The Skin Microbiota and Itch: Is There a Link?

Hei Sung Kim, Gil Yosipovitch, Hei Sung Kim, Gil Yosipovitch

Abstract

Itch is an unpleasant sensation that emanates primarily from the skin. The chemical mediators that drive neuronal activity originate from a complex interaction between keratinocytes, inflammatory cells, nerve endings and the skin microbiota, relaying itch signals to the brain. Stress also exacerbates itch via the skin-brain axis. Recently, the microbiota has surfaced as a major player to regulate this axis, notably during stress settings aroused by actual or perceived homeostatic challenge. The routes of communication between the microbiota and brain are slowly being unraveled and involve neurochemicals (i.e., acetylcholine, histamine, catecholamines, corticotropin) that originate from the microbiota itself. By focusing on itch biology and by referring to the more established field of pain research, this review examines the possible means by which the skin microbiota contributes to itch.

Keywords: itch; microbiota–skin–brain axis; skin microbiota; stress.

Conflict of interest statement

Yosipovitch reports serving on the scientific board and being a consultant for Trevi, Sanofi Regeneron, Galderma, Pfizer, Novartis, Kiniksa, Eli Lilly, Bellus, LEO and is supported by Sun Pharma, Pfizer, Novartis, Kiniksa, Leo Pierre Fabre. None of these involvements had influence on the content of the presented paper.

Figures

Figure 1
Figure 1
Inflammatory circuit of the skin microbiota. Various microbiota (bacteria, fungi and viruses) cover the exterior of a healthy skin where the barrier is intact. In the event of dysbiosis, pathogens release proteases, which may disrupt the epidermal barrier. Delta-toxin causes mast cell degranulation, which prompt inflammation and itching. AMP: antimicrobial peptides; DRG: dorsal root ganglia; IL: interleukin; LTB4: leukotriene B4; PAMP: pathogen associated molecular pattern; PGE2: prostaglandin E2; TLR: Toll-like receptor; TRPA1: transient receptor potential antigen 1; TSLP: thymic stromal lymphopoietin.
Figure 2
Figure 2
Pruriceptor neurons recognize skin pathogens and their molecular ligands by various mechanisms to facilitate itch. LPS, a key cell wall component of Gram-negative bacteria attaches to neuronal TLR4 and primes TRPV1 ion channel or opens the TRPA1 ion channel. S. aureus triggers itch with bacterial N-formyl peptides that bind to FPR1 or via α-hemolysin, which couples with ADAM10. C. albicans stimulates pruriceptors with its cell wall component zymosan. Viral double-strand RNA and single-strand RNA bind to TLR3 and TLR7, respectively, which are believed to sensitize the TRPA1 ion channel. ADAM10: a disintegrin and metalloproteinase domain-containing protein 10; FPR1: formyl peptide receptor 1; LPS: lipopolysaccharide; RNA: ribonucleic acid; TLR: Toll-like receptor; TRPA1: transient receptor potential ankyrin 1; TRPV1: transient receptor potential vanilloid 1.
Figure 3
Figure 3
Brain to microbiota communication under chronic stress. The HPA axis is activated under chronic stress. The final product of the HPA axis, cortisol, directly activates skin microbes. Cortisol activates the amygdala, promoting central sensitization to itch. The amygdala also promotes CRH signaling to the brain stem (PAG), altering the “descending itch modulatory system”. Prolonged exposure to cortisol, NE, and ACTH is associated with increased growth and biofilm genesis and augmented virulence of the skin microbiota. Ach: acetylcholine; ACTH: adrenocorticotropic hormone; CRH: corticotropin-releasing-hormone; HPA: hypothalamic–pituitary–adrenal axis; 5-HT: serotonin; NE: norepinephrine; PNS: parasympathetic nervous system; RVM: rostral ventromedial medulla; SNS: sympathetic nervous system; VLPAG: ventrolateral periaqueductal grey matter
Figure 4
Figure 4
Two main approaches of controlling the human skin microbiota for the itch control. Topical pre- and probiotics target to increase the number of advantageous bacteria (green) and reduce pathogens (red). Skin microbial transplant is a new approach that transfers beneficial microbiota from healthy skin to itchy and dysbiotic skin [167].

References

    1. Sender R., Fuchs S., Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337–340. doi: 10.1016/j.cell.2016.01.013.
    1. Bianconi E., Piovesan A., Facchin F., Beraudi A., Casadei R., Frabetti F., Vitale L., Pelleri M.C., Tassani S., Piva F., et al. An estimation of the number of cells in the human body. Ann. Hum. Biol. 2013;40:463–471. doi: 10.3109/03014460.2013.807878.
    1. Yang N.J., Chiu I.M. Bacterial signaling to the nervous system through toxins and metabolites. J. Mol. Biol. 2017;429:587–605. doi: 10.1016/j.jmb.2016.12.023.
    1. Chen Y.E., Fischbach M.A., Belkaid Y. Skin microbiota-host interactions. Nature. 2018;553:427–436. doi: 10.1038/nature25177.
    1. Gallo R.L. Human skin is the largest epithelial surface for interaction with microbes. J. Investig. Dermatol. 2017;137:1213–1214. doi: 10.1016/j.jid.2016.11.045.
    1. Fyhrquist N., Salava A., Auvinen P., Lauerma A. Skin biomes. Curr. Allergy Asthma Rep. 2016;16:40. doi: 10.1007/s11882-016-0618-5.
    1. Sender R., Fuchs S., Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533. doi: 10.1371/journal.pbio.1002533.
    1. Leyden J.J., McGinley K.J., Nordstrom K.M., Webster G.F. Skin microflora. J. Investig. Dermatol. 1987;88:65s–72s. doi: 10.1111/1523-1747.ep12468965.
    1. Wang W.M., Jin H.Z. Skin microbiome: An actor in the pathogenesis of psoriasis. Chin. Med. J. (Engl.) 2018;131:95–98. doi: 10.4103/0366-6999.221269.
