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WIREs Syst Biol Med
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Our natural “makeup” reveals more than it hides: Modeling the skin and its microbiome

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Abstract Skin is our primary interface with the environment. A structurally and functionally complex organ that hosts a dynamic ecosystem of microbes, and synthesizes many compounds that affect our well‐being and psychosocial interactions. It is a natural platform of signal exchange between internal organs, skin resident microbes, and the environment. These interactions have gained a great deal of attention due to the increased prevalence of atopic diseases, and the co‐occurrence of multiple allergic diseases related to allergic sensitization in early life. Despite significant advances in experimentally characterizing the skin, its microbial ecology, and disease phenotypes, high‐levels of variability in these characteristics even for the same clinical phenotype are observed. Addressing this variability and resolving the relevant biological processes requires a systems approach. This review presents some of our current understanding of the skin, skin–immune, skin–neuroendocrine, skin–microbiome interactions, and computer‐based modeling approaches to simulate this ecosystem in the context of health and disease. The review highlights the need for a systems‐based understanding of this sophisticated ecosystem. This article is categorized under: Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Laboratory Methods and Technologies > Metabolomics Physiology > Organismal Responses to Environment
Schematic of the key layers, structures, and cell populations of the skin. The epidermis consists mostly of keratinocytes at different stages of differentiation and provides the barrier function. It also hosts melanocytes, Langerhans cells, and T cells. Wide range of microbes thrive on the epidermis and penetrate the skin appendages such as hair follicles. Hair follicles are surrounded by immune‐suppressive extracellular matrix components and FAS ligands, they co‐localize microbes with immune cells. Sebaceous glands modulate local immune response and are modulated by neuropeptides like substance P. The dermis consists of extracellular matrix producing fibroblasts, blood vessels, and lymph ducts. The vasculature connects the skin resident immune system to the systemic immune and endocrine systems. The dermis lies on a layer of adipose tissue which contributes to lipid‐dependent immune response as well as steroidogenesis. Figure adapted with permission from figures 1a and 2a of Kabashima, Honda, Ginhoux, and Egawa (2019)
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Schematic of coupling between the skin microbiome, and skin resident immune‐, neuroendocrine‐system, metabolism, and skin physiology as a system of gears. Skin homeostasis is imagined as a spinning top that should spin (shedding, replenishment, and repair) within a torque range to be stable. The immune‐ and neuroendocrine‐system are anchored in the skin and free‐wheel without the engagement of the skin microbiome (anchored in the environment). When engaged they together act as governors that maintain stability. The skin microbiome can either dissipate the kinetic energy (say to help wound healing) or feed kinetic energy (by producing bacteriocins and steroidogenesis) and contribute to homeostasis
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Schematic of ecosystem model reconstruction (a) using agent‐based models where there are fluxes of exchange between microbes, and microbes move within the spatial grid. (b) Algorithmic construction of an ecosystem (right) given the available substrates, desired products (left), and set of available species (middle). (a) Reproduced with permission from Bauer, Zimmermann, Baldini, Thiele, and Kaleta (2017, figure 1) and (b) reproduced with permission from Eng and Borenstein (2016, figure 1)
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Schematic of a multiscale modeling pipeline to model the skin ecosystem. The pipeline begins with the generation of metabolomic, −omic, and physiological data through experiments. Based on the metagenomics data, quantitative genome‐scale metabolic models of microbial species are constructed. Quantitative models are constrained by/validated against other ‐omic data. Additionally (or Alternatively) qualitative metabolic models can also be constructed using reverse ecology‐based techniques. Next, the generated species level models are combined to reflect the ecosystem and a representative supra‐organism model is created. The supra‐organism model is validated against the available ‐omic data. The supra‐organism model is then coupled with physiological models that simulate immune, neuroendocrine and host‐metabolic processes to model the observed skin physiology
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Skin resident neuroendocrine axes and steroidogenic pathways. (a) Skin neuroendocrine system consists of most classical neuroendocrine axes. As platform of signal exchange between internal organs and the environment (orange arrows), skin cells respond to neurohormonal signals(red arrows) and also produce a range of neurochemicals (green and blue arrows) that also modulate the immune system. (b) A subset of steroidogenic pathways in the skin using cholesterol as the initial substrate. DHEA, dehydroepiandrosterone; DHEA‐S, dehydroepiandrosterone sulfate (supplied from adrenal glands); DHT, dihydrotestosterone. Figure a, reproduced with permission from figure 1.2 of Slominski et al. (2012a), figure b, reproduced with permission from figure 2 of Slominski et al. (2013)
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Physiology > Organismal Responses to Environment
Laboratory Methods and Technologies > Metabolomics
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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