o-formylbenzoic acid, oleic acid, palmitic acid, and monoacylated glycerols monoolein and monopalmitin (Bouslimani et al. 2015); mineral oils and waxes (Petry et al. 2017)	Shaping the chemical environment for specific skin microbial communities (Bouslimani et al. 2019) Provide nutrients and promote the growth of lipophilic bacteria (Bouslimani et al. 2015; Unno et al. 2017; Holland et al. 2010)
Vitamins mainly from sweat
Niacin (Sargent et al. 1944); vitamin D (Cornbleet et al. 1936; Lugg and Ellis 1954; Dam 1978; van der Beek 1991); l-ascorbic acid (Vitamin C) (Harshman et al. 2018); vitamin E (Cornbleet et al. 1936; Lugg and Ellis 1954; Dam 1978; van der Beek 1991); niacinamide (Gehring 2004)	Maintenance of epidermal barrier and moisture: niacinamide (Gehring 2004) Anti-inflammatory, anti-aging effect: niacinamide, vitamin C, and vitamin E (Cornbleet et al. 1936; Lugg and Ellis 1954; Dam 1978; van der Beek 1991; Gehring 2004) UV protection: active vitamin D3, and vitamin C (Pullar et al. 2017; Bocheva et al. 2021)
Pheromones from sweat glands and sebaceous glands
Releaser/primer/signaler/modulator pheromones (Preti et al. 2003); adrenal glucocorticoids (Nichols and Miller 1948)	Body odor (Baker 2019) Generate immediate, primarily behavioral responses: releaser pheromones (Preti et al. 2003) Generate slower physiological/endocrine/neuroendocrine responses: primer pheromones (Preti et al. 2003) Mood and multisensory inputs regulation: modulator pheromones (Jacob and McClintock 2000)
Other xenobiotics from the environment, i.e. pollutants or personal care products
PAHs (Leung et al. 2020) POPs (organochlorinated pesticides, polychlorinated biphenyls, perfluorinated compounds) and other toxicants (BPA, heavy metals, phthalate, and polybrominated diphenyl ethers) (Baker 2019)  Drugs (griseofulvin, ketoconazole, beta-lactam antibiotics, ceftazidime, ceftriaxone and isotretinoin) (Hoiby et al. 2000; Sato et al. 1989a, 1989b; Tilles 2014)  Cosmetics (preservatives, moisturizers, foundation, foot powder, deodorant, topical prebiotics, and topical postbiotics) (Salminen et al. 2021; Pinto et al. 2021; Murphy et al. 2021)  Others (e.g., ethanol, pyrrolidine, piperidine, trolamine, and diolamine) (Harshman et al. 2018)	Influence the function and structure of skin microbiome: PAHs (Leung et al. 2020) Promote premature skin aging, pigmentary disorder, acne, and skin cancer: PAHs (Leung et al. 2020) Cause vitamin D deficiency: POPs (Bocheva et al. 2021) Antibiotics increased antibiotic resistance: drugs Modulation of dihydrotestosterone formation: isotretinoin (Tilles 2014) Cosmetics Influence the function and structure of skin microbiome: foundation and foot powder (Bouslimani et al. 2015, 2019; Elpa et al. 2021; Staudinger et al. 2011; Boxberger et al. 2021) Favor the growth of potential pathogens, such as S. aureus: emulsifiers (Krogsgård Nielsen et al. 2016) Provide nutrients and promote the growth of lipophilic bacteria such as Staphylococcus and Propionibacterium: moisturizers (Bouslimani et al. 2015; Unno et al. 2017; Holland et al. 2010) Preservatives exert antimicrobial effect in vitro (Pinto et al. 2021; Wang et al. 2019a; Murphy et al. 2021), such as inhibit the growth and biofilm formation of S. aureus or pathogenic C. acnes in vitro (Gannesen et al. 2019), but no influence on the skin microbiome in vivo (Murphy et al. 2021)

NMF natural moisturizing factor, PIP prolactin inducible protein, CatD cathepsin D, KLKs kallikrein-related peptidases, MMP matrix metalloproteinase, SP substance P, CGRP calcitonin gene-related peptide, DCD dermcidin, hBD human β-defensins, LF Lactoferrin, sIgA Secretory form of immunoglobulin A, S100A7 psoriasin, S100A8 calgranulin A, S100A9 calgranulin B, S100A12 calgranulin C, Lcn2 lipocalin-2, IL Interleukin, TNF-α tumor necrosis factor-α, IFN-β interferon-beta, TG triglyceride, FAs fatty acids, FFAs free fatty acids, PAHs polycyclic aromatic hydrocarbons, POPs persistent organic pollutants, BPA bisphenol-A