Review

Skin Microbiota: Mediator of Interactions Between Metabolic

Disorders and Cutaneous Health and Disease
Magdalini Kreouzi 1 , Nikolaos Theodorakis 2,3,4,5 , Maria Nikolaou 3 , Georgios Feretzakis 5 ,
Athanasios Anastasiou 6 , Konstantinos Kalodanis 7 and Aikaterini Sakagianni 8, *

1 Department of Internal Medicine, Amalia Fleming General Hospital, 14, 25th Martiou Str., 15127 Athens,
Greece; kreouzi.m@live.unic.ac.cy
2 NT-CardioMetabolics, Clinic for Metabolism and Athletic Performance, 47 Tirteou Str., 17564 Palaio Faliro,
Greece; n.theodorakis@flemig-hospital.gr
3 Department of Cardiology & Preventive Cardiology Outpatient Clinic, Amalia Fleming General Hospital,
14, 25th Martiou Str., 15127 Melissia, Greece; m.nikolaou@flemig-hospital.gr
4 School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527 Athens, Greece
5 School of Science and Technology, Hellenic Open University, 18 Aristotelous Str., 26335 Patras, Greece
6 Biomedical Engineering Laboratory, National Technical University of Athens, 15780 Athens, Greece;
aanastasiou@biomed.ntua.gr
7 Department of Informatics & Telematics, Harokopio University of Athens, 17676 Kallithea, Greece;
kkalodanis@hua.gr
8 Intensive Care Unit, Sismanogleio General Hospital, 37 Sismanogleiou Str., 15126 Marousi, Greece
* Correspondence: sakagianni@sismanoglio.gr

Abstract: Metabolic disorders, including type 2 diabetes mellitus (T2DM), obesity, and
metabolic syndrome, are systemic conditions that profoundly impact the skin microbiota, a
dynamic community of bacteria, fungi, viruses, and mites essential for cutaneous health.
Dysbiosis caused by metabolic dysfunction contributes to skin barrier disruption, immune
dysregulation, and increased susceptibility to inflammatory skin diseases, including pso-
riasis, atopic dermatitis, and acne. For instance, hyperglycemia in T2DM leads to the
formation of advanced glycation end products (AGEs), which bind to the receptor for AGEs
(RAGE) on keratinocytes and immune cells, promoting oxidative stress and inflamma-
tion while facilitating Staphylococcus aureus colonization in atopic dermatitis. Similarly,
Academic Editor: Denis Roy obesity-induced dysregulation of sebaceous lipid composition increases saturated fatty
Received: 24 December 2024 acids, favoring pathogenic strains of Cutibacterium acnes, which produce inflammatory
Revised: 5 January 2025 metabolites that exacerbate acne. Advances in metabolomics and microbiome sequencing
Accepted: 14 January 2025
have unveiled critical biomarkers, such as short-chain fatty acids and microbial signatures,
Published: 14 January 2025
predictive of therapeutic outcomes. For example, elevated butyrate levels in psoriasis
Citation: Kreouzi, M.; Theodorakis,
have been associated with reduced Th17-mediated inflammation, while the presence of
N.; Nikolaou, M.; Feretzakis, G.;
specific Lactobacillus strains has shown potential to modulate immune tolerance in atopic
Anastasiou, A.; Kalodanis, K.;
Sakagianni, A. Skin Microbiota:
dermatitis. Furthermore, machine learning models are increasingly used to integrate multi-
Mediator of Interactions Between omics data, enabling personalized interventions. Emerging therapies, such as probiotics
Metabolic Disorders and Cutaneous and postbiotics, aim to restore microbial diversity, while phage therapy selectively targets
Health and Disease. Microorganisms pathogenic bacteria like Staphylococcus aureus without disrupting beneficial flora. Clinical
2025, 13, 161. https://doi.org/
trials have demonstrated significant reductions in inflammatory lesions and improved
10.3390/microorganisms13010161
quality-of-life metrics in patients receiving these microbiota-targeted treatments. This
Copyright: © 2025 by the authors. review synthesizes current evidence on the bidirectional interplay between metabolic dis-
Licensee MDPI, Basel, Switzerland.
orders and skin microbiota, highlighting therapeutic implications and future directions. By
This article is an open access article
addressing systemic metabolic dysfunction and microbiota-mediated pathways, precision
distributed under the terms and
conditions of the Creative Commons
strategies are paving the way for improved patient outcomes in dermatologic care.
Attribution (CC BY) license
(https://creativecommons.org/
licenses/by/4.0/).

Microorganisms 2025, 13, 161 https://doi.org/10.3390/microorganisms13010161

Microorganisms 2025, 13, 161 2 of 32

Keywords: metabolic disorders; skin microbiota; biomarkers; atopic dermatitis; psoriasis;

acne; precision dermatology

1. Introduction
Metabolic disorders, including type 2 diabetes mellitus (T2DM), obesity, and metabolic
syndrome (MetS), pose significant global health challenges due to their systemic effects and
numerous comorbidities [1]. These conditions, characterized by disrupted glucose and lipid
metabolism, insulin resistance, and chronic low-grade inflammation (meta-inflammation),
have traditionally been linked to cardiovascular–renal–hepatic diseases [2]. However,
emerging evidence highlights their far-reaching impact on the skin, particularly through
interactions with the skin microbiota, a dynamic ecosystem critical for cutaneous health [3].
The skin microbiota, comprising bacteria (e.g., Staphylococcus epidermidis, Cutibac-
terium acnes), fungi (e.g., Malassezia spp.), viruses, and mites, is essential for cutaneous
health [4]. This microbial community plays a pivotal role in modulating immune re-
sponses, maintaining epidermal barrier integrity, and competing with pathogenic organ-
isms. Metabolic dysregulation alters these interactions at molecular and cellular levels. For
instance, hyperglycemia-driven advanced glycation end products (AGEs) compromise skin
barrier proteins, while imbalances in adipokines and cytokines in obesity shift immune
responses and modify epidermal lipid composition, reshaping microbial communities [5,6].
These changes exacerbate susceptibility to dermatologic conditions such as psoriasis, atopic
dermatitis (AD), and chronic wounds [7–9].
Additionally, with the rise of integrative ‘omics’ and large-scale clinical data, machine
learning (ML) approaches are increasingly being employed to identify complex patterns,
predict disease risk, and evaluate therapeutic responses. Such computational tools can
integrate data streams from metabolic profiling, microbiome sequencing, and clinical
outcomes, helping to unravel the intricate interplay between metabolic disorders, the skin
microbiome, and dermatologic health [10,11].
This review explores the bidirectional interactions between metabolic dysfunction and
the skin microbiota, focusing on their roles in barrier disruption, immune dysregulation,
and dermatologic conditions such as psoriasis, AD, and acne. We highlight insights from
omics technologies, including metabolomics and microbiomics, which have identified novel
biomarkers predictive of disease risk and therapeutic outcomes. Emerging therapies, such
as probiotics, postbiotics, and phage therapy, are examined for their potential to correct
microbial dysbiosis while addressing underlying metabolic abnormalities. Advances in
ML further enhance our ability to integrate complex multi-omics data, driving innovations
in precision dermatology.
Regarding the topic of this manuscript, there is a significant gap in the literature, with
only a few studies briefly referencing interactions between microbiomics and metabolic
dysregulation within the broader pathophysiology of certain skin diseases. This review
uniquely focuses on the interplay between metabolic disorders, the skin microbiota, and
cutaneous health and disease. By addressing this critical gap, this manuscript provides a
fresh perspective on integrated strategies to improve dermatologic outcomes in patients
with metabolic disorders.

2. Methods
This manuscript is a narrative literature review synthesizing current knowledge on
the role of the skin microbiota as a mediator of interactions between metabolic disorders
and skin health. A comprehensive literature search was conducted in PubMed and Scopus
Microorganisms 2025, 13, 161 3 of 32

for studies published up to 22 December 2024. We utilized a wide range of keywords and
Medical Subject Headings (MeSH) terms to ensure a thorough search, including but not
limited to skin microbiota, metabolic disorders, obesity, diabetes mellitus, dysbiosis, skin
diseases, psoriasis, atopic dermatitis, microbial interactions, and ML. Boolean operators
were applied to refine and optimize the search strategy.
The inclusion criteria were as follows:
■ Study Type: Reviews or original research articles published in English.
■ Focus: Articles that addressed metabolic and immunological factors influencing the
skin microbiota and its role in skin diseases.
■ Therapeutic Studies: Relevant therapeutic studies were defined as those investigating
microbiota-targeted interventions (e.g., probiotics, postbiotics, or phage therapy)
and/or systemic treatments addressing underlying metabolic dysfunction. These
studies were assessed for clinical outcomes, mechanistic insights, and validation
through preclinical or clinical data.
■ ML Applications: Key records describing the application of ML tools or algorithms in
integrating omics datasets (e.g., metabolomics, microbiomics) and predicting disease
outcomes or therapeutic responses were included. Specific ML approaches, such
as supervised learning algorithms (e.g., random forests, support vector machines)
or unsupervised clustering methods, were highlighted for their contributions to
advancing precision dermatology.
The literature search was performed independently by two authors to ensure objec-
tivity and thoroughness. Any inconsistencies in study selection or data extraction were
resolved by consensus with a third author. Articles were initially screened based on their
titles and abstracts to assess relevance, followed by full-text reviews for those meeting the
inclusion criteria. Additional relevant studies were identified through manual reviews of
reference lists from selected articles. The findings were synthesized to present an integrated
and up-to-date perspective on the bidirectional interactions between metabolic disorders,
skin microbiota, and dermatologic health, along with therapeutic and computational ad-
vancements in the field.

3. Metabolic Disorders Overview

Metabolic disorders, including T2DM, obesity, and MetS, are characterized by intricate
interactions among genetic predispositions, environmental exposures, and lifestyle habits.
These conditions disrupt normal metabolic and immune processes, resulting in systemic
effects that extend to various tissues, including the skin. There is significant overlap among
specific skin diseases and metabolic disorders:
■ The prevalence of MetS is estimated to range between 20% and 50% among individuals
with psoriasis, with higher rates observed in those with more severe forms of the
disease [12].
■ The prevalence of MetS in patients with lichen planus (LP) varies in published studies,
ranging from 6% to 77% [13].
■ A cross-sectional study involving 116,816 patients with AD and 116,812 control par-
ticipants revealed that moderate and severe AD were linked to significantly higher
prevalence rates of MetS (17.0% vs. 9.4%) and its individual components, including
obesity (22.2% vs. 18.6%), diabetes (15.9% vs. 9.2%), hypertension (27.9% vs. 15.3%),
and dyslipidemia (47.1% vs. 28.5%) (all p < 0.001) [14].
■ The literature indicates that patients with hidradenitis suppurativa (HS) have an
estimated odds ratio (OR) of 2.66 (95% CI: 1.90–3.72) for developing MetS [15].
■ A small study found that MetS was present in 35.2% of patients with seborrheic
dermatitis (SD) compared to 10.6% of the control group [16]. However, another small
Microorganisms 2025, 13, 161 4 of 32

study observed that only high-density lipoprotein cholesterol (HDL-C) levels were
significantly lower in the patient group compared to the control group [17].
■ According to a recent meta-analysis, MetS has been strongly associated with specific
skin diseases, including HS (OR: 4.46), LP (OR: 3.79), and SD (OR: 2.45). Psoriasis
also showed a significant correlation with MetS, although with high heterogeneity
(OR: 2.89). In contrast, rosacea exhibited a weaker association with MetS, with an
odds ratio (OR) of 1.56 (95% CI: 0.96–2.52). Nonetheless, a significant relationship was
observed between rosacea and high blood pressure (OR: 1.204, 95% CI: 1.09–1.33) as
well as insulin resistance (OR: 2.33, 95% CI: 1.18–4.60) [18].
A closer look at their molecular mechanisms reveals how these disorders drive chronic
inflammation and metabolic dysfunction.

