New Approaches in Acne Vulgaris Treatment: Role of Microbiome, Oxidative Stress, and Precision Dermatology

1.1 Skin Anatomy and Pilosebaceous Unit

The skin comprises three layers: the epidermis, dermis, and hypodermis. The dermis contains connective tissue, blood vessels, nerves, and appendages like hair follicles and sebaceous glands; the hypodermis offers insulation and cushioning; and the epidermis serves as a barrier of defence [1].

The The pilosebaceous unit consists of the sebaceous gland and hair follicle. The sebaceous gland secretes sebum into the follicular canal, primarily in regions like the face, chest, and back, whereas the hair follicle generates hair [2].

Sebum is a lipid-rich discharge composed of triglycerides, wax esters, squalene, and free fatty acids. It maintains skin hydration and provides antimicrobial protection; however, excess sebum and follicular blockage create a favorable environment for bacterial growth and contribute to acne development [3].

Fig. 1. Skin Anatomy and Pilosebaceous Unit

1.2 Acne Vulgaris (AV)

AV is a chronic, multifactorial inflammatory disorder of the pilosebaceous unit that mostly affects adolescents but often persists into adulthood, especially in females. It is one of the most prevalent skin disorders worldwide, presenting as non-inflammatory (comedones) and inflammatory (papules, pustules, nodules, and cysts) lesions that can result in scarring and post-inflammatory hyperpigmentation [4].

Four major variables contribute to its pathogenesis: Cutibacterium acnes colonization, follicular hyperkeratinization, androgen-driven sebum overproduction, and inflammatory pathway activation. Immune dysregulation, oxidative stress, microbiota imbalance, and environmental or lifestyle factors like nutrition, stress, and pollution are further causes. Even when acne is not life-threatening, its psychological and social impacts significantly reduce quality of life. Advances in understanding its molecular mechanisms have led to improved topical, systemic, and combination therapies, with ongoing research focusing on more targeted and personalized treatment approaches [5].

Fig. 2. Normal Skin Vs Acne Skin

1.3 Epidemiology

AV affects 9–10% of people worldwide, making it one of the most prevalent illnesses. It predominantly affects adolescents, with 80–90% incidence in individuals aged 12–24 years, but persists into adulthood in nearly 40–50% of cases, particularly among females due to hormonal influences [6].

Epidemiological patterns indicate significant variation based on genetic, environmental, and lifestyle factors. Heritability studies suggest that up to 80% of susceptibility is genetically determined, supported by genome-wide association studies identifying loci linked to sebaceous activity, inflammation, and androgen metabolism. Urban populations exhibit higher prevalence, likely due to pollution exposure, high glycemic diets, and altered skin microbiome dynamics, whereas lower rates are observed in non-industrialized communities [7].

Sex-related differences are notable, with more severe acne in adolescent males (androgen-driven sebaceous activity) and persistent acne in adult females, often associated with endocrine disorders such as PCOS. Additionally, emerging evidence highlights the role of IGF-1 signaling (diet-induced), oxidative stress, and environmental exposome factors in modulating disease severity. In general, the epidemiology of acne reflects a complex interaction between hormone regulation, genetic predisposition, microbiome alterations, and environmental triggers, contributing to its high global burden and chronicity [8].

1.4 Risk Factors and Etiology

AV is a complex condition influenced by genetic, hormonal, environmental, and lifestyle factors. Genetic predisposition (≈70–80% heritability) affects sebaceous activity, androgen response, and immune regulation.

Lesion formation is facilitated by hormonal variables, particularly androgens and IGF-1, which enhance sebum production and enlarge sebaceous glands. Acne is made worse by conditions like polycystic ovarian syndrome (PCOS) [9].

Environmental factors such as pollution, heat, and humidity promote oxidative stress and increased sebum secretion, while comedogenic cosmetics can block follicles. The severity of acne is exacerbated by dietary factors such as high glycemic index meals and dairy consumption, which raise insulin and IGF-1 levels. Lifestyle influences, including stress (via cortisol/HPA axis activation) and smoking, contribute to inflammation, oxidative damage, and abnormal keratinization. Overall, acne results from the combined effect of sebogenesis, inflammation, follicular blockage, and microbial imbalance [10].

1.5 Pathophysiology of Acne vulgaris

Four interconnected pathways promote the etiology of acne involving endocrine, microbial, and immunological pathways.

1.5.1 Sebum Overproduction

Androgens (testosterone and dihydrotestosterone), which promote sebaceous gland enlargement through androgen receptor signaling, are the main regulators of sebum production. Furthermore, by triggering the mTORC1 pathway, insulin-like growth factor-1 (IGF-1) connects metabolic status to acne severity. which promotes sebogenesis. Altered lipid composition of sebum, including increased squalene oxidation, further contributes to comedogenesis and inflammation [11].