    1. Trivedi B. Microbiome: The surface brigade. Nature. 2012;492:S60–S61. doi: 10.1038/492S60a.
    1. Gontcharova V., Youn E., Sun Y., Wolcott R.D., Dowd S.E. A comparison of bacterial composition in diabetic ulcers and contralateral intact skin. Open Microbiol. J. 2010;4:8–19. doi: 10.2174/1874285801004010008.
    1. Johnson T.R., Gomez B.I., McIntyre M.K., Dubick M.A., Christy R.J., Nicholson S.E., Burmeister D.M. The cutaneous microbiome and wounds: New molecular targets to promote wound healing. Int. J. Mol. Sci. 2018;19:2699. doi: 10.3390/ijms19092699.
    1. Chiu I.M. Infection, pain, and itch. Neurosci. Bull. 2018;34:109–119. doi: 10.1007/s12264-017-0098-1.
    1. Kong H.H., Oh J., Deming C., Conlan S., Grice E.A., Beatson M.A., Nomicos E., Polley E.C., Komarow H.D., Murray P.R., et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012;22:850–859. doi: 10.1101/gr.131029.111.
    1. Blicharz L., Usarek P., Mlynarczyk G., Skowronski K., Rudnicka L., Samochocki Z. Is itch intensity in atopic dermatitis associated with skin colonization by Staphylococcus aureus? Indian J. Dermatol. 2020;65:17–21. doi: 10.4103/ijd.IJD_136_19.
    1. Allen H.B., Vaze N.D., Choi C., Hailu T., Tulbert B.H., Cusack C.A., Joshi S.G. The presence and impact of biofilm-producing staphylococci in atopic dermatitis. JAMA Dermatol. 2014;150:260–265. doi: 10.1001/jamadermatol.2013.8627.
    1. Azimi E., Xia J., Lerner E.A. Peripheral mechanisms of itch. Curr. Probl. Dermatol. 2016;50:18–23. doi: 10.1159/000446012.
    1. Baldwin H.E., Bhatia N.D., Friedman A., Eng R.M., Seite S. The role of cutaneous microbiota harmony in maintaining a functional skin barrier. J. Drugs Dermatol. 2017;16:12–18. doi: 10.25251/skin.1.supp.138.
    1. Sanford J.A., Gallo R.L. Functions of the skin microbiota in health and disease. Semin. Immunol. 2013;25:370–377. doi: 10.1016/j.smim.2013.09.005.
    1. Nakatsuji T., Chiang H.I., Jiang S.B., Nagarajan H., Zengler K., Gallo R.L. The microbiome extends to subepidermal compartments of normal skin. Nat. Commun. 2013;4:1431. doi: 10.1038/ncomms2441.
    1. Proksch E. pH in nature, humans and skin. J. Dermatol. 2018;45:1044–1052. doi: 10.1111/1346-8138.14489.
    1. Boer M., Duchnik E., Maleszka R., Marchlewicz M. Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function. Postepy Dermatol. Alergol. 2016;33:1–5. doi: 10.5114/pdia.2015.48037.
    1. Niyonsaba F., Someya A., Hirata M., Ogawa H., Nagaoka I. Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells. Eur. J. Immunol. 2001;31:1066–1075. doi: 10.1002/1521-4141(200104)31:4<1066::AID-IMMU1066>;2-#.
    1. Capone K.A., Dowd S.E., Stamatas G.N., Nikolovski J. Diversity of the human skin microbiome early in life. J. Investig. Dermatol. 2011;131:2026–2032. doi: 10.1038/jid.2011.168.
    1. Otto M. Staphylococcus epidermidis—The ‘accidental’ pathogen. Nat. Rev. Microbiol. 2009;7:555–567. doi: 10.1038/nrmicro2182.
    1. Mah T.F., O’Toole G.A. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9:34–39. doi: 10.1016/S0966-842X(00)01913-2.
    1. Iwase T., Uehara Y., Shinji H., Tajima A., Seo H., Takada K., Agata T., Mizunoe Y. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature. 2010;465:346–349. doi: 10.1038/nature09074.
    1. Shu M., Wang Y., Yu J., Kuo S., Coda A., Jiang Y., Gallo R.L., Huang C.M. Fermentation of Propionibacterium acnes, a commensal bacterium in the human skin microbiome, as skin probiotics against methicillin-resistant Staphylococcus aureus. PLoS ONE. 2013;8:e55380. doi: 10.1371/journal.pone.0055380.
    1. Grice E.A., Segre J.A. The skin microbiome. Nat. Rev. Microbiol. 2011;9:244–253. doi: 10.1038/nrmicro2537.
    1. Korting H.C., Hubner K., Greiner K., Hamm G., Braun-Falco O. Differences in the skin surface pH and bacterial microflora due to the long-term application of synthetic detergent preparations of pH 5.5 and pH 7.0. Results of a crossover trial in healthy volunteers. Acta Derm. Venereol. 1990;70:429–431.
    1. Ali S.M., Yosipovitch G. Skin pH: From basic science to basic skin care. Acta Derm. Venereol. 2013;93:261–267. doi: 10.2340/00015555-1531.
    1. Van Smeden J., Bouwstra J.A. Stratum corneum lipids: Their role for the skin barrier function in healthy subjects and atopic dermatitis patients. Curr. Probl. Dermatol. 2016;49:8–26. doi: 10.1159/000441540.
    1. Baker B.S. The role of microorganisms in atopic dermatitis. Clin. Exp. Immunol. 2006;144:1–9. doi: 10.1111/j.1365-2249.2005.02980.x.
    1. Ohnishi Y., Okino N., Ito M., Imayama S. Ceramidase activity in bacterial skin flora as a possible cause of ceramide deficiency in atopic dermatitis. Clin. Diagn. Lab. Immunol. 1999;6:101–104. doi: 10.1128/CDLI.6.1.101-104.1999.
    1. Kim J.E., Kim H.S. Microbiome of the skin and gut in atopic dermatitis (AD): Understanding the pathophysiology and finding novel management strategies. J. Clin. Med. 2019;8:444. doi: 10.3390/jcm8040444.