3.1. T2DM
■ Core Mechanisms of T2DM [19,20]:
o Progressive insulin resistance and declining insulin secretion are hallmarks.
o Insulin resistance originates from defects in insulin receptor signaling, particu-
larly at the level of insulin receptor substrate-1 (IRS-1).
o Impaired IRS-1 phosphorylation disrupts interaction with phosphoinositide
3-kinase (PI3K), a critical enzyme for glucose uptake.
o Dysfunctional PI3K prevents activation of Akt (protein kinase B), inhibiting
GLUT4 translocation to the cell membrane and reducing glucose uptake in
skeletal muscle and adipocytes.
■ Role of Hyperglycemia and Glucotoxicity [19,20]:
o Chronic hyperglycemia exacerbates insulin resistance through glucotoxicity.
o High glucose levels increase the mitochondrial production of reactive oxygen
species (ROS), which damage IRS proteins and β-cells, further impairing
insulin sensitivity and secretion.
■ Systemic Metabolic Inflammation in T2DM (meta-inflammation) [19,20]:
o Mediated by pro-inflammatory cytokines largely produced by dysfunctional
adipose tissue, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6
(IL-6).
o TNF-α induces serine phosphorylation of IRS-1, impairing insulin receptor
signaling.
o IL-6 disrupts insulin sensitivity via the janus kinase/signal transducers and
activators of transcription (JAK/STAT) pathways.
■ Advanced Glycation End Products (AGEs) and RAGE Pathway [19–22]:
o Prolonged hyperglycemia in metabolic disorders leads to the non-enzymatic
glycation of proteins and lipids, forming AGEs.
o These molecules engage RAGE, a receptor expressed on immune and endothe-
lial cells, triggering several downstream effects.
o AGE-RAGE interactions stimulate the production of ROS through nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase, amplifying oxidative stress.
o The resulting activation of NF-κB promotes the transcription of pro-inflammatory
cytokines, such as TNF-α and IL-1β, and vascular adhesion molecules, facili-
tating leukocyte recruitment and chronic inflammation.
o In the skin, AGEs have profound effects on structure and function. They
cross-link collagen and elastin fibers in the extracellular matrix, reducing skin
elasticity and barrier integrity.
Microorganisms 2025, 13, 161 5 of 32

o AGEs also impair keratinocyte differentiation and antimicrobial peptide (AMP)

production, leaving the skin more susceptible to infections.
o This cascade is particularly pronounced in individuals with T2DM, where AGE
accumulation is linked to complications such as poor wound healing, chronic
ulcers, and heightened susceptibility to microbial infections.

3.2. Obesity
■ Core Characteristics [23–25]:
o Obesity is characterized by excessive and dysfunctional adipose tissue accu-
mulation, which acts as an active endocrine organ.
o Adipose tissue secretes hormones, cytokines, and adipokines that regulate
metabolism and immune responses.
■ Inflammatory Response [23–25]:
o Adipose tissue expansion leads to hypoxia, triggering macrophage infiltration.
o Infiltrating macrophages adopt a pro-inflammatory M1 phenotype, releasing
cytokines such as TNF-α, IL-1β, and IL-6.
■ Adipokine Dysregulation [23–25]:
o Dysregulated secretion of adipokines, including elevated leptin and resistin,
contributes to inflammation and metabolic dysfunction.
o Leptin: Promotes inflammation via activation of the JAK/STAT signaling
pathway.
o Resistin: Exacerbates insulin resistance by interacting with Toll-like receptor-4
(TLR-4).
■ Lipid Metabolism Dysregulation [23–25]:
o Excess circulating free fatty acids activate protein kinase C (PKC), impairing
insulin receptor signaling and exacerbating systemic insulin resistance.
o Lipotoxicity damages pancreatic β-cells and hepatocytes, further compound-
ing metabolic dysfunction.
■ Chronic Low-Grade Inflammation (Meta-Inflammation) [23–25]:
o A systemic inflammatory state driven by dysregulated adipokines and cytokines.
o This inflammatory milieu affects multiple organs and promotes insulin resis-
tance and obesity-related complications.

3.3. Metabolic Syndrome

■ Overview [26,27]:
o MetS comprises central obesity, hypertension, dyslipidemia, and insulin resistance.
o These interrelated conditions collectively increase the risk of cardiovascular
diseases, T2DM, and systemic complications.
■ Visceral Adiposity [26,27]:
o Central to MetS is visceral adiposity, with fat accumulation around abdominal
organs.
o This fat depot acts as an endocrine organ, secreting the following:
- Elevated levels of pro-inflammatory adipokines, such as leptin, resistin,
and visfatin.
- Reduced levels of anti-inflammatory adiponectin.
o This imbalance induces chronic low-grade inflammation (meta-inflammation),
driving systemic immune activation and exacerbating metabolic dysfunction.
Microorganisms 2025, 13, 161 6 of 32

■ Pro-Inflammatory Signaling Pathways [26,27]:

o Pro-inflammatory adipokines and cytokines, including TNF-α and IL-6, acti-
vate key signaling pathways: NF-κB and JAK/STAT.
o These pathways disrupt insulin signaling, alter macrophage polarization,
and impair endothelial function, creating a feedback loop that perpetuates
metabolic and cardiovascular risks.
■ Dyslipidemia [26,27]:
o Features include elevated triglycerides, HDL, and small dense low-density
lipoprotein (LDL) particles.
o Consequences of lipid imbalance:
- Oxidized LDL infiltrates vascular walls, triggering macrophage recruit-
ment and foam cell formation, key events in atherogenesis.
- Reduced HDL-C impairs reverse cholesterol transport, limiting the re-
moval of cholesterol from atherosclerotic plaques.
■ Hypertension and Vascular Dysfunction [26,27]:
o Hypertension exacerbates risks by reducing nitric oxide (NO) bioavailability,
driven by oxidative stress and impaired endothelial NO synthase activity.
o Outcomes include vasoconstriction, endothelial activation, vascular remodel-
ing, arterial stiffness, and hypertension.
■ Combined Impact: These interconnected conditions create a highly atherogenic and
pro-inflammatory environment, predisposing individuals to complications such as
coronary artery disease, stroke, heart failure with preserved ejection fraction, chronic
kidney disease, and metabolic dysfunction-associated steatotic liver disease [25,26].

4. Skin Microbiota: A Key Mediator of Cutaneous Health

The skin microbiota represents a complex and dynamic community of microorganisms,
including bacteria, fungi, viruses, and mites, which inhabit the diverse ecological niches of
the skin. These microorganisms are not randomly distributed but are shaped by variations
in the skin’s biophysical properties, such as pH, moisture levels, lipid content, and exposure
to environmental factors. Sebaceous areas, for example, are rich in lipids and promote
the growth of lipophilic organisms like C. acnes, which metabolizes sebum triglycerides
into free fatty acids. Moist areas, such as the axillae, host Corynebacterium species, while
dry regions predominantly harbor S. epidermidis and other resilient bacteria. Fungi, such
as species from the genus Malassezia, are also common in sebaceous areas, while other
microbial communities vary across different body sites and skin types [4].
The skin microbiota plays an essential role in maintaining skin homeostasis and
preventing disease. Commensal microorganisms interact with the host to perform crit-
ical functions, such as fortifying the skin barrier, modulating immune responses, and
outcompeting potential pathogens. For instance, S. epidermidis produces AMPs, such
as phenol-soluble modulins, which inhibit the colonization of pathogenic bacteria like
Staphylococcus aureus. Similarly, C. acnes can regulate the skin’s pH by hydrolyzing sebum
triglycerides, contributing to an acidic environment unfavorable to pathogens. Beyond
these chemical defenses, commensals also influence physical barrier integrity by promoting
keratinocyte differentiation and lipid production, essential for the formation of the stratum
corneum [28].
The interaction between the skin microbiota and the host immune system is another
critical component of skin health. Commensals engage with host pattern recognition re-
ceptors (PRRs), such as TLRs and nucleotide-binding oligomerization domain (NOD)-like
receptors, to modulate immune responses. These interactions ensure a balance between
Microorganisms 2025, 13, 161 7 of 32

immune tolerance to commensals and activation against invading pathogens. For exam-
ple, S. epidermidis can activate TLR2 on keratinocytes to induce AMP production while
also promoting regulatory T-cell (Treg) activity, which prevents excessive inflammation.
These immune-regulating functions of the microbiota are crucial for maintaining a bal-
anced immune tone in the skin, reducing the likelihood of inflammatory and autoimmune
conditions [29].
Disruptions in the skin microbiota, known as dysbiosis, are implicated in a range
of skin diseases. Dysbiosis can arise from factors such as antibiotic use, harsh skincare
products, genetic predispositions, or underlying immune dysfunction. In inflammatory
conditions like AD, dysbiosis is mostly characterized by an overgrowth of S. aureus, which
exacerbates inflammation and disrupts the epidermal barrier. Psoriasis is another condition
linked to dysbiosis, characterized by additional shifts in the microbial composition that
may amplify T-helper (Th)17-mediated inflammatory responses. Specifically, in psoriasis,
there is an increase in S. aureus and S. pyogenes in plaques. Furthermore, psoriasis shows
a reduced presence of commensal bacteria such as Cutibacterium and Corynebacterium.
Similarly, acne vulgaris is associated with changes in the abundance and activity of C. acnes,
where certain strains may overproduce pro-inflammatory lipids and contribute to follicular
inflammation [30].
Fungal and viral components of the microbiota also play significant roles in skin health
and disease. Malassezia species, while commensal in healthy skin, are associated with
conditions such as SD and pityriasis versicolor when their growth becomes uncontrolled.
Viruses, such as human papillomaviruses and herpesviruses, can remain dormant in the
skin but may become pathogenic under conditions of immunosuppression or barrier
disruption. The interplay between microbial communities, the host immune system, and
external factors defines the balance between health and disease [30].
The composition of the skin microbiota undergoes significant changes with aging,
influenced by shifts in host factors such as sebaceous gland activity, skin lipids, natural
moisturizing factors (NMFs), and antimicrobial peptides (AMPs). A study examining
158 Caucasian females aged 20 to 74 found that bacterial diversity increases with age
across the forearm, buttock, and facial skin. Notably, the abundance of Cutibacterium and
Lactobacillus decreased with age at all sites, correlating with a reduction in sebaceous gland
size and lipid production, which are critical for maintaining these bacteria. Conversely,
genera such as Streptococcus and Anaerococcus showed site-specific increases, likely
driven by shifts in the availability of skin lipids and other host factors. Increased NMFs and
AMPs with age were positively correlated with bacterial genera like Corynebacterium and
Finegoldia, highlighting how host changes influence microbial dynamics. These findings
suggest that age-related alterations in skin biology drive the restructuring of microbial
communities [31].
Race and ethnicity also significantly influence microbiota composition, with differences
emerging as early as three months of age and persisting through childhood and adulthood.
Variability in microbial taxa is linked to inequitable environmental and social factors, rather
than biological differences. For example, specific taxa like Bifidobacterium and Lactobacil-
lus are enriched in racial groups with higher breastfeeding rates, while other differences
correlate with factors such as diet and hygiene. ML models using gut microbiome data from
children have demonstrated an 87% accuracy in predicting caregiver-identified race and
ethnicity, underscoring the role of structural disparities in shaping microbial communities.
These findings emphasize the need for personalized approaches in microbiome research to
address demographic variability and health disparities [32].
An overview of the commensal and pathogenic interactions of bacteria colonizing the
skin and/or being part of the human skin flora is presented in Table 1.
Microorganisms 2025, 13, 161 8 of 32

Table 1. Roles of commensal and pathogenic bacteria in skin barrier modulation.

Barrier Type Commensal Role Pathogen Role References

- S. epidermidis: produces AMPs, - S. pyogenes: produces proteases,
strengthens keratinocyte adhesion. disrupting structural proteins.
Physical Barrier
- Corynebacterium: supports skin integrity - S. aureus: forms biofilms, aiding
by interacting with lipids. invasion.

- Corynebacterium and Cutibacterium:

contribute to sebum metabolism, - S. aureus: reduces AMP production
producing fatty acids with (e.g., β-defensins).
Chemical Barrier
antimicrobial properties. - S. pyogenes: secretes exotoxins,
- Lactobacilli: enhance AMP production amplifying inflammation.
like defensins.

- Bifidobacterium: modulates Tregs,

- S. aureus: secretes superantigens,
promoting immune tolerance. [4,28–32]
driving T-cell activation.
Immune Barrier - Lactobacilli: reduce Th2/Th17-driven
- S. pyogenes: triggers excessive immune
inflammation, balancing immune
responses.
responses.

- Cutibacterium: maintain an acidic

- S. aureus: alters lipid profiles,
environment, modulate lipid
promoting inflammation.
Lipid Barrier metabolism.
- C. acnes (pathogenic strains): produces
- Lactobacilli: stabilize lipid profiles,
porphyrins, triggering inflammation.
supporting barrier function.

- Corynebacterium and Bifidobacterium: - S. pyogenes and S. aureus: create

Microenvironmental regulate pH and microbial balance. oxidative stress, damaging lipids and
Factors - Lactobacilli: maintain a low pH, proteins.
deterring pathogenic growth. - Malassezia: disrupts lipid homeostasis.

