Targeting the gut-skin axis-Probiotics as new tools for skin disorder management?

The existence of a gut-skin axis is supported by increasing evidence, but its translational potential is not widely recognized. Studies linked inflammatory skin diseases to an imbalanced gut microbiome; hence, the modulation of the gut microbiota to improve skin condition seems to be a feasible approach. Today, there is a growing interest in natural products as alternatives to synthetic drugs. In this respect, oral probiotics could be a simple, safe and cheap modality in the therapeutic management of skin inflammation. Unfortunately, very few studies have looked into how probiotic supplementation influences inflammatory skin disorders. The result, though promising, are difficult to implement in clinical practice due to the heterogeneity of the applied supplemental regimen in the different studies. In this Viewpoint, we aim to encourage the conduction of more research in that direction to explore unambiguously the therapeutic potential of oral probiotics in dermatology. We focus on the most common inflammatory skin diseases (atopic dermatitis, psoriasis, rosacea, acne vulgaris) with an associated gut dysbiosis, but we also discuss some less common, but very serious skin pathologies (eg erythema nodosum, pyoderma gangrenosum, hidradenitis suppurativa) that are possibly linked to a disturbed gut flora composition. We dissect the possible mechanisms along the gut-skin axis and highlight novel points where probiotics could interfere in this communication in the diseased state.

PPARγ-mediated and arachidonic acid-dependent signaling is involved in differentiation and lipid production of human sebocytes.

The transcriptional basis of sebocyte differentiation and lipid production is mostly unclear. Peroxisome proliferator-activated receptor gamma (PPARγ), a lipid-activated transcription factor, has been implicated in differentiation and lipid metabolism of various cell types. Here, we show that PPARγ is differentially expressed in normal and pathological human sebocytes and appears to have roles in their differentiation and lipid production. We used laser-microdissected normal and pathological human sebaceous glands (SGs) and SZ95 cells (immortalized sebocyte cell line) analyzed by real-time quantitative PCR and immunohistochemistry. Lipids were analyzed by quantitative fluorimetry- and mass spectrometry-based approaches. We have observed that PPARγ and its target genes, ADRP (adipose differentiation-related protein) and PGAR (PPARγ angiopoietin-related protein), are expressed in sebocytes and show association with their level of differentiation. Also, PPARγ is present in normal and hyperplastic SG, whereas its expression levels are decreased in SG adenoma and SG carcinoma cells, reflecting a maturation-linked expression pattern. Furthermore, in SZ95 sebocytes, naturally occurring lipids, including arachidonic acid and arachidonic acid keto-metabolites (e.g., 5-KETE (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid), 12-KETE (12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid)), appear to regulate PPARγ signaling pathways, which in turn modulate phospholipid biosynthesis and induce neutral lipid synthesis. Collectively, our findings highlight the importance of endogenous ligand-activated PPARγ signaling in human sebocyte biology and suggest that PPARγ might be a promising candidate for the clinical management of SG disorders.

Carboxypeptidase-M is regulated by lipids and CSFs in macrophages and dendritic cells and expressed selectively in tissue granulomas and foam cells.