1.5.2 Follicular Hyperkeratinization

Dysregulated keratinocyte proliferation and differentiation within the follicular infundibulum led to microcomedone formation, the earliest acne lesion. Molecular alterations include overexpression of keratins (K6, K16) and impaired desquamation. Increased IL-1α signaling also promotes hyperkeratinization and follicular plugging [12].

1.5.3 Microbial Colonization

Cutibacterium acnes, a gram-positive anaerobe, proliferates in the lipid-rich follicular environment. It produces lipases, proteases, and porphyrins, which degrade sebum into pro-inflammatory free fatty acids. Certain virulent strains activate biofilm formation and enhance pathogenicity, contributing to persistent and resistant acne [13].

1.5.4 Inflammatory Response

Toll-like receptor-2 (TLR 2) activation causes inflammation, It is a crucial early event that sets off the MAPK and NF-κB pathways. This leads to the release of chemokines and cytokines (IL-1β, IL-6, and TNF-α). NLRP3 inflammasome activation and elevated reactive oxygen species (ROS) further exacerbate tissue damage, leading to the formation of papules, pustules, nodules, and cysts are formed when oxygen species (ROS) exacerbate tissue damage [14].

Overall, acne pathophysiology involves a complex interaction of hormonal signaling, keratinocyte dysfunction, microbial imbalance, and immune activation, providing multiple targets for advanced therapeutic strategies [15].

1.6 Clinical Features and Types of Lesions

Acne lesions reflecting different stages of disease progression and underlying pathogenic mechanisms. These lesions are broadly classified into inflammatory and non-inflammatory types

1.6.1 Non-inflammatory lesions include:

• Open comedones (blackheads): Formed due to follicular plugging with oxidized melanin and lipids, giving a dark appearance.
• Closed comedones (whiteheads): Result from complete follicular occlusion with accumulated sebum and keratin, appearing as small, white, raised lesions [16].

1.6.2 Inflammatory lesions develop due to immune activation and microbial involvement:

• Papules: Small, erythematous, raised lesions without pus, indicating early inflammation.
• Pustules: Similar to papules but filled with purulent material due to neutrophilic infiltration.
• Nodules: Larger, deeper, solid lesions involving dermal inflammation, often painful and prone to scarring.
• Cysts: Severe, pus-filled lesions with extensive tissue damage, frequently leading to permanent scars [17].

Fig. 3. Types of Acne Lesions

Lesions are typically distributed in sebaceous gland-rich regions such the shoulders, back, chest, and face. Advanced cases may result in post-inflammatory hyperpigmentation (PIH), atrophic or hypertrophic scars, and keloids. Acne is also linked to serious psychological effects, such as diminished self-worth and an increased risk of sadness and anxiety [18].

1.7 Classification and Severity Grading of Acne vulgaris

The classification of AV is essential for accurate diagnosis, severity assessment, and selection of appropriate therapeutic strategies. It is generally categorized based on lesion type, clinical severity, age of onset, and etiological factors.

1.7.1 Based on Lesion Type

AV lesions are broadly divided into:

• Non-inflammatory lesions: These comprise closed comedones (whiteheads) and open comedones (blackheads). They are the first stage of acne development and are caused by follicular blockage brought on by an accumulation of keratin and excess sebum.
• Inflammatory lesions include papules, pustules, nodules, and cysts. They occur when follicular rupture triggers an inflammatory response mediated by immune cells and cytokines following bacterial proliferation [19].

1.7.2 Based on Severity

Severity grading is clinically important for treatment selection:

• Mild acne: Characterized mainly by comedones with few inflammatory lesions. Usually localized and responds well to topical therapy.
• Moderate acne: Presence of multiple papules and pustules along with comedones. Lesions are more widespread and may require combination therapy.
• Severe acne: Marked by nodules, cysts, and extensive inflammatory lesions. Often associated with scarring and requires systemic treatment such as oral isotretinoin [20].

1.7.3 Based on Age of Onset

• Adolescent acne: Most common form, occurring during puberty due to increased androgen levels increasing the production of sebum and activating sebaceous glands.
• Adult acne: Persists beyond adolescence or appears after 25 years of age. It is more prevalent in women and may be influenced by hormonal imbalance, stress, and lifestyle factors [21].