5. Interactions Between Metabolic Disorders and the Skin Microbiota

Metabolic disorders, including T2DM and obesity, create a systemic environment of
chronic low-grade inflammation, also known as meta-inflammation. This state profoundly
affects the skin microbiota by altering the biochemical, structural, and immune landscape of
the epidermis. Elevated levels of pro-inflammatory cytokines, such IL-6, TNF-α, and IL-1β,
play pivotal roles in driving these changes. These cytokines, produced by hypertrophic
adipocytes, immune cells, and the liver, directly influence keratinocyte gene expression by
activating intracellular signaling pathways, including the NF-κB- and mitogen-activated
protein kinase (MAPK) cascades [33,34].

5.1. Impact on Keratinocytes and the Epidermal Barrier

Keratinocytes, the primary cell type in the epidermis, rely on tightly regulated pro-
cesses of proliferation, differentiation, and lipid synthesis to maintain the integrity of the
stratum corneum. In metabolic disorders, elevated cytokine levels disrupt these processes
by altering the expression of genes encoding structural proteins such as involucrin, loricrin,
and filaggrin. For example, TNF-α and IL-1β activate the NF-κB pathway, leading to
the suppression of involucrin and loricrin transcription. These proteins are essential for
forming the cornified envelope, a critical component of the skin’s physical barrier. The
reduction in filaggrin levels compromises the production of natural moisturizing factors,
which are derived from filaggrin degradation and include hygroscopic molecules such
as urocanic acid and pyrrolidone carboxylic acid. This depletion of natural moisturizing
factors increases transepidermal water loss and desiccates the epidermis, setting the stage
for microbial invasion [35,36].
Microorganisms 2025, 13, 161 9 of 32

Furthermore, IL-6 signaling through its receptor complex (IL-6R and gp130) activates
the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in
keratinocytes, leading to the expression of pro-inflammatory genes and a shift in AMP pro-
duction. Cathelicidins (e.g., LL-37) and β-defensins, crucial AMPs that maintain microbial
balance, are downregulated, weakening the skin’s chemical defense against pathogens. The
cumulative effect of these changes is a weakened epidermal barrier that is highly permeable
to environmental insults and opportunistic microbes [35,36].
Emerging evidence highlights a critical link between glucose metabolism reprogram-
ming in keratinocytes and the pathogenesis of psoriasis, particularly in the context of
MetS. A recent study by Yan et al. (2024) demonstrated that psoriatic keratinocytes exhibit
enhanced glycolysis, evidenced by elevated levels of glycolysis-related metabolites such
as glucose-6-phosphate, fructose-1,6-bisphosphate, and lactate. In patients with psoriasis
and MetS, glycolysis-related protein expression (e.g., GLUT1, HK2, and PFKFB3) was
significantly upregulated, correlating with disease severity. Importantly, high-glucose
and high-fat culture intensified this metabolic reprogramming through the AKT/mTOR
pathway, exacerbating keratinocyte proliferation and inflammatory cytokine production.
Glycolysis inhibition via agents like 2-deoxyglucose effectively attenuated these pathologi-
cal features, offering potential therapeutic avenues [37].
Cathelicidin, an AMP, plays a dual role in innate immunity and systemic metabolic
regulation. Studies have linked LL-37 to inflammation and insulin resistance in MetS.
Activation of Toll-like receptors (e.g., TLR4) by LL-37 promotes pro-inflammatory cytokine
secretion, disrupting adipocyte insulin signaling and lipid metabolism. Notably, LL-37 lev-
els inversely correlate with HDL cholesterol while positively associating with triglycerides,
highlighting its potential role in atherogenic dyslipidemia. Beyond metabolic regulation,
LL-37 is implicated in psoriasis-related inflammation by modulating keratinocyte immune
responses and promoting cytokine production. These findings underscore LL-37’s role as
both a mediator of systemic inflammation and a biomarker for metabolic and inflammatory
conditions [38].

5.2. RAGE Pathway

AGEs accumulate in individuals with diabetes and obesity due to prolonged hyper-
glycemia and oxidative stress. These molecules irreversibly cross-link proteins such as
collagen and elastin, stiffening the extracellular matrix and impairing the biomechanical
properties of the dermis. AGEs bind to RAGE, a PRR expressed on keratinocytes, endothe-
lial cells, and immune cells. Activation of RAGE triggers the recruitment of intracellular
adapter molecules such as myeloid differentiation primary response 88 (MyD88) and Toll–
interleukin 1 receptor domain-containing adapter protein (TIRAP), initiating downstream
signaling cascades. These cascades involve NF-κB and extracellular signal-regulated ki-
nases (ERK1/2), resulting in the transcription of pro-inflammatory cytokines and matrix
metalloproteinases (MMPs). MMP-9 and MMP-2 degrade the extracellular matrix, further
disrupting the dermal architecture and facilitating microbial infiltration [21,22].
The interaction of AGEs with RAGE also generates ROS via the activation of NADPH
oxidase, leading to oxidative damage of keratinocyte membranes and intracellular or-
ganelles. This oxidative stress reduces mitochondrial function and impairs ATP production,
critical for keratinocyte proliferation and differentiation. Additionally, ROS interact with
lipid peroxidation pathways, generating malondialdehyde and 4-hydroxynonenal, which
further exacerbate cellular damage and impair lipid synthesis. These lipid alterations
directly affect sebum composition and the skin’s ability to sustain commensal micro-
biota [21,22].
Microorganisms 2025, 13, 161 10 of 32

5.3. Alterations in Sebum Composition and Microbial Metabolism

Sebaceous glands, under the regulation of insulin and androgens, secrete a complex
mixture of lipids, including triglycerides, wax esters, cholesterol, and squalene. In metabolic
disorders, insulin resistance alters sebaceous gland function, skewing the lipid profile
toward increased production of saturated fatty acids and decreased levels of unsaturated
fatty acids. These lipid changes directly influence the metabolic activity of the microbiota.
For instance, C. acnes, a dominant commensal in sebaceous-rich areas, relies on triglycerides
and unsaturated fatty acids for its metabolic processes. A reduction in these substrates
hampers the growth of commensal strains, while favoring opportunistic pathogens capable
of metabolizing saturated fatty acids. Pathogenic strains of C. acnes produce porphyrins
and short-chain fatty acids (SCFAs), which trigger the expression of inflammatory cytokines
in keratinocytes via activation of aryl hydrocarbon receptors. This inflammatory feedback
loop exacerbates skin conditions such as acne and folliculitis. Lipase and protease activity
from resident and pathogenic microbes also modulate the stratum corneum’s permeability.
Lipases hydrolyze sebum triglycerides into free fatty acids, which can disrupt tight junctions
between keratinocytes. Proteases degrade corneodesmosomal proteins such as desmoglein-
1 and corneodesmosin, weakening cell–cell adhesion and facilitating microbial penetration
into deeper layers of the epidermis [39,40].

5.4. Immune Dysregulation and Microbial Dynamics

Chronic systemic inflammation associated with metabolic disorders disrupts immune
surveillance in the skin. The trafficking and function of Langerhans cells and dermal
dendritic cells are altered by the inflammatory milieu. TNF-α and IL-6 suppress the
migration of Langerhans cells to draining lymph nodes, reducing their ability to present
antigens to naïve T cells. Instead, these cells remain in the epidermis, where they promote
the activation of effector T cells, particularly Th17 cells. The resultant production of IL-17
and IL-22 drives keratinocyte hyperproliferation and disrupts epidermal differentiation,
creating conditions that favor dysbiosis [41].
These immune shifts also impair the skin’s ability to tolerate commensal microorgan-
isms. For example, S. epidermidis, a commensal that normally promotes immune tolerance
through the production of lipoteichoic acid, becomes less effective in modulating im-
mune responses. The reduced Treg activity and increased Th1/Th17 polarization skew
the immune environment toward an inflammatory state, further destabilizing microbial
communities [41].
In inflammatory skin diseases, cytokines such as TNF-α and IL-6 play a dual role in in-
fluencing skin microbiota dynamics and being modulated by microbial shifts. For instance,
in psoriasis, TNF-α and IL-6 are significantly upregulated, leading to enhanced keratinocyte
proliferation and immune cell infiltration. These cytokines create an inflammatory milieu
that disrupts microbial homeostasis, favoring pathogenic taxa like Staphylococcus aureus
and Streptococcus pyogenes. Conversely, microbial dysbiosis exacerbates cytokine produc-
tion. S. aureus releases superantigens like SEB, which activate dendritic cells to produce
IL-12 and IL-23, further amplifying Th17-mediated cytokine cascades, including IL-17 and
IL-22. These interactions exemplify a self-reinforcing loop where cytokine-driven inflamma-
tion alters microbial communities, and microbial products sustain and intensify cytokine
responses, perpetuating chronic skin inflammation. Such findings highlight the importance
of targeting both microbiota and cytokine pathways for therapeutic interventions [42].

5.5. Microvascular Impairment and Hypoxia

Microvascular complications, a hallmark of diabetes, significantly impact skin home-
ostasis. Hyperglycemia-induced endothelial dysfunction reduces nitric oxide (NO) bioavail-
Microorganisms 2025, 13, 161 11 of 32

ability, impairing vasodilation and capillary perfusion. The resultant hypoxic conditions
activate hypoxia-inducible factor 1-alpha (HIF-1α) in keratinocytes and sebocytes, alter-
ing their metabolic activity. HIF-1α upregulates glycolytic enzymes, shifting cellular
metabolism toward anaerobic glycolysis. This metabolic shift reduces ATP availability and
affects keratinocyte turnover, creating niches that favor anaerobic or facultative anaerobic
microbes such as C. acnes and Pseudomonas aeruginosa. Reduced perfusion also delays the
clearance of metabolic byproducts and toxins, further modifying the microbial habitat [43].
Sweat gland dysfunction, commonly observed in diabetic neuropathy, exacerbates
these issues. Reduced sweat secretion alters ionic gradients and skin hydration, favor-
ing the colonization of halophilic and xerophilic species such as S. aureus and certain
fungi. Neural inputs that regulate microvascular tone and glandular activity are also
disrupted, creating patchy areas of skin with distinct microbial communities. Over time,
these microenvironmental disparities increase the risk of localized infections and biofilm
formation [43].

6. Psoriasis
Psoriasis is a chronic immune-mediated skin condition characterized by erythematous,
scaly plaques resulting from excessive keratinocyte proliferation and incomplete differen-
tiation. At the core of its pathogenesis lies the IL-23/IL-17 axis, driven by Th17 cells and
their cytokines, which create a pro-inflammatory environment. Recent evidence highlights
how metabolic disorders, such as obesity and MetS, and disruptions in the skin microbiome
interact to amplify the inflammatory pathways underlying psoriasis, forming a vicious
cycle of immune activation and microbial dysbiosis [44].
Dendritic cells play a critical role in psoriasis by responding to environmental trig-
gers, microbial antigens, and damage-associated molecular patterns like DNA and LL-37
complexes. These cells release IL-23, which is essential for maintaining Th17 cells. Th17
cells secrete IL-17A, IL-17F, and IL-22, which promote keratinocyte hyperproliferation and
inhibit proper differentiation. These cytokines synergistically upregulate AMPs such as
β-defensins and S100 proteins in keratinocytes, attracting neutrophils and intensifying
inflammation. This process becomes exacerbated in the presence of MetS, as hypertrophic
adipocytes and infiltrating macrophages secrete high levels of pro-inflammatory cytokines,
including TNF-α, IL-6, and IL-1β. These cytokines activate NF-κB signaling in keratinocytes
and immune cells, heightening inflammatory responses. Elevated leptin in obesity pro-
motes Th17 cell polarization, while decreased adiponectin removes an anti-inflammatory
control, further fueling psoriatic inflammation [45].
The microbiome in psoriasis is characterized by dysbiosis, marked by reduced mi-
crobial diversity and a shift toward pathogenic species. In psoriatic lesions, S. aureus and
Streptococcus pyogenes are overrepresented and can act as superantigens, stimulating T-cell
activation. Conversely, commensal bacteria like Cutibacterium and Corynebacterium are
diminished, leading to weakened immune regulation. Dysbiosis amplifies inflammation
through PRRs on keratinocytes, including TLRs (TLR2, TLR4) and NOD-like receptors, cre-
ating a feedback loop that sustains inflammation and further disrupts the microbiome [46].
Psoriatic plaques also exhibit altered lipid composition, including reduced ceramides,
elevated free fatty acids, and increased cholesterol sulfate. These changes compromise the
stratum corneum’s barrier integrity, increasing transepidermal water loss and exposing
underlying layers to microbial invasion. S. aureus exacerbates this disruption by producing
enterotoxins that activate IL-23 and IL-17 pathways, intensifying keratinocyte activation
and neutrophilic infiltration.
Recent studies emphasize the role of lipid metabolism dysregulation in psoriasis and
its potential therapeutic implications. For instance, a meta-analysis demonstrated signifi-
Microorganisms 2025, 13, 161 12 of 32