    1. Swe P.M., Zakrzewski M., Kelly A., Krause L., Fischer K. Scabies mites alter the skin microbiome and promote growth of opportunistic pathogens in a porcine model. PLoS Negl. Trop. Dis. 2014;8:e2897. doi: 10.1371/journal.pntd.0002897.
    1. Xu J., Saunders C.W., Hu P., Grant R.A., Boekhout T., Kuramae E.E., Kronstad J.W., Deangelis Y.M., Reeder N.L., Johnstone K.R., et al. Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens. Proc. Natl. Acad. Sci. USA. 2007;104:18730–18735. doi: 10.1073/pnas.0706756104.
    1. Mack M.R., Kim B.S. The itch-scratch cycle: A neuroimmune perspective. Trends Immunol. 2018;39:980–991. doi: 10.1016/j.it.2018.10.001.
    1. Potenzieri C., Undem B.J. Basic mechanisms of itch. Clin. Exp. Allergy. 2012;42:8–19. doi: 10.1111/j.1365-2222.2011.03791.x.
    1. Borgono C.A., Michael I.P., Komatsu N., Jayakumar A., Kapadia R., Clayman G.L., Sotiropoulou G., Diamandis E.P. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J. Biol. Chem. 2007;282:3640–3652. doi: 10.1074/jbc.M607567200.
    1. Yosipovitch G., Misery L., Proksch E., Metz M., Stander S., Schmelz M. Skin barrier damage and itch: Review of mechanisms, topical management and future directions. Acta Derm. Venereol. 2019;99:1201–1209. doi: 10.2340/00015555-3296.
    1. Komatsu N., Saijoh K., Kuk C., Liu A.C., Khan S., Shirasaki F., Takehara K., Diamandis E.P. Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. Exp. Dermatol. 2007;16:513–519. doi: 10.1111/j.1600-0625.2007.00562.x.
    1. Steinhoff M., Neisius U., Ikoma A., Fartasch M., Heyer G., Skov P.S., Luger T.A., Schmelz M. Proteinase-activated receptor-2 mediates itch: A novel pathway for pruritus in human skin. J. Neurosci. 2003;23:6176–6180. doi: 10.1523/JNEUROSCI.23-15-06176.2003.
    1. Stefansson K., Brattsand M., Roosterman D., Kempkes C., Bocheva G., Steinhoff M., Egelrud T. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Investig. Dermatol. 2008;128:18–25. doi: 10.1038/sj.jid.5700965.
    1. Sanders K.M., Nattkemper L.A., Rosen J.D., Andersen H.H., Hsiang J., Romanelli P., Bernigaud C., Guillot J., Chosidow O., Yosipovitch G. Non-histaminergic itch mediators elevated in the skin of a porcine model of scabies and of human scabies patients. J. Investig. Dermatol. 2019;139:971–973. doi: 10.1016/j.jid.2018.09.032.
    1. Niyonsaba F., Ushio H., Hara M., Yokoi H., Tominaga M., Takamori K., Kajiwara N., Saito H., Nagaoka I., Ogawa H., et al. Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J. Immunol. 2010;184:3526–3534. doi: 10.4049/jimmunol.0900712.
    1. Cevikbas F., Wang X., Akiyama T., Kempkes C., Savinko T., Antal A., Kukova G., Buhl T., Ikoma A., Buddenkotte J., et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 2014;133:448–460. doi: 10.1016/j.jaci.2013.10.048.
    1. Naik S., Bouladoux N., Wilhelm C., Molloy M.J., Salcedo R., Kastenmuller W., Deming C., Quinones M., Koo L., Conlan S., et al. Compartmentalized control of skin immunity by resident commensals. Science. 2012;337:1115–1119. doi: 10.1126/science.1225152.
    1. Chehoud C., Rafail S., Tyldsley A.S., Seykora J.T., Lambris J.D., Grice E.A. Complement modulates the cutaneous microbiome and inflammatory milieu. Proc. Natl. Acad. Sci. USA. 2013;110:15061–15066. doi: 10.1073/pnas.1307855110.
    1. Lai Y., Cogen A.L., Radek K.A., Park H.J., Macleod D.T., Leichtle A., Ryan A.F., Di Nardo A., Gallo R.L. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J. Investig. Dermatol. 2010;130:2211–2221. doi: 10.1038/jid.2010.123.
    1. Stacy A., Belkaid Y. Microbial guardians of skin health. Science. 2019;363:227–228. doi: 10.1126/science.aat4326.
    1. Lai Y., Di Nardo A., Nakatsuji T., Leichtle A., Yang Y., Cogen A.L., Wu Z.R., Hooper L.V., Schmidt R.R., Von Aulock S., et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat. Med. 2009;15:1377–1382. doi: 10.1038/nm.2062.
    1. Menzies B.E., Kenoyer A. Signal transduction and nuclear responses in Staphylococcus aureus-induced expression of human beta-defensin 3 in skin keratinocytes. Infect. Immun. 2006;74:6847–6854. doi: 10.1128/IAI.00389-06.
    1. Hashimoto M., Tawaratsumida K., Kariya H., Aoyama K., Tamura T., Suda Y. Lipoprotein is a predominant Toll-like receptor 2 ligand in Staphylococcus aureus cell wall components. Int. Immunol. 2006;18:355–362. doi: 10.1093/intimm/dxh374.
    1. Bubeck Wardenburg J., Williams W.A., Missiakas D. Host defenses against Staphylococcus aureus infection require recognition of bacterial lipoproteins. Proc. Natl. Acad. Sci. USA. 2006;103:13831–13836. doi: 10.1073/pnas.0603072103.
    1. Kim J., Ochoa M.T., Krutzik S.R., Takeuchi O., Uematsu S., Legaspi A.J., Brightbill H.D., Holland D., Cunliffe W.J., Akira S., et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J. Immunol. 2002;169:1535–1541. doi: 10.4049/jimmunol.169.3.1535.
