Adipocytes exhibit remarkable plasticity, dynamically gaining and losing lipid content. However, during skin fibrosis, this adaptability becomes detrimental as adipocytes undergo lipid depletion associated with disease pathology. We previously identified the WNT signalling pathway-acting through Dipeptidyl Peptidase IV (DPP4) - as a key mediator of lipid depletion associated with skin fibrosis, but the mechanism remains unclear. DPP4 is an exopeptidase that cleaves a wide array of substrates across different cell types. Here, we investigate whether modulation of lipid-regulating DPP4 substrates is sufficient to preserve lipid content in WNT-activated dermal adipocytes. Using two complementary strategies, we found that supplementation with the DPP4 substrates Neuropeptide Y (NPY) and Glucose-dependent Insulinotropic Peptide (GIP) can partially protect lipid content in dermal adipocytes. When used in combination, we found that the protection against lipid depletion was more effective than monotherapy alone. These findings demonstrate that supplementation with DPP4 substrates provides a basis for targeted treatments for lipodystrophy syndromes and skin fibrosis.
During pregnancy and after childbirth, women's skin undergoes significant changes which may affect the skin's functional and structural characteristics and microbial diversity. Like their mothers, the newborns also experience various skin challenges in the months following birth. Temporal changes in skin microbiome in special groups such as pregnant women and newborns, as well as the interrelation between their skin's microbial diversity, have not been investigated. We followed women from pregnancy through 6 months after delivery, and their infants from 4 weeks to 6 months of age to investigate their skin characteristics and the microbiome, and potential associations. We enrolled 109 pregnant females residing in Berlin, Germany, with 93 mothers-infant pairs completing the study. Microbiome investigations included DNA isolation as single-site sampling using volar forearm skin swabs. Bioinformatic analysis involved OTU clustering at 97% sequence identity, taxonomic assignment using NCBI reference databases, and calculation of biodiversity metrics, including relative abundance of the dominant bacterial phylotypes, bacterial diversity and Shannon diversity index. The maternal skin microbiome showed mild to moderate changes throughout pregnancy and the 6 months postpartum period. In infants, alpha diversity significantly increased (mean species richness from 82.6 at 4 weeks to 116.1 at 6 months), although it did not reach maternal diversity levels (145.4 at 6 months postpartum). Regarding the microbiome consistency of the included women and infants, the within-pair similarity was always significantly higher than between-pair similarity for both time points. Therefore, we conclude that there is likely a relationship between the microbiome of the mother and that of her child.
Dysbiosis of the skin microbiome, characterised by Staphylococcus aureus overgrowth and imbalance of commensals such as Staphylococcus epidermidis (S. epidermidis), is closely associated with atopic dermatitis (AD). However, the therapeutic relevance of defined S. epidermidis-associated indole metabolite, especially indole-3-acetic acid (IAA), in AD-like inflammation remains incompletely characterised. Here, we investigated the role of IAA, a tryptophan-derived metabolite enriched in the culture supernatant of the tested S. epidermidis strain, in AD-like inflammation. Public transcriptomic analyses suggested impaired AHR-associated and tryptophan-metabolism signatures in AD skin, particularly in lesional skin, while human metagenomic data indicated AD-associated staphylococcal alterations. Targeted metabolomics identified IAA as an enriched indole metabolite in S. epidermidis culture supernatant. In an MC903-induced AD-like mouse model, cutaneous IAA levels and S. epidermidis abundance were reduced. Topical IAA attenuated AD-like phenotypes, improved barrier-related proteins and reduced inflammatory indices. These protective effects were diminished by the AHR antagonist CH223191. Molecular docking predicted a possible interaction between IAA and AHR, and in vitro assays showed that IAA modulated keratinocyte AHR-associated inflammatory and barrier-related responses. Together, our findings support IAA as a microbiome-associated postbiotic candidate for AD management, at least partly through AHR-associated signalling.
Cutibacterium acnes is a common skin bacterium that inhabits sebaceous follicles and comprises multiple phylotypes. Healthy skin is colonized by a C. acnes population dominated by phylotypes IA, IB, and II. In acne, this diversity is reduced, with a predominance of phylotype IA. Quantifying C. acnes phylotypes has been challenging due to the lack of specific methods. Here, we developed a droplet digital PCR (ddPCR) assay that separately quantifies phylotype IA and phylotypes IB/II, based on a difference in the hyaluronidase gene. The method was applied to skin swabs from 14 healthy individuals and 14 acne patients. Healthy skin contained nearly equal amounts of IA and IB/II, whereas acne samples showed a 111-fold predominance of IA over IB/II, due to a marked depletion of IB/II, instead of an increase of IA. After 4-6 months of isotretinoin treatment, C. acnes levels decreased drastically, with phylotype IA reduced by 50-fold. Twelve to 15 months after treatment, both phylotypes rebounded, although IB/II recovered only partially. Taken together, this ddPCR method can quantitatively distinguish the acne-dominant phylotype IA from healthy skin-associated phylotypes IB/II, and is thus a useful tool for skin microbiome studies and specifically for assessing C. acnes dysbiosis in acne.
Female-pattern hair loss is common in obese women with polycystic ovary syndrome (PCOS), recently proposed as polyendocrine metabolic ovarian syndrome (PMOS) and is often associated with hypertriglyceridemia (TG), although the underlying mechanisms remain unclear. This study investigated how metabolic factors and androgens contribute to hair loss in female mice exposed to a high-fat diet (HFD). A controlled, parallel-group study using 8-week-old female C57BL/6 mice fed either an HFD (60% kcal fat) or a standard diet for 16 weeks. Mice were sacrificed at baseline and 4-week intervals for serial evaluation of metabolic, hormonal and skin changes (n = 6/group/time point). Hair loss was quantified from digital photographs using the ImageJ and further supported by histological examination. Circulating metabolic and hormonal profiles were measured. In dorsal skin, oxidative stress (malondialdehyde, MDA) and androgen-related markers-5-alpha-reductase type II (5αR2), dihydrotestosterone (DHT) and androgen receptor (AR)-were evaluated using immunohistochemistry, Western blot and enzyme-linked immunosorbent assay. From Week 12 onward, HFD-fed mice exhibited greater weight gain, pronounced dorsal hair thinning and elevated TG, insulin and free androgen index (FAI) levels. Skin MDA, 5αR2, DHT and AR levels also progressively increased. In the second experiment, 8-week-old female mice were assigned to four groups (n = 6/group): HFD with N-acetylcysteine (NAC), finasteride, spironolactone, or vehicle administered by oral gavage for 12 weeks. Compared with HFD-vehicle, antioxidant or anti-androgen co-treatment significantly lowered serum TG, tissue MDA and ameliorated hair thinning despite similar weight gain and 5αR2 levels. NAC reduced TG, FAI and decreased tissue MDA, DHT and AR. Finasteride lowered TG, MDA, DHT and AR, whereas spironolactone reduced TG and MDA. HFD-induced obesity exacerbates hair loss in female mice by enhancing oxidative stress and activating androgen signalling in the skin. Targeting these pathways, such as antioxidants and antiandrogens, may mitigate HFD-accelerated hair loss.