Granulomatous inflammations, characterized by the presence of activated macrophages (MAs) forming epithelioid cell (EPC) clusters, are usually easy to recognize. However, in ambiguous cases the use of a MA marker that expresses selectively in EPCs may be needed. Here, we report that carboxypeptidase-M (CPM), a MA-differentiation marker, is preferentially induced in EPCs of all granuloma types studied, but not in resting MAs. As CPM is not expressed constitutively in MAs, this allows utilization of CPM-immunohistochemistry in diagnostics of minute granuloma detection when dense non-granulomatous MAs are also present. Despite this rule, hardly any detectable CPM was found in advanced/active tubercle caseous disease, albeit in early tuberculosis granuloma, MAs still expressed CPM. Indeed, in vitro both the CPM-protein and -mRNA became downregulated when MAs were infected with live mycobacteria. In vitro, MA-CPM transcript is neither induced remarkably by interferon-γ, known to cause classical MA activation, nor by IL-4, an alternative MA activator. Instead, CPM is selectively expressed in lipid-laden MAs, including the foam cells of atherosclerotic plaques, xanthomatous lesions and lipid pneumonias. By using serum, rich in lipids, and low-density lipoprotein (LDL) or VLDL, CPM upregulation could be reproduced in vitro in monocyte-derived MAs both at transcriptional and protein levels, and the increase is repressed under lipid-depleted conditions. The microarray analyses support the notion that CPM induction correlates with a robust progressive increase in CPM gene expression during monocyte to MA maturation and dendritic cell (DC) differentiation mediated by granulocyte-MA-colony-stimulating factor+IL-4. M-CSF alone also induced CPM. These results collectively indicate that CPM upregulation in MAs is preferentially associated with increased lipid uptake, and exposure to CSF, features of EPCs, also. Therefore, CPM-immunohistochemistry is useful for granuloma and foam MA detections in tissue sections. Furthermore, the present data offer CPM for the first time to be a novel marker and cellular player in lipid uptake and/or metabolism of MAs by promoting foam cell formation.

Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology.

Transient receptor potential vanilloid-1 (TRPV1), originally described as a central integrator of nociception, is expressed on human epidermal and hair follicle keratinocytes and is involved in regulation of cell growth and death. In human pilosebaceous units, we had shown that TRPV1 stimulation inhibits hair shaft elongation and matrix keratinocyte proliferation, and induces premature hair follicle regression and keratinocyte apoptosis. In the current study, we have explored the role of TRPV1-mediated signaling in sebaceous gland (SG) biology, using a human sebocyte cell culture model (SZ95 sebocytes). Demonstrating that human skin SG in situ and SZ95 sebocytes in vitro express TRPV1, we show that the prototypic TRPV1 agonist, capsaicin, selectively inhibits basal and arachidonic acid-induced lipid synthesis in a dose-, time-, and extracellular calcium-dependent and a TRPV1-specific manner. Low-dose capsaicin stimulates cellular proliferation via TRPV1, whereas higher concentrations inhibit sebocyte growth and induce cell death independent of TRPV1. Moreover, capsaicin suppresses the expression of genes involved in lipid homeostasis and of selected proinflammatory cytokines. Collectively, these findings support the concept that TRPV1 signaling is a significant, previously unreported player in human sebocyte biology and identify TRPV1 as a promising target in the clinical management of inflammatory SG disorders (for example, acne vulgaris).

Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling.

We had previously shown that both locally produced endocannabinoids and exocannabinoids, via cannabinoid receptor-1 (CB1), are powerful inhibitors of human hair growth. To further investigate the role of the cannabinoid system in pilosebaceous unit biology, we have explored in the current study whether and how endocannabinoids have an impact on human sebaceous gland biology, using human SZ95 sebocytes as cell culture model. Here, we provide the first evidence that SZ95 sebocytes express CB2 but not CB1. Also, prototypic endocannabinoids (arachidonoyl ethanolamide/anandamide, 2-arachidonoyl glycerol) are present in SZ95 sebocytes and dose-dependently induce lipid production and (chiefly apoptosis-driven) cell death. Endocannabinoids also up-regulate the expression of key genes involved in lipid synthesis (e.g., PPAR transcription factors and some of their target genes). These actions are selectively mediated by CB2-coupled signaling involving the MAPK pathway, as revealed by specific agonists/antagonists and by RNA interference. Because cells with "silenced" CB2 exhibited significantly suppressed basal lipid production, our results collectively suggest that human sebocytes utilize a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death. CB2 antagonists or agonists therefore deserve to be explored in the management of skin disorders characterized by sebaceous gland dysfunctions (e.g., acne vulgaris, seborrhea, dry skin).