    1. Linehan J.L., Harrison O.J., Han S.J., Byrd A.L., Vujkovic-Cvijin I., Villarino A.V., Sen S.K., Shaik J., Smelkinson M., Tamoutounour S., et al. Non-classical immunity controls microbiota impact on skin immunity and tissue repair. Cell. 2018;172:784–796.e18. doi: 10.1016/j.cell.2017.12.033.
    1. Nakamura Y., Oscherwitz J., Cease K.B., Chan S.M., Munoz-Planillo R., Hasegawa M., Villaruz A.E., Cheung G.Y., McGavin M.J., Travers J.B., et al. Staphylococcus delta-toxin induces allergic skin disease by activating mast cells. Nature. 2013;503:397–401. doi: 10.1038/nature12655.
    1. Williams M.R., Nakatsuji T., Gallo R.L. Staphylococcus aureus: Master manipulator of the skin. Cell Host Microbe. 2017;22:579–581. doi: 10.1016/j.chom.2017.10.015.
    1. Tebruegge M., Kuruvilla M., Margarson I. Does the use of calamine or antihistamine provide symptomatic relief from pruritus in children with varicella zoster infection? Arch. Dis. Child. 2006;91:1035–1036. doi: 10.1136/adc.2006.105114.
    1. McKenzie R.C., Sauder D.N. Keratinocyte cytokines and growth factors. Functions in skin immunity and homeostasis. Dermatol. Clin. 1990;8:649–661. doi: 10.1016/S0733-8635(18)30452-2.
    1. Kollisch G., Kalali B.N., Voelcker V., Wallich R., Behrendt H., Ring J., Bauer S., Jakob T., Mempel M., Ollert M. Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology. 2005;114:531–541. doi: 10.1111/j.1365-2567.2005.02122.x.
    1. Lebre M.C., Van der Aar A.M., Van Baarsen L., Van Capel T.M., Schuitemaker J.H., Kapsenberg M.L., De Jong E.C. Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J. Investig. Dermatol. 2007;127:331–341. doi: 10.1038/sj.jid.5700530.
    1. Olaru F., Jensen L.E. Chemokine expression by human keratinocyte cell lines after activation of Toll-like receptors. Exp. Dermatol. 2010;19:e314–e316. doi: 10.1111/j.1600-0625.2009.01026.x.
    1. Dainichi T., Kitoh A., Otsuka A., Nakajima S., Nomura T., Kaplan D.H., Kabashima K. The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis. Nat. Immunol. 2018;19:1286–1298. doi: 10.1038/s41590-018-0256-2.
    1. Hofmann A.M., Abraham S.N. New roles for mast cells in modulating allergic reactions and immunity against pathogens. Curr. Opin. Immunol. 2009;21:679–686. doi: 10.1016/j.coi.2009.09.007.
    1. Igawa S., Di Nardo A. Skin microbiome and mast cells. Transl. Res. 2017;184:68–76. doi: 10.1016/j.trsl.2017.03.003.
    1. Leon A., Rosen J.D., Hashimoto T., Fostini A.C., Paus R., Yosipovitch G. Itching for an answer: A review of potential mechanisms of scalp itch in psoriasis. Exp. Dermatol. 2019;28:1397–1404. doi: 10.1111/exd.13947.
    1. Trier A.M., Mack M.R., Kim B.S. The neuroimmune axis in skin sensation, inflammation, and immunity. J. Immunol. 2019;202:2829–2835. doi: 10.4049/jimmunol.1801473.
    1. Walsh C.M., Hill R.Z., Schwendinger-Schreck J., Deguine J., Brock E.C., Kucirek N., Rifi Z., Wei J., Gronert K., Brem R.B., et al. Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis. Elife. 2019;8 doi: 10.7554/eLife.48448.
    1. Hashimoto T., Rosen J.D., Sanders K.M., Yosipovitch G. Possible role of neutrophils in itch. Itch. 2018;3:e17. doi: 10.1097/itx.0000000000000017.
    1. Luo J., Feng J., Liu S., Walters E.T., Hu H. Molecular and cellular mechanisms that initiate pain and itch. Cell. Mol. Life Sci. 2015;72:3201–3223. doi: 10.1007/s00018-015-1904-4.
    1. Hashimoto T., Satoh T., Yokozeki H. Pruritus in ordinary scabies: IL-31 from macrophages induced by overexpression of thymic stromal lymphopoietin and periostin. Allergy. 2019;74:1727–1737. doi: 10.1111/all.13870.
    1. Hashimoto T., Kursewicz C.D., Fayne R.A., Nanda S., Shah S.M., Nattkemper L., Yokozeki H., Yosipovitch G. Mechanisms of itch in stasis dermatitis: Significant role of IL-31 from macrophages. J. Investig. Dermatol. 2020;140:850–859. doi: 10.1016/j.jid.2019.09.012.
    1. Sonkoly E., Muller A., Lauerma A.I., Pivarcsi A., Soto H., Kemeny L., Alenius H., Dieu-Nosjean M.C., Meller S., Rieker J., et al. IL-31: A new link between T cells and pruritus in atopic skin inflammation. J. Allergy Clin. Immunol. 2006;117:411–417. doi: 10.1016/j.jaci.2005.10.033.
    1. Baral P., Mills K., Pinho-Ribeiro F.A., Chiu I.M. Pain and itch: Beneficial or harmful to antimicrobial defense? Cell Host Microbe. 2016;19:755–759. doi: 10.1016/j.chom.2016.05.010.
    1. Liu T., Gao Y.J., Ji R.R. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci. Bull. 2012;28:131–144. doi: 10.1007/s12264-012-1219-5.
    1. Liu T., Xu Z.Z., Park C.K., Berta T., Ji R.R. Toll-like receptor 7 mediates pruritus. Nat. Neurosci. 2010;13:1460–1462. doi: 10.1038/nn.2683.