cantly higher levels of total cholesterol, LDL, and triglycerides, with a marked reduction in
HDL in psoriasis patients compared to controls (p < 0.05). These changes compromise the
stratum corneum’s barrier integrity, increasing transepidermal water loss and exposing
underlying layers to microbial invasion. Aberrant lipid profiles were further associated
with elevated serum IL-6, which positively correlated with the LDL/HDL ratio (r = 0.48,
p < 0.01). Dysregulated lipid metabolism contributes to microbial dysbiosis, where lipid-
rich psoriatic plaques foster pathogenic taxa such as Staphylococcus aureus while depleting
beneficial commensals of Cutibacterium. S. aureus exacerbates the epidermal barrier dis-
ruption by producing enterotoxins that activate IL-23 and IL-17 pathways, intensifying
keratinocyte activation and neutrophilic infiltration. Fungal dysbiosis, particularly with
Malassezia species, further contributes to psoriasis by degrading sebaceous lipids into
free fatty acids, which irritate keratinocytes and drive dendritic cell and Th17 activation,
especially in sebaceous-rich areas like the scalp [47,48].
Metabolic disorders amplify these processes through systemic effects. In obesity and
T2DM, AGEs accumulate in the skin, binding to RAGE receptors on keratinocytes and
endothelial cells. This activates MAPK and NF-κB pathways, triggering the production of
cytokines, chemokines, and adhesion molecules that perpetuate inflammation. AGEs also
impair dermal elasticity and microvascular function by cross-linking collagen and elastin,
reducing oxygen and nutrient delivery to psoriatic plaques. Hypoxia in plaques stabilizes
HIF-1α, which further drives keratinocyte hyperproliferation and AMP expression [49].
Dysregulated lipid metabolism in MetS compounds the problem. Elevated circulating
LDL and triglycerides infiltrate the dermis, where they oxidize and activate macrophages
via scavenger receptors such as CD36. This enhances the production of TNF-α and IL-
1β, creating a pro-inflammatory environment. Simultaneously, reduced ceramides in
psoriatic lesions impair epidermal lipid organization, weakening the skin’s ability to
prevent microbial colonization and promoting dysbiosis [50].
Therapeutic strategies targeting metabolic dysfunction have shown promise. Weight
loss through dietary interventions or bariatric surgery reduces systemic inflammation,
normalizes adipokine levels, and improves insulin sensitivity, thereby mitigating psori-
atic inflammation. Pharmacologic agents like glucagon-like peptide-1 receptor agonists
(GLP-1RAs) might improve psoriasis severity by addressing metabolic abnormalities and
meta-inflammation [51]. Experimental interventions targeting lipid metabolism, such as
fibrates and PPARγ agonists, demonstrated modest improvements in skin inflammation by
restoring microbial equilibrium. These findings suggest that managing lipid dysregulation
through microbiota-friendly dietary modifications or lipid-lowering agents could offer a
dual benefit in controlling systemic and localized inflammation [47,48].
Microbiome-targeted therapies are emerging as adjunctive treatments for psoriasis.
Topical or systemic probiotics that enhance commensal bacteria like Corynebacterium and
Cutibacterium are under investigation. For instance, lactobacilli have shown immunomodu-
latory effects by promoting regulatory Treg activity and suppressing Th17-driven inflam-
mation. Postbiotics are bioactive compounds produced during the fermentation process
by probiotic microorganisms. They include metabolic byproducts such as short-chain
fatty acids (SCFAs), bacteriocins, enzymes, vitamins, and other molecules that exert health
benefits. Unlike live probiotics, postbiotics are non-living and are considered safer for
use in certain populations. They play a role in modulating the microbiome, inhibiting
pathogenic microbes, and enhancing host physiological functions, including skin barrier
restoration [52].
An emerging area of interest in psoriasis management involves harnessing bacterio-
phages (phages) to selectively reduce pathogenic bacteria and rebalance the skin micro-
biome. Recent studies suggest that supplementing lesional skin with phages that target
Microorganisms 2025, 13, 161 13 of 32

species like S. aureus or Pseudomonas aeruginosa—microbes frequently implicated in psori-

atic dysbiosis—can help decrease inflammation and restore microbial diversity. Practical
strategies include topically applied phage cocktails, which may be formulated as creams,
ointments, or gels for direct application to psoriatic plaques, as well as oral phage prepara-
tions aimed at modulating both the gut and skin microbiota. In preliminary ex vivo and
murine models of skin infection, phages effectively reduced bacterial load and lowered
levels of pro-inflammatory cytokines, indicating their potential utility in psoriasis. Early
anecdotal reports of phage-rich water ingestion (e.g., Ganga river water) have also shown
promise in improving psoriasis symptoms for some individuals, although well-designed
clinical trials are needed to establish optimal phage combinations, dosing regimens, and
delivery methods. If validated, phage therapy could offer a targeted, microbiome-focused
adjunct to existing anti-inflammatory and immunomodulatory treatments, potentially
improving outcomes in patients who do not respond well to current therapies [53].
These findings highlight the intricate connections between metabolic disorders, the mi-
crobiome, and psoriasis, providing new opportunities for integrated treatment approaches
that target both systemic and local factors.

7. Atopic Dermatitis
AD is a chronic inflammatory skin condition defined by intense itching, eczematous
lesions, and impaired epidermal barrier function. Its pathogenesis hinges on mutations
in structural proteins like filaggrin and dysregulated Th2 immune responses. Metabolic
disorders such as obesity and T2DM exacerbate AD by amplifying systemic inflammation,
altering lipid metabolism, and fostering microbial dysbiosis. Together, these factors perpet-
uate the cycle of barrier dysfunction, immune activation, and microbial imbalance central
to AD pathology [54].
The epidermal barrier serves as a critical defense against transepidermal water loss,
environmental allergens, and microbial invasion. Filaggrin, a key barrier protein, is crucial
for forming the cornified envelope and generating natural moisturizing factors such as
urocanic acid and pyrrolidone carboxylic acid, which maintain an acidic skin pH. Mutations
in the filaggrin gene, commonly seen in AD, reduce natural moisturizing factor produc-
tion, impair barrier integrity, and facilitate allergen and microbial penetration, initiating
inflammation. Metabolic disorders exacerbate this barrier dysfunction by promoting the
accumulation of AGEs. These molecules cross-link keratinocyte and extracellular matrix
proteins, stiffening the epidermis and activating RAGE on keratinocytes. RAGE signaling
induces NF-κB activation, increasing the production of pro-inflammatory cytokines such as
IL-1β, TNF-α, and IL-6, which further impair keratinocyte differentiation and reduce the
expression of filaggrin, involucrin, and loricrin [35,36,54].
Th2-driven inflammation dominates AD’s immune landscape, with cytokines like IL-4,
IL-5, and IL-13 impairing keratinocyte differentiation and suppressing AMP production.
IL-4 and IL-13 further reduce filaggrin expression and promote IgE-mediated allergic
sensitization. Chronic inflammation can shift to mixed Th2/Th22 or Th1/Th17 responses,
especially in severe or chronic lesions. Metabolic inflammation amplifies these immune
dysregulations, with adipokines like leptin promoting Th2 polarization and IL-4/IL-13
production. Simultaneously, adiponectin, an anti-inflammatory adipokine, is reduced in
obesity and T2DM, removing a regulatory brake on Th2 activity. This dual effect intensifies
AD’s chronic inflammatory state [55].
AD is strongly associated with microbial dysbiosis, characterized by overgrowth of
S. aureus and diminished diversity of commensal microbes. S. aureus plays a direct role in
inflammation by producing virulence factors, including superantigens like staphylococcal
enterotoxins that activate T cells and amplify Th2 and Th17 responses. Additionally, S. au-
Microorganisms 2025, 13, 161 14 of 32

reus secretes proteases, such as V8 protease, which degrade filaggrin and further weaken the
epidermal barrier. Its ability to form biofilms enhances resistance to antimicrobial defenses
and contributes to persistent inflammation. Hyperglycemia and altered lipid metabolism
in metabolic disorders exacerbate S. aureus colonization by providing an environment rich
in nutrients and substrates, including glucose and free fatty acids. Dysregulated AMP
production in AD further weakens microbial control, allowing S. aureus to dominate and
outcompete commensals [56].
Lipid composition in the stratum corneum is critical for maintaining barrier integrity
and microbial balance. Ceramides, cholesterol, and free fatty acids are organized into lamel-
lar structures that prevent TEWL and microbial penetration. Systemic lipid abnormalities
in AD, such as increased LDL cholesterol and altered HDL composition, correlate with
disease severity and systemic inflammation, as measured by SCORAD scores (r = 0.64,
p < 0.001). Notably, ceramide abnormalities in the stratum corneum impair the lipid barrier,
predisposing the skin to colonization by Staphylococcus aureus and contributing to chronic
inflammation. Furthermore, metabolic disorders exacerbate cutaneous lipid abnormalities
by influencing sebaceous gland activity and epidermal lipid synthesis. For instance, insulin
resistance increases the ratio of saturated to unsaturated fatty acids, favoring colonization
by pro-inflammatory microbes like S. aureus over commensal species such as C. acnes. S.
aureus lipases further degrade lipids into irritant free fatty acids, aggravating keratinocyte
dysfunction and inflammation [57].
Clinically, patients with AD and coexisting metabolic disorders often present with
more severe and widespread lesions. Systemic inflammation, oxidative stress, and dysbiosis
associated with metabolic dysfunction worsen disease activity and reduce responsiveness
to standard treatments like topical corticosteroids and calcineurin inhibitors. However, im-
proved metabolic control can significantly mitigate these effects. Weight loss and glycemic
management reduce systemic inflammation, restore AMP production, and improve barrier
integrity, thereby decreasing S. aureus colonization and inflammation [14].
Emerging microbiome-targeted therapies are gaining attention in AD management.
Probiotics, including lactobacilli and Bifidobacterium species, enhance microbial diversity
and modulate immune responses by increasing Treg activity and reducing Th2 polariza-
tion. Postbiotics, such as SCFAs, strengthen the epidermal barrier and suppress S. aureus
virulence [52].
Recent research demonstrates that bacteriophages can specifically target Staphylococ-
cus aureus—a bacterial species closely linked to AD flares—while preserving beneficial
skin microbes such as S. epidermidis. In a 2020 study investigating a phage called SaGU1,
scientists observed a sharp reduction in S. aureus populations both in vitro and on the skin
of atopic mouse models. Notably, SaGU1 did not harm S. epidermidis, suggesting a targeted
antimicrobial effect. In vitro, S. aureus began re-emerging after 14 h, which may reflect the
development of phage resistance; however, adding S. epidermidis alongside SaGU1 pre-
vented this bacterial rebound, highlighting a potential synergy between beneficial skin flora
and phage therapy. Interestingly, in vivo experiments demonstrated that phage therapy
alone was effective enough to suppress S. aureus overgrowth, with no statistically significant
additional benefit observed when S. epidermidis was combined with SaGU1. These findings
underscore the promise of phage-based treatments in AD, particularly those designed to
selectively eliminate pathogenic staphylococci while leaving commensals intact. Future
research will clarify the best formulations, dosing strategies, and adjunctive options—such
as pairing phages with topical probiotics or supportive skincare regimens—to enhance
barrier function and achieve longer-lasting disease control in AD [53].
When combined with metabolic interventions, these approaches offer a holistic strat-
egy for managing AD, addressing both its systemic and localized drivers. This dual
Microorganisms 2025, 13, 161 15 of 32

focus could lead to more effective, long-term control of AD in patients with metabolic
dysfunctions [58].