    1. Liu T., Berta T., Xu Z.Z., Park C.K., Zhang L., Lu N., Liu Q., Liu Y., Gao Y.J., Liu Y.C., et al. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J. Clin. Investig. 2012;122:2195–2207. doi: 10.1172/jci45414.
    1. Diogenes A., Ferraz C.C., Akopian A.N., Henry M.A., Hargreaves K.M. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J. Dent. Res. 2011;90:759–764. doi: 10.1177/0022034511400225.
    1. Calil I.L., Zarpelon A.C., Guerrero A.T., Alves-Filho J.C., Ferreira S.H., Cunha F.Q., Cunha T.M., Verri W.A., Jr. Lipopolysaccharide induces inflammatory hyperalgesia triggering a TLR4/MyD88-dependent cytokine cascade in the mice paw. PLoS ONE. 2014;9:e90013. doi: 10.1371/journal.pone.0090013.
    1. Min H., Lee H., Lim H., Jang Y.H., Chung S.J., Lee C.J., Lee S.J. TLR4 enhances histamine-mediated pruritus by potentiating TRPV1 activity. Mol. Brain. 2014;7:59. doi: 10.1186/s13041-014-0059-9.
    1. Meseguer V., Alpizar Y.A., Luis E., Tajada S., Denlinger B., Fajardo O., Manenschijn J.A., Fernandez-Pena C., Talavera A., Kichko T., et al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat. Commun. 2014;5:3125. doi: 10.1038/ncomms4125.
    1. Startek J.B., Talavera K., Voets T., Alpizar Y.A. Differential interactions of bacterial lipopolysaccharides with lipid membranes: Implications for TRPA1-mediated chemosensation. Sci. Rep. 2018;8:12010. doi: 10.1038/s41598-018-30534-2.
    1. Kashem S.W., Riedl M.S., Yao C., Honda C.N., Vulchanova L., Kaplan D.H. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity. 2015;43:515–526. doi: 10.1016/j.immuni.2015.08.016.
    1. Chiu I.M., Heesters B.A., Ghasemlou N., Von Hehn C.A., Zhao F., Tran J., Wainger B., Strominger A., Muralidharan S., Horswill A.R., et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature. 2013;501:52–57. doi: 10.1038/nature12479.
    1. Pinho-Ribeiro F.A., Baddal B., Haarsma R., O’Seaghdha M., Yang N.J., Blake K.J., Portley M., Verri W.A., Dale J.B., Wessels M.R., et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell. 2018;173:1083–1097.e22. doi: 10.1016/j.cell.2018.04.006.
    1. Hashimoto T., Yosipovitch G. Itching as a systemic disease. J. Allergy Clin. Immunol. 2019;144:375–380. doi: 10.1016/j.jaci.2019.04.005.
    1. Bajaj J.S., Fagan A., Sikaroodi M., Kakiyama G., Takei H., Degefu Y., Pandak W.M., Hylemon P.B., Fuchs M., John B., et al. Alterations in skin microbiomes of patients with cirrhosis. Clin. Gastroenterol. Hepatol. 2019;17:2581–2591.e15. doi: 10.1016/j.cgh.2019.03.028.
    1. Kremer A.E., Martens J.J., Kulik W., Rueff F., Kuiper E.M., Van Buuren H.R., Van Erpecum K.J., Kondrackiene J., Prieto J., Rust C., et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010;139:1008–1018.e1. doi: 10.1053/j.gastro.2010.05.009.
    1. Beuers U., Kremer A.E., Bolier R., Elferink R.P. Pruritus in cholestasis: Facts and fiction. Hepatology. 2014;60:399–407. doi: 10.1002/hep.26909.
    1. Nieto-Posadas A., Picazo-Juarez G., Llorente I., Jara-Oseguera A., Morales-Lazaro S., Escalante-Alcalde D., Islas L.D., Rosenbaum T. Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. Nat. Chem. Biol. 2011;8:78–85. doi: 10.1038/nchembio.712.
    1. Roosterman D., Goerge T., Schneider S.W., Bunnett N.W., Steinhoff M. Neuronal control of skin function: The skin as a neuroimmunoendocrine organ. Physiol. Rev. 2006;86:1309–1379. doi: 10.1152/physrev.00026.2005.
    1. Pereira U., Boulais N., Lebonvallet N., Lefeuvre L., Gougerot A., Misery L. Development of an in vitro coculture of primary sensitive pig neurons and keratinocytes for the study of cutaneous neurogenic inflammation. Exp. Dermatol. 2010;19:931–935. doi: 10.1111/j.1600-0625.2010.01119.x.
    1. Mijouin L., Hillion M., Ramdani Y., Jaouen T., Duclairoir-Poc C., Follet-Gueye M.L., Lati E., Yvergnaux F., Driouich A., Lefeuvre L., et al. Effects of a skin neuropeptide (substance p) on cutaneous microflora. PLoS ONE. 2013;8:e78773. doi: 10.1371/journal.pone.0078773.
    1. N’Diaye A., Gannesen A., Borrel V., Maillot O., Enault J., Racine P.J., Plakunov V., Chevalier S., Lesouhaitier O., Feuilloley M.G. Substance P and calcitonin gene-related peptide: Key regulators of cutaneous microbiota homeostasis. Front. Endocrinol. (Lausanne) 2017;8:15. doi: 10.3389/fendo.2017.00015.
    1. N’Diaye A., Mijouin L., Hillion M., Diaz S., Konto-Ghiorghi Y., Percoco G., Chevalier S., Lefeuvre L., Harmer N.J., Lesouhaitier O., et al. Effect of substance P in Staphylococcus aureus and Staphylococcus epidermidis virulence: Implication for skin homeostasis. Front. Microbiol. 2016;7:506. doi: 10.3389/fmicb.2016.00506.
    1. Raap U., Stander S., Metz M. Pathophysiology of itch and new treatments. Curr. Opin. Allergy Clin. Immunol. 2011;11:420–427. doi: 10.1097/ACI.0b013e32834a41c2.
    1. Lenard J. Mammalian hormones in microbial cells. Trends Biochem. Sci. 1992;17:147–150. doi: 10.1016/0968-0004(92)90323-2.
    1. Kawashima K., Misawa H., Moriwaki Y., Fujii Y.X., Fujii T., Horiuchi Y., Yamada T., Imanaka T., Kamekura M. Ubiquitous expression of acetylcholine and its biological functions in life forms without nervous systems. Life Sci. 2007;80:2206–2209. doi: 10.1016/j.lfs.2007.01.059.
    1. Stephenson M., Rowatt E. The production of acetylcholine by a strain of Lactobacillus plantarum. J. Gen. Microbiol. 1947;1:279–298. doi: 10.1099/00221287-1-3-279.
    1. Masson F., Talon R., Montel M.C. Histamine and tyramine production by bacteria from meat products. Int. J. Food Microbiol. 1996;32:199–207. doi: 10.1016/0168-1605(96)01104-X.
    1. Thomas C.M., Hong T., Van Pijkeren J.P., Hemarajata P., Trinh D.V., Hu W., Britton R.A., Kalkum M., Versalovic J. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS ONE. 2012;7:e31951. doi: 10.1371/journal.pone.0031951.
    1. Hurley R., Leask B.G., Ruthven C.R., Sandler M., Southgate J. Investigation of 5-hydroxytryptamine production by Candida albicans in vitro and in vivo. Microbios. 1971;4:133–143.
    1. Asano Y., Hiramoto T., Nishino R., Aiba Y., Kimura T., Yoshihara K., Koga Y., Sudo N. Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2012;303:G1288–G1295. doi: 10.1152/ajpgi.00341.2012.
    1. Tsavkelova E.A., Botvinko I.V., Kudrin V.S., Oleskin A.V. Detection of neurotransmitter amines in microorganisms with the use of high-performance liquid chromatography. Dokl. Biochem. 2000;372:115–117.
    1. Raasch W., Regunathan S., Li G., Reis D.J. Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci. 1995;56:2319–2330. doi: 10.1016/0024-3205(95)00226-V.
    1. Arena M.E., Manca de Nadra M.C. Biogenic amine production by Lactobacillus. J. Appl. Microbiol. 2001;90:158–162. doi: 10.1046/j.1365-2672.2001.01223.x.
    1. Leroith D., Liotta A.S., Roth J., Shiloach J., Lewis M.E., Pert C.B., Krieger D.T. Corticotropin and beta-endorphin-like materials are native to unicellular organisms. Proc. Natl. Acad. Sci. USA. 1982;79:2086–2090. doi: 10.1073/pnas.79.6.2086.
    1. LeRoith D., Pickens W., Vinik A.I., Shiloach J. Bacillus subtilis contains multiple forms of somatostatin-like material. Biochem. Biophys. Res. Commun. 1985;127:713–719. doi: 10.1016/S0006-291X(85)80001-2.
    1. Schar G., Stover E.P., Clemons K.V., Feldman D., Stevens D.A. Progesterone binding and inhibition of growth in Trichophyton mentagrophytes. Infect. Immun. 1986;52:763–767. doi: 10.1128/IAI.52.3.763-767.1986.
    1. Cryan J.F., Dinan T.G. Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 2012;13:701–712. doi: 10.1038/nrn3346.
    1. SM O.M., Dinan T.G., Cryan J.F. The gut microbiota as a key regulator of visceral pain. Pain. 2017;158(Suppl. 1):S19–S28. doi: 10.1097/j.pain.0000000000000779.
    1. Holzer P., Farzi A. Neuropeptides and the microbiota-gut-brain axis. Adv. Exp. Med. Biol. 2014;817:195–219. doi: 10.1007/978-1-4939-0897-4_9.
    1. Yosipovitch G., Ansari N., Goon A., Chan Y.H., Goh C.L. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br. J. Dermatol. 2002;147:32–36. doi: 10.1046/j.1365-2133.2002.04758.x.
    1. Yosipovitch G., Goon A., Wee J., Chan Y.H., Goh C.L. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br. J. Dermatol. 2000;143:969–973. doi: 10.1046/j.1365-2133.2000.03829.x.
    1. Yosipovitch G., Goon A.T., Wee J., Chan Y.H., Zucker I., Goh C.L. Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int. J. Dermatol. 2002;41:212–216. doi: 10.1046/j.1365-4362.2002.01460.x.
    1. Golpanian R.S., Kim H.S., Yosipovitch G. Effects of stress on itch. Clin. Ther. 2020 doi: 10.1016/j.clinthera.2020.01.025.
    1. Yosipovitch G., Mochizuki H. Neuroimaging of itch as a tool of assessment of chronic itch and its management. Handb. Exp. Pharmacol. 2015;226:57–70. doi: 10.1007/978-3-662-44605-8_4.
    1. Galley J.D., Nelson M.C., Yu Z., Dowd S.E., Walter J., Kumar P.S., Lyte M., Bailey M.T. Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. BMC Microbiol. 2014;14:189. doi: 10.1186/1471-2180-14-189.
    1. Bailey M.T. Influence of stressor-induced nervous system activation on the intestinal microbiota and the importance for immunomodulation. Adv. Exp. Med. Biol. 2014;817:255–276. doi: 10.1007/978-1-4939-0897-4_12.
    1. Slominski A. A nervous breakdown in the skin: Stress and the epidermal barrier. J. Clin. Investig. 2007;117:3166–3169. doi: 10.1172/JCI33508.
    1. Aberg K.M., Radek K.A., Choi E.H., Kim D.K., Demerjian M., Hupe M., Kerbleski J., Gallo R.L., Ganz T., Mauro T., et al. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J. Clin. Investig. 2007;117:3339–3349. doi: 10.1172/JCI31726.
    1. Radek K.A. Antimicrobial anxiety: The impact of stress on antimicrobial immunity. J. Leukoc. Biol. 2010;88:263–277. doi: 10.1189/jlb.1109740.