8. Acne
Acne vulgaris is a multifactorial inflammatory condition that primarily affects the
pilosebaceous unit. It is clinically characterized by comedones, inflammatory papules, pus-
tules, and nodules. Its pathogenesis is driven by hyperseborrhea, follicular hyperkeratiniza-
tion, microbial dysbiosis—particularly involving C. acnes—and inflammation. Metabolic
disorders, such as obesity and insulin resistance, exacerbate acne through systemic and lo-
calized mechanisms, including altered sebaceous gland activity, lipid composition changes,
immune dysregulation, and microbial shifts, fostering an environment conducive to acne
development [59].
Emerging evidence highlights a significant relationship between insulin resistance and acne
vulgaris. In a study by Gruszczyńska et al., involving 41 acne vulgaris patients and 47 healthy
BMI-matched controls, insulin resistance was assessed using the homeostasis model assessment
of insulin resistance (HOMA-IR). The mean HOMA-IR value was significantly higher in the
acne group (3.40 ± 1.49) compared to controls (2.34 ± 0.91, p < 0.001). Furthermore, 78% of
acne patients met the criteria for insulin resistance (HOMA-IR > 2.1), versus 55% in the control
group (p = 0.026). When the cut-off value was adjusted to 2.69 (as per the Polish population
standard), 63% of acne patients and 30% of controls were diagnosed with insulin resistance,
further emphasizing the association (p = 0.002). Elevated fasting glucose levels were also observed
in the acne group (94.88 ± 7.73 mg/dL) compared to controls (79.51 ± 7.18 mg/dL, p < 0.001).
These findings suggest that insulin resistance may be an independent factor in acne pathogenesis,
warranting consideration during diagnosis and treatment [60].
Elevated insulin levels increase the secretion of insulin-like growth factor-1 (IGF-1),
which directly enhances sebaceous gland activity. IGF-1 activates the phosphoinositide
3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) pathways,
driving sebocyte proliferation and increasing sebum lipid synthesis. The overproduc-
tion of sebum provides a nutrient-rich substrate for C. acnes, promoting its colonization
and metabolic activity. Moreover, IGF-1 suppresses the nuclear receptor peroxisome
proliferator-activated receptor gamma (PPAR-γ), disrupting sebocyte differentiation and
lipid homeostasis, which further contributes to sebaceous gland dysfunction [60,61].
Additionally, obesity and insulin resistance compound acne-related inflammation
through the secretion of pro-inflammatory adipokines like leptin, which promotes Th1 and
Th17 polarization and increases cytokines such as interferon-gamma (IFN-γ), IL-17, and
IL-22. These cytokines drive keratinocyte hyperproliferation and sebaceous gland dysfunc-
tion. Simultaneously, reduced adiponectin removes a critical anti-inflammatory mediator,
exacerbating immune activation. Hyperglycemia further promotes the accumulation of
AGEs, which bind to RAGE on keratinocytes and immune cells, activating NF-κB and
MAPK pathways and amplifying the inflammatory milieu [60,61].
The composition of sebaceous lipids undergoes significant changes in metabolic disor-
ders. Insulin resistance shifts the balance toward a higher ratio of saturated to unsaturated
fatty acids, which have pro-inflammatory properties. Saturated fatty acids stimulate ker-
atinocytes via TLR2, promoting cytokine production, including IL-1β and IL-8. These
cytokines recruit neutrophils and drive inflammation. Concurrently, oxidative stress associ-
ated with hyperglycemia generates lipid peroxidation products, such as malondialdehyde,
which disrupt sebaceous lipid profiles, exacerbating inflammation [60,61].
Polycystic ovary syndrome (PCOS), a common metabolic–endocrine disorder, is in-
tricately linked to acne through hyperandrogenism and insulin resistance. Elevated an-
drogens, such as testosterone and dihydrotestosterone, stimulate sebaceous gland hyper-
Microorganisms 2025, 13, 161 16 of 32

trophy and sebum overproduction. Hyperinsulinemia in PCOS amplifies these effects by

suppressing sex hormone-binding globulin, increasing the bioavailability of androgens.
Sebum in PCOS-associated acne is enriched in squalene and saturated fatty acids, which
serve as substrates for C. acnes metabolism. These substrates promote the production of
pro-inflammatory metabolites, including porphyrins and short-chain fatty acids, which
activate the NLRP3 inflammasome in macrophages and keratinocytes. This inflamma-
some activation triggers the release of IL-1β and IL-18, contributing to the development of
inflammatory lesions [62].
Microbial dysbiosis, particularly involving C. acnes, plays a pivotal role in acne patho-
genesis. As an anaerobic commensal, C. acnes thrives in the lipid-rich environment of
sebaceous follicles. It metabolizes triglycerides into free fatty acids through lipase activ-
ity, disrupting keratinocyte differentiation and increasing follicular permeability. Certain
strains of C. acnes are highly pro-inflammatory, producing porphyrins that generate ROS
and activate the NLRP3 inflammasome, leading to neutrophilic infiltration and the for-
mation of pustules and nodules. Metabolic disorders worsen this dysbiosis by altering
sebaceous lipid composition and increasing follicular pH, favoring the dominance of
pathogenic C. acnes strains. These strains form biofilms, which protect them from AMPs
like cathelicidins and defensins, enhancing their resistance to treatments and sustaining
chronic inflammation [39].
Sebaceous lipids are not only a nutrient source for C. acnes but also modulate the
immune response. Free fatty acids such as palmitic and lauric acids activate TLR2 and
TLR4 on keratinocytes and immune cells, inducing cytokine production, including IL-
8, TNF-α, and IL-6. These cytokines recruit neutrophils and monocytes to the follicle,
amplifying inflammation. Lipid peroxidation products like malondialdehyde generated
under oxidative stress further enhance inflammatory cascades. Additionally, C. acnes
utilizes quorum sensing to regulate biofilm formation and virulence factor expression, such as
lipases, proteases, and hyaluronidases. These enzymes degrade the extracellular matrix and
follicular walls, allowing bacterial invasion and perpetuating tissue inflammation [57,63].
Clinically, patients with acne and concurrent metabolic disorders present with more
severe and persistent lesions, including nodulocystic acne. These patients are often less
responsive to standard therapies, such as retinoids and antibiotics, due to underlying
metabolic and microbial dysregulation. Addressing the metabolic contributions to acne
is therefore critical. Metformin, a cornerstone treatment for insulin resistance, has shown
promise in acne management by reducing mTORC1 signaling, mitigating oxidative stress,
and normalizing sebaceous gland activity. Lifestyle interventions like weight loss have
been associated with reductions in systemic inflammation and acne severity [64–66].
Microbiome-based therapies are emerging as adjunctive treatments for acne. Probi-
otics are particularly valuable in modulating the immune system and restoring microbial
equilibrium. Species such as Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, and
Bifidobacterium breve have shown potential in enhancing regulatory T-cell (Treg) activity,
which is essential for maintaining immune tolerance and reducing the hyper-inflammatory
responses typical of acne. These probiotics work by suppressing pro-inflammatory cy-
tokines such as IL-17 and IL-22, which are associated with Th17-driven immune responses,
while simultaneously promoting anti-inflammatory cytokines like IL-10. This dual action
helps to mitigate the inflammation and hyperkeratinization observed in acne [52,67].
Postbiotics, including short-chain fatty acids (SCFAs) like acetate, propionate, and
butyrate, produced by probiotic fermentation, have been shown to exert anti-inflammatory
and antimicrobial effects. For instance, SCFAs can inhibit C. acnes virulence factors by
disrupting its biofilm formation—a critical mechanism that protects the bacteria from host
defenses and treatments. Biofilms are known to foster a chronic inflammatory environment
Microorganisms 2025, 13, 161 17 of 32

by promoting the persistence of pathogenic C. acnes strains, making their disruption a key
target for acne therapy. In addition, SCFAs modulate keratinocyte differentiation and lipid
metabolism, contributing to a healthier skin barrier and reducing the sebum production
that fuels C. acnes growth [52,67].
Bacteriocins, another class of postbiotics, are antimicrobial peptides produced by
probiotics that specifically target pathogenic bacteria without affecting commensal popu-
lations. For instance, bacteriocins like nisin and pediocin have demonstrated the ability
to selectively inhibit C. acnes proliferation. They achieve this by permeabilizing bacterial
membranes or interfering with cell wall synthesis, offering a highly targeted approach to
microbial regulation [67].
Furthermore, emerging research suggests that probiotics and postbiotics can alter the
skin’s pH and lipid composition, creating an environment less conducive to pathogenic bac-
terial colonization. By promoting the growth of beneficial commensals such as Staphylococ-
cus epidermidis, these interventions not only counteract the dominance of acne-associated
C. acnes strains but also restore microbial diversity—a hallmark of healthy skin. Preclinical
studies have shown that S. epidermidis can antagonize C. acnes through the production of
antimicrobial peptides, further emphasizing the synergistic role of commensal bacteria in
acne management [67].
In addition to their direct effects on the microbiome, probiotics and postbiotics have
systemic benefits. Oral administration of probiotics has been linked to reduced systemic
inflammation and oxidative stress, factors that exacerbate acne severity. These benefits
extend to the regulation of metabolic pathways, including insulin sensitivity and lipid
metabolism, which are often dysregulated in individuals with acne [67].
Bacteriophage-based treatments for acne aim to selectively eliminate C. acnes without
disturbing the broader skin microbiome. Recent murine experiments have shown that
injecting bacteriophages targeting C. acnes can reduce inflammatory nodules and epidermal
thickening in mice, supporting the therapeutic potential of phages as an alternative or
complement to antibiotics—especially given growing antibiotic resistance. Topical formu-
lations containing C. acnes-lytic phages have also been investigated: semi-solid creams
and hydrogels maintained significant phage viability for weeks to months under proper
storage conditions (e.g., refrigeration and limited light exposure). Preliminary human trials
with topical phage cocktails have demonstrated a dose-dependent reduction in C. acnes
colonization, suggesting that optimized phage concentrations could be key to improving
clinical outcomes. Future research will need to explore long-term efficacy, ideal phage com-
binations, and potential synergy with established acne therapies such as topical retinoids
or benzoyl peroxide. If validated, phage therapy could offer patients a novel, targeted
approach to controlling C. acnes overgrowth and associated inflammation while preserving
beneficial cutaneous microbes [53].
These approaches, combined with metabolic interventions, offer a comprehensive
strategy for managing acne, addressing both the systemic and localized drivers of this
multifactorial disease [67].

9. Rosacea
Rosacea is a chronic inflammatory skin disorder affecting approximately 5% of the
global population. It presents as facial erythema, telangiectasia, and inflammatory lesions
such as papules and pustules, with severe cases leading to phymatous changes character-
ized by thickened and irregular skin. Beyond its visible manifestations, rosacea involves
complex interactions between immune dysregulation, neurovascular mechanisms, and
environmental triggers. Increasingly, the role of the skin microbiome and its interaction
Microorganisms 2025, 13, 161 18 of 32

with metabolic dysfunctions, such as obesity and dyslipidemia, has come under scrutiny,
highlighting their collective contribution to rosacea’s pathogenesis [68].
Rosacea is strongly associated with alterations in the skin microbiome, particularly an
overgrowth of Demodex mites, including Demodex folliculorum and Demodex brevis. These
mites are found in significantly higher densities on the skin of rosacea patients—ranging
from 0.7/cm² in healthy controls to 10.8/cm² in affected individuals. Their exoskeleton and
endosymbiotic bacterium Bacillus oleronius contribute to inflammation by releasing proteins
and heat-shock proteins that activate Toll-like receptor 2 (TLR2) on keratinocytes, trigger-
ing innate immune responses. This activation results in the production of cathelicidins,
AMPs that are excessively expressed in rosacea and contribute to both the condition’s
pro-inflammatory and vasoactive properties. These inflammatory responses are further
amplified by metabolic dysfunction. For instance, elevated levels of TNF-α and IL-6 in
obesity and MetS enhance microbial overgrowth and contribute to persistent inflamma-
tion, creating a feedback loop between dysbiosis and immune activation. Additionally,
Staphylococcus epidermidis overgrowth and reduced C. acnes abundance are noted, with
other species like Geobacillus and Gordonia correlating with disease severity. These microbial
disruptions, alongside environmental and neurological factors, exacerbate skin barrier
dysfunction, promote inflammation, and intensify rosacea symptoms, including erythema
and telangiectasia [69–71].
The neurovascular component of rosacea intricately interfaces with the microbiome
through activation of transient receptor potential (TRP) channels, particularly TRPV1 and
TRPA1. These channels, expressed on sensory neurons, keratinocytes, and immune cells,
are highly sensitive to microbial metabolites such as SCFAs, lipopolysaccharides, and other
bacterial byproducts. Environmental stimuli, including ultraviolet (UV) radiation, heat,
and dietary triggers (e.g., capsaicin and alcohol), further potentiate their activation. Upon
activation, TRPV1 and TRPA1 stimulate the release of pro-inflammatory neuropeptides,
such as substance P and calcitonin gene-related peptide (CGRP), which contribute to
neurogenic inflammation. This cascade disrupts neurocutaneous signaling, impairing
the production of AMPs such as cathelicidins and β-defensins. AMPs are critical for
maintaining microbial homeostasis by directly inhibiting pathogenic bacterial growth and
preserving skin barrier integrity. Dysregulated signaling creates a permissive environment
for microbial overgrowth, particularly of Demodex folliculorum, which harbors symbiotic
bacteria such as Bacillus oleronius. These bacteria release antigens that further amplify
inflammation by activating Toll-like receptor 2 (TLR2) on keratinocytes and immune cells.
Additionally, the altered microenvironment fosters the growth of opportunistic pathogens,
including S. epidermidis and C. acnes. The interaction between these microbial populations
and the impaired neurovascular signaling exacerbates inflammatory pathways, disrupts
skin barrier function, and reinforces the chronicity of rosacea. Importantly, the feedback
loop of inflammation, microbial imbalance, and neurovascular dysfunction underscores
the need for targeted therapies addressing both microbial and neurovascular components
in rosacea management [69,70].
Cutaneous barrier dysfunction in rosacea exacerbates microbial dysbiosis. Downregu-
lation of the ABCA12 gene, a key regulator of lipid lamellae formation, has been observed
in rosacea patients. This defect compromises the skin barrier, increasing transepidermal
water loss and facilitating microbial infiltration. Dyslipidemia further alters the skin’s
lipid environment. Elevated LDL and triglycerides, along with reduced HDL, shift the
sebaceous lipid composition, favoring conditions conducive to pathogenic growth. For
example, S. epidermidis, typically a commensal, may adopt pathogenic traits in response
to an altered lipid environment, while oxidative modifications of lipids, such as oxidized
Microorganisms 2025, 13, 161 19 of 32

LDL (ox-LDL), activate nucleotide-binding oligomerization domain-like receptor protein 3

(NLRP3) inflammasome pathways, sustaining inflammation [57,72].
Obesity and dyslipidemia intensify these microbiome alterations. Adipokines, such as
leptin and resistin, secreted by hypertrophic adipose tissue in obesity, enhance Th1 and Th17
polarization, contributing to pro-inflammatory cytokine production that disrupts microbial
homeostasis. Reduced adiponectin, a key anti-inflammatory adipokine, further exacerbates
this imbalance [23]. Hyperglycemia, commonly associated with MetS, increases nutrient
availability for microbial growth, promoting overgrowth of inflammatory taxa. AGEs
formed under hyperglycemic conditions interact with RAGE receptors on keratinocytes
and immune cells, amplifying NF-κB-driven inflammation and contributing to microbial
dysbiosis [73].
A case–control study investigated the connection between rosacea, insulin resistance,
and MetS in 47 rosacea patients and 50 controls. Results indicated that IR was significantly
higher among rosacea patients (44.7%) compared to controls (20%) (p = 0.009), while the
prevalence of MS did not differ significantly between the groups (p = 0.186). Rosacea
patients exhibited elevated levels of fasting blood glucose, LDL, triglycerides, total choles-
terol, CRP, and both systolic and diastolic blood pressure compared to controls (p < 0.05).
These findings underscore the potential role of systemic metabolic dysfunctions, including
insulin resistance, in the pathogenesis of rosacea and its associated cardiovascular risks.
Notably, markers of inflammation, such as elevated cathelicidin LL-37 levels, oxidative
stress, and endoplasmic reticulum stress, are implicated in both rosacea and metabolic
disorders, suggesting overlapping pathogenic pathways. These results highlight the impor-
tance of evaluating IR in rosacea patients, particularly for those at risk of metabolic and
cardiovascular comorbidities [73].
Regarding microbiome-targeted therapies, as already stated, rosacea is linked to the
overexpression of TLR2 receptors, which drive inflammatory responses and disrupt the
skin microbiome. While scalp rosacea has been managed successfully with a combination
of oral probiotics and doxycycline, the potential of topical probiotics for treating rosacea
remains unexplored and warrants further investigation [71].
Additionally, systemic metabolic control is critical for addressing the microbiome–
metabolism–skin axis in rosacea. Weight loss and dietary interventions targeting dys-
lipidemia and hyperglycemia have demonstrated reductions in systemic inflammation,
normalization of lipid profiles, and improved skin outcomes. Pharmacologic agents like
metformin and statins not only improve metabolic parameters but also indirectly enhance
microbial diversity by restoring AMP production and reducing inflammatory drivers of
dysbiosis. These integrated approaches, combining microbiome-targeted therapies and
metabolic interventions, represent a holistic strategy for managing rosacea and mitigating
its systemic comorbidities [72].

10. Seborrheic Dermatitis

SD is a chronic inflammatory skin disorder that affects 1–3% of the population. It
is characterized by erythematous, scaly lesions predominantly localized to sebaceous
gland-rich areas such as the face, scalp, and chest. SD’s pathogenesis involves a multi-
faceted interaction of sebaceous gland activity, microbial dysbiosis—particularly involving
Malassezia species—and immune system dysregulation. These localized factors are sig-
nificantly influenced by systemic metabolic conditions such as dyslipidemia and MetS,
highlighting the interplay between systemic metabolic health and skin microbiota in SD
development [41].
Sebaceous gland activity plays a central role in SD by producing sebum enriched
in triglycerides, free fatty acids, wax esters, cholesterol, and squalene, which provide
Microorganisms 2025, 13, 161 20 of 32

substrates for Malassezia. Through lipase activity, Malassezia species metabolize these lipids
into pro-inflammatory free fatty acids that irritate keratinocytes, inducing the release of
IL-6 and IL-1β. These cytokines drive inflammation, disrupt lipid organization in the
stratum corneum, and weaken the epidermal barrier, perpetuating clinical symptoms such
as scaling, redness, and skin peeling. The inflammatory microenvironment also stimulates
abnormal keratinocyte proliferation, further disrupting the epidermal barrier. Although
increased sebum production was historically considered essential in SD, newer evidence
suggests that seborrhea is not strictly required, underscoring the importance of microbiota
and immune factors in disease pathogenesis [51,57].
Altered lipid metabolism contributes significantly to SD’s pathology. Skin lipidomics
studies have revealed unique profiles in SD lesions compared to healthy skin, with older
research identifying decreased squalene, wax esters, and free fatty acids alongside increased
cholesterol and triglycerides in lesional skin. These findings suggest disrupted lipid
homeostasis due to abnormal keratinization and sebaceous gland dysfunction. Recent
work has shown higher mean skin surface lipid levels in SD patients, correlating with
disease severity. Systemic lipid abnormalities, including elevated total cholesterol, LDL,
and reduced HDL, are also common in SD patients, with studies linking these dyslipidemias
to increased SD severity. Reduced HDL, in particular, diminishes its antimicrobial functions,
allowing Malassezia overgrowth, sustaining inflammation, and exacerbating dysbiosis [57].
Malassezia species are central to SD, with their lipase-driven metabolism of sebaceous
lipids fueling inflammation. By hydrolyzing triglycerides into free fatty acids, Malassezia
disrupts keratinocyte membranes and activates PRRs, such as TLR2, triggering cytokine
production and neutrophil recruitment. Different species, including M. globosa and M. re-
stricta, exhibit variations in lipase activity and immune interactions, leading to site-specific
manifestations. In SD-affected skin, microbial dysbiosis is evident, with reduced bacterial
diversity and a dominance of Malassezia. This imbalance disrupts the competitive effects of
commensal bacteria, such as S. epidermidis, further enabling Malassezia colonization. Addi-
tionally, altered ceramide and squalene levels in SD create a lipid environment favorable
for Malassezia proliferation, exacerbating inflammation [74].
The exaggerated inflammatory response in SD involves the upregulation of cytokines
like TNF-α, IL-6, and IL-1β, alongside activation of NF-κB and MAPK pathways. These
inflammatory signals promote keratinocyte hyperproliferation, barrier dysfunction, and
scaling. MetS and dyslipidemia amplify these immune dysregulations, with hypertriglyc-
eridemia and elevated LDL levels activating TLRs on keratinocytes and macrophages. This
activation promotes further cytokine release and oxidative stress, creating a feedback loop
between systemic lipid imbalances and local skin inflammation. Reduced HDL removes
a critical anti-inflammatory factor, worsening the inflammatory cascade and microbial
dysbiosis in SD [75].
Treatment of SD traditionally focuses on managing inflammation and Malassezia
overgrowth. Topical antifungal agents, such as ketoconazole and ciclopirox, and anti-
inflammatory therapies, such as calcineurin inhibitors and corticosteroids, form the corner-
stone of therapy. For severe cases, oral antifungals like itraconazole or systemic retinoids
may be required. However, systemic metabolic factors offer additional therapeutic targets.
Weight loss and dietary interventions improve lipid profiles and reduce systemic inflam-
mation, indirectly benefiting SD. Statins, which lower LDL and exhibit anti-inflammatory
effects, could serve as an adjunct therapy in SD patients with significant dyslipidemia or
MetS [76].
Emerging therapies targeting lipid metabolism and the skin microbiome present ex-
citing opportunities for SD management. Topical formulations restoring ceramides and
squalene levels may strengthen the epidermal barrier and reduce Malassezia colonization.
Microorganisms 2025, 13, 161 21 of 32

Probiotics and postbiotics, aimed at enhancing microbial diversity, can suppress inflamma-
tion and dysbiosis. For instance, probiotics such as lactobacilli and Bifidobacterium species
modulate immune responses and increase commensal bacterial populations, countering
Malassezia overgrowth. Postbiotic compounds, including SCFAs, may further stabilize
microbial communities and reduce cytokine-driven inflammation [77,78].
Specifically, a recently published study evaluated the efficacy of EUTOPLAC, a
probiotic-enriched oily suspension containing Lactobacillus crispatus P17631 and Lacticas-
eibacillus paracasei I1688, in modulating the skin mycobiome–bacteriome and alleviating
SD symptoms. The study enrolled 25 patients with moderate to severe SD who applied
EUTOPLAC daily for one week. Symptom severity, assessed using the Seborrheic Der-
matitis Area Severity Index (SDASI), significantly improved, with mean SDASI scores
decreasing from baseline (T0) to T8 (p < 0.0001). Improvements persisted three weeks
post-treatment (T28), though scores plateaued between T8 and T28. Fungal diversity,
measured via Shannon and Pielou indices, significantly increased at T8 (Shannon index:
2.66 ± 0.99 vs. T0: 1.37 ± 0.07; p < 0.0001), accompanied by a reduction in Malassezia
relative abundance (74.8% at T8 vs. 96.5% at T0; p < 0.0001). By T28, Malassezia abundance
partially rebounded to 93.0%. Bacteriome analysis showed a marked rise in Lactobacillus
and Lacticaseibacillus genera at T8 (23.1% and 0.6%, respectively, vs. 0.1% and 0.003%
at T0; p < 0.0001), accompanied by a significant decrease in Staphylococcus (6.9% at T8
vs. 28.7% at T0; p < 0.0001). These effects were transient, normalizing by T28. Network
analysis revealed significant disruptions in microbial correlations at T8, reflecting transient
community instability post-treatment. These findings highlight EUTOPLAC’s potential
as a targeted SD therapy, offering temporary symptom relief and microbiome modulation
without long-term dysbiosis. Further randomized controlled trials are needed to confirm
these benefits and optimize probiotic formulations [77].
These integrative approaches, targeting both systemic and local factors, hold promise
for improving outcomes in SD while addressing its complex pathophysiology [76–78].