    1. Kim H.S., Yosipovitch G. An aberrant parasympathetic response: A new perspective linking chronic stress and itch. Exp. Dermatol. 2013;22:239–244. doi: 10.1111/exd.12070.
    1. Tran B.W., Papoiu A.D., Russoniello C.V., Wang H., Patel T.S., Chan Y.H., Yosipovitch G. Effect of itch, scratching and mental stress on autonomic nervous system function in atopic dermatitis. Acta Derm. Venereol. 2010;90:354–361. doi: 10.2340/00015555-0890.
    1. Curtis B.J., Radek K.A. Cholinergic regulation of keratinocyte innate immunity and permeability barrier integrity: New perspectives in epidermal immunity and disease. J. Investig. Dermatol. 2012;132:28–42. doi: 10.1038/jid.2011.264.
    1. Radek K.A., Elias P.M., Taupenot L., Mahata S.K., O’Connor D.T., Gallo R.L. Neuroendocrine nicotinic receptor activation increases susceptibility to bacterial infections by suppressing antimicrobial peptide production. Cell Host Microbe. 2010;7:277–289. doi: 10.1016/j.chom.2010.03.009.
    1. Curtis B.J., Plichta J.K., Blatt H., Droho S., Griffin T.M., Radek K.A. Nicotinic acetylcholine receptor stimulation impairs epidermal permeability barrier function and recovery and modulates cornified envelope proteins. Life Sci. 2012;91:1070–1076. doi: 10.1016/j.lfs.2012.08.020.
    1. Lyte M., Freestone P.P., Neal C.P., Olson B.A., Haigh R.D., Bayston R., Williams P.H. Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes. Lancet. 2003;361:130–135. doi: 10.1016/S0140-6736(03)12231-3.
    1. Freestone P.P., Haigh R.D., Williams P.H., Lyte M. Stimulation of bacterial growth by heat-stable, norepinephrine-induced autoinducers. FEMS Microbiol. Lett. 1999;172:53–60. doi: 10.1111/j.1574-6968.1999.tb13449.x.
    1. Neal C.P., Freestone P.P., Maggs A.F., Haigh R.D., Williams P.H., Lyte M. Catecholamine inotropes as growth factors for Staphylococcus epidermidis and other coagulase-negative staphylococci. FEMS Microbiol. Lett. 2001;194:163–169. doi: 10.1111/j.1574-6968.2001.tb09463.x.
    1. Borrel V., Thomas P., Catovic C., Racine P.J., Konto-Ghiorghi Y., Lefeuvre L., Duclairoir-Poc C., Zouboulis C.C., Feuilloley M.G.J. Acne and stress: Impact of catecholamines on Cutibacterium acnes. Front. Med. (Lausanne) 2019;6:155. doi: 10.3389/fmed.2019.00155.
    1. Clarke S.R., Mohamed R., Bian L., Routh A.F., Kokai-Kun J.F., Mond J.J., Tarkowski A., Foster S.J. The Staphylococcus aureus surface protein IsdA mediates resistance to innate defenses of human skin. Cell Host Microbe. 2007;1:199–212. doi: 10.1016/j.chom.2007.04.005.
    1. Freestone P.P., Sandrini S.M., Haigh R.D., Lyte M. Microbial endocrinology: How stress influences susceptibility to infection. Trends Microbiol. 2008;16:55–64. doi: 10.1016/j.tim.2007.11.005.
    1. Pastar I., Nusbaum A.G., Gil J., Patel S.B., Chen J., Valdes J., Stojadinovic O., Plano L.R., Tomic-Canic M., Davis S.C. Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection. PLoS ONE. 2013;8:e56846. doi: 10.1371/journal.pone.0056846.
    1. Choi E.H., Demerjian M., Crumrine D., Brown B.E., Mauro T., Elias P.M., Feingold K.R. Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006;291:R1657–R1662. doi: 10.1152/ajpregu.00010.2006.
    1. Sandrini S.M., Shergill R., Woodward J., Muralikuttan R., Haigh R.D., Lyte M., Freestone P.P. Elucidation of the mechanism by which catecholamine stress hormones liberate iron from the innate immune defense proteins transferrin and lactoferrin. J. Bacteriol. 2010;192:587–594. doi: 10.1128/JB.01028-09.
    1. Shibata M., Katsuyama M., Onodera T., Ehama R., Hosoi J., Tagami H. Glucocorticoids enhance Toll-like receptor 2 expression in human keratinocytes stimulated with Propionibacterium acnes or proinflammatory cytokines. J. Investig. Dermatol. 2009;129:375–382. doi: 10.1038/jid.2008.237.
    1. Seth A.K., Geringer M.R., Nguyen K.T., Agnew S.P., Dumanian Z., Galiano R.D., Leung K.P., Mustoe T.A., Hong S.J. Bacteriophage therapy for Staphylococcus aureus biofilm-infected wounds: A new approach to chronic wound care. Plast. Reconstr. Surg. 2013;131:225–234. doi: 10.1097/PRS.0b013e31827e47cd.
    1. Rojas I.G., Padgett D.A., Sheridan J.F., Marucha P.T. Stress-induced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav. Immun. 2002;16:74–84. doi: 10.1006/brbi.2000.0619.
    1. Cogen A.L., Nizet V., Gallo R.L. Skin microbiota: A source of disease or defence? Br. J. Dermatol. 2008;158:442–455. doi: 10.1111/j.1365-2133.2008.08437.x.
    1. Sonnex C. Influence of ovarian hormones on urogenital infection. Sex. Transm. Infect. 1998;74:11–19. doi: 10.1136/sti.74.1.11.
    1. Veinante P., Yalcin I., Barrot M. The amygdala between sensation and affect: A role in pain. J. Mol. Psychiatry. 2013;1:9. doi: 10.1186/2049-9256-1-9.
    1. Neugebauer V., Li W. Differential sensitization of amygdala neurons to afferent inputs in a model of arthritic pain. J. Neurophysiol. 2003;89:716–727. doi: 10.1152/jn.00799.2002.