11. Hidradenitis Suppurativa

HS is a chronic inflammatory skin condition primarily affecting intertriginous areas,
including the armpits, groin, submammary folds, and perianal regions. It is characterized
by recurrent painful nodules, abscesses, fistulae, and significant scarring, with a profound
impact on quality of life. While HS is often underdiagnosed, recent advances have illu-
minated its complex pathogenesis, linking follicular occlusion, dysregulated immunity,
microbial dysbiosis, and systemic metabolic disturbances. A notable connection between
HS and MetS has underscored the role of the microbiome as a mediator between metabolic
dysfunction and the chronic inflammation observed in HS [15,79].
The initial event in HS involves follicular hyperkeratosis, resulting in the plugging
and dilation of pilosebaceous units. Follicular rupture releases keratin and sebum into the
dermis, triggering a robust inflammatory response. Both innate and adaptive immunity
play critical roles, with elevated levels of IL-1β, IL-17, TNF-α, and IL-12/23 perpetuating
inflammation. Dysbiosis of the skin microbiome significantly amplifies these responses,
with lesional areas dominated by pathogenic bacteria such as S. aureus, S. pyogenes, and C.
acnes. Biofilms formed by these pathogens further protect them from immune clearance
and antimicrobial treatments, fostering chronicity [15,79].
The correlation between MetS and HS is well documented, with an estimated odds
ratio of HS patients for MetS development being 2.66 (95 CI: 1.90–3.72) [15]. Metabolic dys-
function exacerbates this dysbiosis, creating a skin environment conducive to pathogenic
microbial overgrowth. Elevated glucose levels associated with hyperglycemia provide
abundant nutrients for bacterial proliferation, while dysregulated sebaceous lipid profiles
Microorganisms 2025, 13, 161 22 of 32

favor the colonization of pathogenic strains over commensals. Hyperinsulinemia and

insulin resistance, both hallmarks of MetS, activate the mammalian target of rapamycin
complex 1 signaling pathway, promoting keratinocyte hyperproliferation and follicular
plugging, thus aggravating HS lesions. Inflammatory cytokines such as TNF-α and IL-17,
elevated in both HS and metabolis syndrome, disrupt AMP production, further compro-
mising microbial homeostasis and exacerbating dysbiosis [15,80].
Obesity, particularly abdominal obesity, is strongly associated with HS severity, as
visceral adipose tissue secretes pro-inflammatory adipokines like leptin and resistin, which
promote Th1 and Th17 polarization. Reduced levels of adiponectin, an anti-inflammatory
adipokine, remove a critical regulatory mechanism against inflammation, intensifying
systemic and localized immune dysregulation. Hypertriglyceridemia and reduced HDL
in HS patients reflect a pro-atherogenic lipid profile, while inconsistent findings on LDL
and total cholesterol levels highlight the need for further research. The involvement of
metabolic dysfunction-associated steatotic liver disease in HS patients further underscores
the systemic metabolic impact of the disease [15,80].
Skin lipidomics studies have provided key insights into the metabolic interplay in
HS. Lesional skin in HS exhibits an imbalance between pro- and anti-inflammatory lipid
mediators, with elevated omega-6 fatty acid metabolites derived from 5-lipoxygenase
(5-LO) and reduced levels of omega-3 fatty acids such as docosahexaenoic acid (DHA). This
shift in lipid mediator profiles perpetuates localized inflammation and delays resolution.
Additionally, elevated triglycerides and reduced HDL-C levels commonly observed in
HS patients disrupt lipid organization in the skin’s sebaceous environment, facilitating
pathogenic colonization and biofilm formation [57].
Microbial dysbiosis in HS is marked by reduced diversity and overrepresentation of
pathogenic taxa. These microbial shifts are closely tied to the inflammatory microenviron-
ment in HS lesions. C. acnes, a facultative anaerobe, metabolizes sebaceous triglycerides into
free fatty acids, which disrupt keratinocyte membranes and trigger inflammatory responses
via TLR2. Biofilms produced by C. acnes and other pathogenic bacteria shield these microbes
from host immune defenses and antimicrobial treatments, enabling sustained inflammation
and tissue damage. Dysbiosis-associated microbial metabolites, including SCFAs and ROS,
exacerbate keratinocyte dysfunction and further perpetuate the inflammatory cycle [81].
Therapeutic strategies for HS must address the interactions between the skin micro-
biome, metabolic dysfunction, and chronic inflammation. Standard treatments, including
TNF-α inhibitors like adalimumab and IL-17 or IL-12/23 inhibitors such as secukinumab
and ustekinumab, target key inflammatory pathways but do not address underlying
metabolic contributors. Weight loss through lifestyle interventions or bariatric surgery
has been shown to improve HS severity, likely by reducing systemic inflammation and
restoring metabolic balance [15,80].
According to this systematic review, GLP1-RAs, particularly liraglutide and semaglutide,
demonstrate significant therapeutic potential in managing HS. Liraglutide, administered
at 3 mg for three months in a prospective case series, resulted in a reduction in BMI from
39.3 ± 6.2 to 35.6 ± 5.8 (p = 0.002), waist circumference from 121.3 ± 19.2 cm to 110.6 ± 18.1 cm
(p = 0.01), and C-reactive protein (CRP) levels from 4.5 ± 2.2 mg/L to 3.0 ± 2.1 mg/L (p = 0.04).
Significant improvements in HS severity were observed, with Hurley stage scores decreasing
from 2.6 ± 0.5 to 1.1 ± 0.3 (p = 0.002), and Dermatology Life Quality Index (DLQI) scores
improving from 12.3 ± 2.8 to 9.7 ± 6.9 (p = 0.04). Semaglutide was similarly associated
with weight reduction (mean body weight decrease from 117.7 kg to 111.6 kg; p < 0.001) and
improved quality of life (DLQI score reduction from 13 to 9; p = 0.001). However, reductions
in HS flare frequency and CRP levels did not reach statistical significance. These findings
Microorganisms 2025, 13, 161 23 of 32

support the role of GLP1-RAs in addressing both metabolic and inflammatory components of
HS, warranting further investigation in controlled trials [82].
Microbiome-targeted therapies are emerging as adjuncts in HS management. Pro-
biotics, such as lactobacilli and Bifidobacterium strains, enhance microbial diversity and
modulate immune responses by increasing Treg activity and suppressing Th17-driven
inflammation. Postbiotics, including SCFAs, directly inhibit pathogenic biofilm formation
and virulence while promoting commensal populations. These approaches, combined with
systemic metabolic interventions, provide a comprehensive strategy for addressing both the
localized and systemic drivers of HS, highlighting the central role of the skin microbiome
in mediating metabolic interactions in this debilitating condition [81].
Lifestyle interventions, including weight loss, smoking cessation, and dietary adjust-
ments, play a significant role in managing HS. These modifications not only have the
potential to alleviate disease symptoms but also influence microbial diversity. For example,
smoking has been associated with an increase in the gut phyla Proteobacteria and Bac-
teroidetes while reducing Actinobacteria and Firmicutes. Smoking also lowers overall gut
microbiome diversity through mechanisms such as oxidative stress, alterations in mucin
composition, and disruption of intestinal tight junctions. Consequently, smoking cessation
may restore microbial balance, providing an additional pathway for therapeutic benefit.
Probiotics have emerged as a promising adjunctive treatment in HS due to their ability to
restore microbial homeostasis, particularly by increasing beneficial skin bacteria such as
Cutibacterium spp., Corynebacterium, and Staphylococcus. Targeting prelesional skin with
topical probiotics or using oral formulations to modulate gut microbiota offers potential
therapeutic advantages. Probiotics can impact systemic inflammation, oxidative stress,
glycemic control, and lipid metabolism, all of which are implicated in HS pathogenesis.
While extensive evidence supports the use of probiotics in conditions like AD and psoria-
sis, their role in HS is still underexplored. More studies are needed to identify the most
effective strains and their mechanisms. Dietary interventions, such as reducing high-fat
and high-sugar intake, avoiding dairy, and eliminating brewer’s yeast, may also benefit
HS patients. However, the full impact of diet on HS severity remains insufficiently under-
stood, necessitating further research to establish evidence-based dietary recommendations.
Together, these lifestyle and dietary approaches could pave the way for personalized HS
management strategies [81].
A schematic illustration of the effects of Metabolic Disorders on Skin Microbiome and
Cutaneous Health is presented in Figure 1. An overview of the correlations between skin
diseases, microbiota shifts, metabolic influences, and therapeutic opportunities is presented
in Table 2. A flowchart of the complex interactions between AGE-RAGE pathway and the
skin is illustrated in Figure 2.

Table 2. Correlation between skin diseases, microbiota shifts, metabolic influences, and therapeutic
opportunities.

Disease Key Microbiota Shifts Metabolic Influences Therapeutic Opportunities References

Obesity-induced
Reduced Cutibacterium inflammation (elevated Weight loss, GLP-1 receptor agonists, probiotics
and Corynebacterium, TNF-α, IL-6), (e.g., Lactobacillus species), postbiotics (SCFAs),
Psoriasis dyslipidemia, and [44–53]
increased S. aureus and topical and systemic anti-inflammatory agents,
S. pyogenes. advanced glycation end microbiome restoration therapies.
products (AGEs).
Hyperglycemia, AGE Improved metabolic control (e.g., glycemic
Overgrowth of S. aureus, formation, adipokine management), probiotics (e.g., lactobacilli and
Atopic Dermatitis reduced microbial dysregulation (e.g., Bifidobacterium), postbiotics, topical prebiotics, [14,54–58]
diversity. elevated leptin, reduced barrier repair therapies (e.g., ceramide-based
adiponectin). creams).
Microorganisms 2025, 13, 161 24 of 32

Table 2. Cont.

Disease Key Microbiota Shifts Metabolic Influences Therapeutic Opportunities References

Metformin, lifestyle interventions (e.g., reduced
Dysbiosis with Insulin resistance, IGF-1 glycemic load), probiotics (Lacticaseibacillus
overrepresentation of elevation, sebaceous
Acne gland dysregulation rhamnosus), postbiotics, anti-inflammatory [59–67]
pathogenic C. acnes agents targeting sebaceous activity, topical
strains. (altered lipid profiles).
retinoids.
Increased Demodex Weight loss, statins for dyslipidemia, probiotics
Dyslipidemia, oxidative
folliculorum, reduced stress, systemic (Lacticaseibacillus rhamnosus), postbiotics (e.g.,
Rosacea microbial diversity; SCFAs), topical agents targeting Demodex and [23,57,68–73]
inflammation (e.g.,
overgrowth of S. reducing neurogenic inflammation (e.g.,
epidermidis. elevated TNF-α, IL-6).
calcineurin inhibitors).
Antifungal agents (e.g., ketoconazole),
Dyslipidemia, altered ceramide-based barrier repair, probiotics to
Dominance of Malassezia sebaceous lipid restore microbial diversity, dietary
Seborrheic species, reduced [41,51,57,74–78]
Dermatitis metabolism, systemic interventions to improve lipid profiles,
bacterial diversity.
inflammation. anti-inflammatory therapies (e.g., calcineurin
inhibitors).
GLP-1 receptor agonists (e.g., liraglutide),
Reduced diversity, Obesity,
weight loss, targeted probiotics, postbiotics,
Hidradenitis overgrowth of S. aureus, hyperinsulinemia, [15,57,79–82]
Suppurativa biologics (e.g., TNF-α inhibitors), lifestyle
S. pyogenes, and C. acnes. elevated IL-17/TNF-α,
dyslipidemia. interventions to address metabolic
dysregulation.
Abbreviations.
Microorganisms 2025, 13, xAGEs (Advanced
FOR PEER Glycation End Products); GLP-1 (Glucagon-Like Peptide-1); IL
REVIEW (Interleukin);
24 of 33
IGF-1 (Insulin-Like Growth Factor-1); SCFAs (Short-Chain Fatty Acids); TNF-α (Tumor Necrosis Factor-Alpha).

Figure 1. Interconnected pathways

Figure linking
1. Interconnected metabolic
pathways linking disorders to skin
metabolic disorders microbiome
to skin microbiome dysbiosis
dysbiosis andand cuta-
cutaneous disease. Metabolic disorders influence skin health and the microbiome through intercon-
neous disease. Metabolic disorders influence skin health and the microbiome through interconnected
nected mechanisms. Chronic low-grade inflammation, or meta-inflammation, driven by pro-inflam-
mechanisms. Chronicmatory
low-grade
cytokinesinflammation,
such as TNF-α, IL-6,orandmeta-inflammation,
IL-1β, disrupts keratinocyte driven by pro-inflammatory
differentiation, weakens the
cytokines such as TNF-α, IL-6,
epidermal andand
barrier, IL-1β, disrupts
alters AMP keratinocyte
production, differentiation,
increasing susceptibility weakens
to infections the epider-
and dysbiosis.

mal barrier, and altersImmune

AMP dysregulation
production, plays a significant role, as adipokines like leptin promote Th1/Th17 polari-
increasing susceptibility to infections and dysbiosis. Immune
zation, while reduced adiponectin removes anti-inflammatory control, intensifying immune activa-
tion and microbial imbalances. Neurovascular dysregulation, a notable mechanism in rosacea, is
driven by the increased activation of pathways such as TRPV1 channels and exacerbates skin sensi-
tivity and dysbiosis. Microvascular dysfunction and reduced capillary perfusion create hypoxic con-
ditions that favor anaerobic or facultative anaerobic microbes, altering microbial ecology. Dysregu-
lated lipid metabolism, particularly altered sebaceous gland activity in insulin resistance, leads to
changes in sebum composition, such as increased saturated fatty acids, which promote the
Microorganisms 2025, 13, 161 25 of 32

dysregulation plays a significant role, as adipokines like leptin promote Th1/Th17 polarization,
while reduced adiponectin removes anti-inflammatory control, intensifying immune activation and
microbial imbalances. Neurovascular dysregulation, a notable mechanism in rosacea, is driven by
the increased activation of pathways such as TRPV1 channels and exacerbates skin sensitivity and
dysbiosis. Microvascular dysfunction and reduced capillary perfusion create hypoxic conditions
that favor anaerobic or facultative anaerobic microbes, altering microbial ecology. Dysregulated
Microorganisms 2025, 13, x FOR PEER lipid
REVIEWmetabolism, particularly altered sebaceous gland activity in insulin resistance, 26 of 33 leads to changes
in sebum composition, such as increased saturated fatty acids, which promote the colonization of
pathogenic microbes and disrupt the balance of commensal microbes. Systemic nutritional and
dietary interventions
metabolic influences, including hyperglycemia to im- provide substrates for microbial
and dyslipidemia,
prove lipid profiles, anti-in-
growth, destabilizing skin homeostasis. Oxidative stress and lipid peroxidation further damage ker-
flammatory therapies (e.g.,
atinocytes and lipids, compromising skin integrity and promoting microbial overgrowth. Sebaceous
calcineurin inhibitors).
gland hyperactivity, induced by hyperinsulinemia and IGF-1, stimulates excessive lipid production,
GLP-1 receptor agonists (e.g.,
creating a nutrient-rich environmentliraglutide),
for opportunistic microbes.
weight loss, tar- Cytokines and oxidative stress
reduce over-
Reduced diversity, the expression of barrier proteins
Obesity, hyperinsuline- getedlike filaggrin
probiotics, and involucrin, increasing transepidermal
postbiotics,
Hidradenitis
growth of S.water
aureus,loss
S. and
mia,weakening physical defenses
elevated IL-17/TNF- biologicsagainst microbial
(e.g., TNF-α inhibi-invasion. AGEs, formed under hy-
[15,57,79–82]
Suppurativa
pyogenes, and C. acnes. α,
perglycemic dyslipidemia.
conditions, tors), lifestyle
bind to their receptor RAGE, interventions to
triggering NF-κB-mediated inflammation and
oxidative stress. This process impairs address metabolic
skin barrier dysregula-
proteins, disrupts collagen cross-linking, and
tion.
affects keratinocyte function. These mechanisms collectively illustrate how metabolic disorders create
Abbreviations. AGEs (Advanced Glycation End Products);
both systemic and localized environments conducive GLP-1to(Glucagon-Like Peptide-1);
skin dysbiosis, IL (In-
inflammation, and disease,
terleukin); IGF-1 (Insulin-Like Growth Factor-1); SCFAs (Short-Chain Fatty Acids); TNF-α (Tumor
underscoring the need for integrated therapeutic strategies targeting metabolic dysfunction and skin
Necrosis Factor-Alpha).
health. Systemic effects are marked in blue, while localized effects are marked in orange.

Flowchart
Figure2.2.Flowchart
Figure of complex
of the the complex interactions
interactions betweenbetween AGE-RAGE
AGE-RAGE pathway
pathway and the skin.and the skin. Abbrevi-
Abbre-
ations. AGEs
viations. (Advanced
AGEs (Advanced Glycation
Glycation EndEnd Products);
Products); AMP (Antimicrobial
AMP (Antimicrobial Peptides);Peptides);
NF-κB (Nu-NF-κB (Nuclear
Factor
clear Kappa-Light-Chain-Enhancer
Factor Kappa-Light-Chain-Enhancer ofof Activated
Activated B cells);
B cells); RAGERAGE (Receptor
(Receptor for Advanced
for Advanced Gly- Glycation
End Products);
cation ROS
End Products); (Reactive
ROS (ReactiveOxygen Species);TEWL
Oxygen Species); TEWL (Transepidermal
(Transepidermal Loss); Loss);
WaterWater (in- ↑ (increased);
 (decreased).
↓ (decreased).
creased);
Microorganisms 2025, 13, 161 26 of 32

12. Integrated Therapeutic Implications and the Role of ML

Comprehensive management of metabolic disorders—through lifestyle modifications,
pharmacotherapy (e.g., metformin, sodium–glucose cotransporter-2 inhibitors, glucagon-
like peptide-1 receptor agonists), and sometimes bariatric surgery—can alleviate systemic
inflammation and modulate skin lipid profiles. Improved metabolic control can restore
normal AMP production, reduce AGE formation, and promote commensal dominance
over pathogenic taxa [5,9]. Additionally, interventions that enhance insulin sensitivity
and decrease adipose-derived inflammation can indirectly stabilize the cutaneous immune
environment, making it less susceptible to microbial imbalances. These systemic strategies
not only reduce skin inflammation but also improve the efficacy of topical treatments. When
local therapeutics fail to eradicate problematic microbes completely, the improved systemic
environment ensures that the skin becomes less favorable for pathogenic colonization. Over
time, this integrated approach may reduce the recurrence of inflammatory skin conditions
and infections, resulting in improved long-term patient outcomes.
Therapeutic strategies targeting the skin microbiota, such as topical prebiotics, pro-
biotics, or bacteriophage therapy, represent direct methods to restore microbial equilib-
rium [77,83–85]. Advances in postbiotic formulations (e.g., microbial metabolites like
short-chain fatty acids, bacteriocins, and bioactive peptides) have shown promise in en-
hancing skin barrier function, increasing AMP activity, and reducing pro-inflammatory
signaling pathways. For example, SCFAs, derived from probiotic fermentation, not only
suppress pathogenic biofilm formation but also enhance keratinocyte differentiation and
lipid metabolism. These treatments are particularly beneficial when combined with sys-
temic metabolic interventions, ensuring a synergistic effect that improves skin health while
addressing the root causes of dysbiosis [86]. By simultaneously correcting underlying
metabolic disturbances and stabilizing microbial communities, clinicians may achieve more
durable and long-lasting improvements in the cutaneous ecosystem. This approach is espe-
cially critical for conditions prone to relapse, where fostering a stable, health-promoting
microbial community reduces the frequency and intensity of disease flares.
Recent advancements in understanding the skin microbiome have unveiled significant
insights into its role in immune regulation and host–microbe interactions. A study by
Bousbaine et al. (2024) highlights the skin’s ability to generate a potent, durable antibody
response against Staphylococcus epidermidis, a common commensal. This immune re-
sponse, which involves both CD8+ T cells and antibodies, specifically targets the surface
protein Aap of S. epidermidis, offering potential for novel topical vaccination strategies. By
engineering S. epidermidis strains to express immunogenic proteins, researchers were able
to elicit strong antibody responses, including robust IgA in mucosal sites, under physiologic
colonization conditions. Meanwhile, research by Gribonika et al. (2024) further expands the
role of the skin as an autonomous lymphoid organ, where microbial colonization triggers
dual immune responses. Skin commensals promote the formation of classical germinal
centers in lymph nodes for systemic IgG responses and induce the development of tertiary
lymphoid organs within the skin to locally produce IgG antibodies, effectively controlling
microbial biomass and preventing systemic infection. Together, these studies underscore
the skin’s dynamic immune functions, revealing its capacity for both local and systemic
regulation of microbial symbiosis and potential pathogenesis [87,88].
These findings hold significant implications for the development of therapeutics
targeting the skin microbiome. By harnessing the skin’s ability to generate both localized
and systemic immune responses, it may be possible to design innovative treatments that
leverage the skin’s natural immunological processes. For instance, engineered S. epidermidis
strains, as described by Bousbaine et al. [87] could be used in topical vaccines that stimulate
robust immune responses without the need for systemic interventions. Additionally, the
Microorganisms 2025, 13, 161 27 of 32

identification of skin-specific immune mechanisms, as shown by Gribonika et al. [88] offers

potential for localized therapeutic strategies aimed at modulating microbial interactions
and controlling inflammation or infection directly at the skin barrier. These insights provide
a promising framework for developing microbiome-based therapies to address a range of
dermatological and systemic diseases.
Despite these advances, the clinical translation of combined metabolic and microbiota-
targeted therapies faces significant challenges. Variability in patient responses to probiotics
or postbiotics, stemming from differences in baseline microbiota composition, genetic
predispositions, and environmental exposures, complicates the standardization of these
treatments. Regulatory hurdles, including inconsistent definitions and approval pathways
for probiotics and postbiotics, further hinder their widespread clinical use. Additionally,
the lack of long-term studies evaluating the safety and efficacy of these interventions limits
their integration into standard practice. Addressing these barriers requires robust clinical
trials that explore personalized approaches, optimize therapeutic formulations, and assess
the sustainability of microbiota modulation over time.
Emerging ML technologies provide tools to overcome many of these challenges by
integrating complex datasets to predict patient-specific responses and guide treatment
decisions. ML algorithms, using multi-omic datasets such as metabolomics, lipidomics,
microbiome profiles, and clinical records, can uncover previously unrecognized microbial
signatures correlated with metabolic parameters and disease outcomes. For example, su-
pervised learning models (e.g., random forests, gradient boosting machines) can predict
which patients will benefit most from probiotic or postbiotic interventions based on their
baseline microbiome composition. Deep learning models go further by integrating tem-
poral data, identifying prognostic biomarkers, and differentiating between inflammatory
skin conditions with overlapping clinical features. These computational tools enable clini-
cians to tailor interventions precisely, reducing trial-and-error prescribing and improving
outcomes [10,11,89].
Furthermore, ML-driven biomarker discovery can enhance the correlation between
molecular biomarkers—such as serum cytokines, microbial taxa, or lipid profiles—and
clinical outcomes. Identifying predictive biomarkers not only ensures that metabolic
and microbiome-directed therapies are applied to patients most likely to benefit but also
facilitates earlier interventions that could prevent disease progression. As these biomarkers
are validated, they can be incorporated into clinical decision support systems, allowing
physicians to predict treatment responses with greater confidence and refine therapeutic
protocols for individual patients. Over time, these advancements may improve the precision
and personalization of dermatological care, particularly for individuals with underlying
metabolic dysfunctions [89–91].
The integration of ML into clinical practice is not without its challenges. Data het-
erogeneity, the need for standardization across multi-omics platforms, and ethical consid-
erations related to patient data privacy must be addressed to fully realize the potential
of these technologies. Nonetheless, as more data become available and ML models grow
more accurate, their capacity to unravel the complex interplay between metabolic disorders,
the microbiota, and skin health will only expand, enabling transformative advances in
personalized medicine.

13. Conclusions and Future Directions

In conclusion, this review highlights the intricate interplay between metabolic dis-
orders, skin microbiota, and dermatologic health, emphasizing the systemic drivers of
inflammatory skin conditions such as psoriasis, atopic dermatitis, and acne. Metabolic dys-
Microorganisms 2025, 13, 161 28 of 32

regulation profoundly affects microbial equilibrium, immune responses, and skin barrier
function, contributing to disease onset and progression.
Comprehensive management strategies that address metabolic dysfunction—through
lifestyle modifications, pharmacological interventions like GLP-1 receptor agonists and
SGLT-2 inhibitors, and bariatric surgery—can mitigate systemic inflammation and re-
store microbial homeostasis. Concurrently, microbiome-targeted therapies, including
probiotics, prebiotics, postbiotics, and bacteriophage treatments, have shown promise
in re-establishing microbial balance and enhancing barrier integrity. Integrating these
approaches with ML models allows for the identification of predictive biomarkers and
enables the development of highly personalized, effective therapeutic strategies.
Future research must focus on overcoming clinical translation barriers, such as patient
variability, regulatory challenges, and the lack of long-term studies on microbiota-targeted
therapies. High-resolution, longitudinal studies integrating multi-omics datasets will be
essential to elucidate host–microbiome dynamics. Interdisciplinary collaboration across
dermatology, endocrinology, microbiology, and computational biology will be crucial
in advancing precision medicine. These efforts aim to create durable, patient-specific
treatments that bridge systemic and localized therapies, ultimately improving outcomes
and reducing the burden of skin diseases influenced by metabolic dysfunction.

Author Contributions: Conceptualization, M.K. and N.T.; methodology, M.N. and G.F.; writing—original
draft preparation, M.K., N.T. and A.A.; writing—review and editing, G.F., A.S., M.N. and K.K.; visualization,
K.K.; supervision, A.S. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflicts of interest.

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