    1. Neugebauer V., Li W., Bird G.C., Han J.S. The amygdala and persistent pain. Neuroscientist. 2004;10:221–234. doi: 10.1177/1073858403261077.
    1. Sanders K.M., Akiyama T. The vicious cycle of itch and anxiety. Neurosci. Biobehav Rev. 2018;87:17–26. doi: 10.1016/j.neubiorev.2018.01.009.
    1. Mu D., Deng J., Liu K.F., Wu Z.Y., Shi Y.F., Guo W.M., Mao Q.Q., Liu X.J., Li H., Sun Y.G. A central neural circuit for itch sensation. Science. 2017;357:695–699. doi: 10.1126/science.aaf4918.
    1. Jeong K.Y., Kang J.H. Investigation of the pruritus-induced functional activity in the rat brain using manganese-enhanced MRI. J. Magn. Reson. Imaging. 2015;42:709–716. doi: 10.1002/jmri.24832.
    1. Davidson S., Zhang X., Khasabov S.G., Simone D.A., Giesler G.J., Jr. Relief of itch by scratching: State-dependent inhibition of primate spinothalamic tract neurons. Nat. Neurosci. 2009;12:544–546. doi: 10.1038/nn.2292.
    1. Roozendaal B., McEwen B.S., Chattarji S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 2009;10:423–433. doi: 10.1038/nrn2651.
    1. Pavlenko D., Akiyama T. Why does stress aggravate itch? A possible role of the amygdala. Exp. Dermatol. 2019;28:1439–1441. doi: 10.1111/exd.13941.
    1. Mochizuki H., Hernandez L.E., Yosipovitch G. What does brain imaging tell us about itch? Itch. 2019;4:e23. doi: 10.1097/itx.0000000000000023.
    1. Cowan C.S.M., Hoban A.E., Ventura-Silva A.P., Dinan T.G., Clarke G., Cryan J.F. Gutsy moves: The amygdala as a critical node in microbiota to brain signaling. Bioessays. 2018;40 doi: 10.1002/bies.201700172.
    1. Stilling R.M., Ryan F.J., Hoban A.E., Shanahan F., Clarke G., Claesson M.J., Dinan T.G., Cryan J.F. Microbes & neurodevelopment—Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav. Immun. 2015;50:209–220. doi: 10.1016/j.bbi.2015.07.009.
    1. Hoban A.E., Stilling R.M., Moloney G.M., Moloney R.D., Shanahan F., Dinan T.G., Cryan J.F., Clarke G. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome. 2017;5:102. doi: 10.1186/s40168-017-0321-3.
    1. Luczynski P., Tramullas M., Viola M., Shanahan F., Clarke G., O’Mahony S., Dinan T.G., Cryan J.F. Microbiota regulates visceral pain in the mouse. Elife. 2017;6 doi: 10.7554/eLife.25887.
    1. Sudo N., Chida Y., Aiba Y., Sonoda J., Oyama N., Yu X.N., Kubo C., Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 2004;558:263–275. doi: 10.1113/jphysiol.2004.063388.
    1. Clarke G., Grenham S., Scully P., Fitzgerald P., Moloney R.D., Shanahan F., Dinan T.G., Cryan J.F. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry. 2013;18:666–673. doi: 10.1038/mp.2012.77.
    1. Onaolapo O.J., Onaolapo A.Y., Olowe A.O. The neurobehavioral implications of the brain and microbiota interaction. Front. Biosci. (Landmark Ed.) 2020;25:363–397. doi: 10.2741/4810.
    1. O’Neill C.A., Monteleone G., McLaughlin J.T., Paus R. The gut-skin axis in health and disease: A paradigm with therapeutic implications. Bioessays. 2016;38:1167–1176. doi: 10.1002/bies.201600008.
    1. Salem I., Ramser A., Isham N., Ghannoum M.A. The gut microbiome as a major regulator of the gut-skin axis. Front. Microbiol. 2018;9:1459. doi: 10.3389/fmicb.2018.01459.
    1. Arck P., Handjiski B., Hagen E., Pincus M., Bruenahl C., Bienenstock J., Paus R. Is there a ‘gut-brain-skin axis’? Exp. Dermatol. 2010;19:401–405. doi: 10.1111/j.1600-0625.2009.01060.x.
    1. Lee Y.B., Byun E.J., Kim H.S. Potential role of the microbiome in acne: A comprehensive review. J. Clin. Med. 2019;8:987. doi: 10.3390/jcm8070987.
    1. Sanders K.M., Nattkemper L.A., Yosipovitch G. The gut-itch connection. Exp. Dermatol. 2016;25:344–345. doi: 10.1111/exd.12994.
    1. Castro J., Harrington A.M., Lieu T., Garcia-Caraballo S., Maddern J., Schober G., O’Donnell T., Grundy L., Lumsden A.L., Miller P., et al. Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity. JCI Insight. 2019;4 doi: 10.1172/jci.insight.131712.
    1. Egert M., Simmering R., Riedel C.U. The association of the skin microbiota with health, immunity, and disease. Clin. Pharmacol. Ther. 2017;102:62–69. doi: 10.1002/cpt.698.
    1. Dreno B., Araviiskaia E., Berardesca E., Gontijo G., Sanchez Viera M., Xiang L.F., Martin R., Bieber T. Microbiome in healthy skin, update for dermatologists. J. Eur. Acad. Dermatol. Venereol. 2016;30:2038–2047. doi: 10.1111/jdv.13965.
    1. Bastiaanssen T.F.S., Cowan C.S.M., Claesson M.J., Dinan T.G., Cryan J.F. Making sense of … the microbiome in psychiatry. Int. J. Neuropsychopharmacol. 2019;22:37–52. doi: 10.1093/ijnp/pyy067.
    1. Davani-Davari D., Negahdaripour M., Karimzadeh I., Seifan M., Mohkam M., Masoumi S.J., Berenjian A., Ghasemi Y. Prebiotics: Definition, types, sources, mechanisms, and clinical applications. Foods. 2019;8:92. doi: 10.3390/foods8030092.

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