1.7.4 Based on Etiology

• Hormonal acne: Caused primarily by androgen-induced sebaceous gland stimulation. It commonly affects the chin, jawline, and lower face, and is often associated with menstrual cycles in females.
• Drug-induced acne: caused by drugs like androgens, lithium, or corticosteroids.
• Cosmetic acne: Resulting from comedogenic cosmetic products that block hair follicles [22].

Table 1. Classification Matrix of Acne Vulgaris

2. Differential Diagnosis of Acne vulgaris

2.1 Clinical Diagnosis

The primary techniques for making the clinical diagnosis of AV include a comprehensive patient history and physical examination. The presence of inflammatory lesions (papules, pustules, nodules, and cysts) in addition to non-inflammatory lesions (open and closed comedones) is diagnostic in specific sebaceous-rich areas such as the face, chest, shoulders, and back.

Important history factors include:

• Age of onset and duration of lesions
• Exacerbating factors such as hormonal fluctuations, stress, diet, and cosmetic use
• Family history of acne
• Previous treatment response

No routine laboratory tests are required unless an underlying endocrine disorder (e.g., hyperandrogenism) is suspected 

2.2 Clinical Severity Assessment

Severity assessment is crucial for therapeutic planning:

• Mild acne: Predominantly comedonal lesions with few inflammatory papules; minimal risk of scarring.
• Moderate acne: Presence of multiple papules and pustules with comedones; lesions are more widespread and may cause post-inflammatory hyperpigmentation.
• Severe acne: Characterized by nodules, cysts, and extensive inflammation; often associated with scarring, psychological distress, and requires systemic therapy such as oral isotretinoin.

Several grading systems (e.g., Global Acne Grading System) are used in clinical and research settings for standardization [23].

2.3 Differential Diagnosis

Accurate differentiation from other dermatological conditions is essential:

• Rosacea: Presents with persistent facial erythema, telangiectasia, and papulopustular lesions. Unlike acne, comedones are absent, and flushing is common.
• Folliculitis: Involves infection or inflammation of hair follicles, presenting as uniform pustules often associated with itching or tenderness. Lesions are typically centered on hair follicles and may be bacterial or fungal in origin.
• Perioral Dermatitis: Characterized by erythematous papules around the mouth, nose, and eyes with a clear zone around the border in vermilion. It is frequently associated with the use of cosmetics or topical steroids.
• Seborrheic Dermatitis: This condition lacks comedones and nodular lesions but manifests as greasy scales and erythema in sebaceous regions.
• Drug-induced acneiform eruptions: Caused by corticosteroids, lithium, or androgens; lesions are usually monomorphic and appear suddenly [24].
  1. 3. Limitations of Current Therapies for Acne vulgaris

Despite the availability of multiple therapeutic options, the management of AV still faces several clinical and pharmacological limitations:

3.1 Antibiotic Resistance

Cutibacterium acnes strains that are resistant to antibiotics have emerged as a result of prolonged and frequent usage of topical and systemic antibiotics including tetracyclines and clindamycin. This raises the possibility of therapy failure and dramatically lowers therapeutic efficacy [25].

3.2 Adverse Skin Reactions

Common first-line agents such as retinoids and benzoyl peroxide often result in local adverse effects, such as:

• Erythema

• Peeling and dryness
• Burning sensation
• Photosensitivity

These effects often reduce patient compliance

3.3 Systemic Drug Limitations

• Oral isotretinoin is highly effective but connected to severe side effects include possible hepatotoxicity, mucocutaneous dryness, and teratogenicity.
• Hormonal therapies may cause menstrual irregularities, weight changes, or thromboembolic risk in susceptible individuals [26].

3.4 High Recurrence Rate

Even after successful treatment, acne commonly recurs due to persistent underlying factors such as hormonal imbalance, sebaceous gland activity, and genetic predisposition [27].

3.5 Long Treatment Duration

Acne therapy typically requires weeks to months for visible improvement. This delayed response often leads to poor adherence and discontinuation of therapy.

3.6 Limited Target Specificity

Most conventional therapies act broadly rather than targeting specific pathogenic pathways such as inflammation mediators or microbiome imbalance, leading to partial or temporary control.

3.7 Psychological and Social Burden

Chronic Acne has a major impact on mental health, quality of life, and self-esteem. especially in adolescents, even when lesions are clinically mild [28].

4. Prevention and Lifestyle Modification in Acne vulgaris

Prevention of acne involves simple but consistent lifestyle and skincare practices aimed at reducing flare-ups and controlling severity [29].

1. 1. Skincare routine: Regular gentle cleansing helps remove excess oil and prevents follicular blockage. Non-comedogenic products are recommended.
   2. Diet control: Low glycemic index diets and reduced intake of dairy and high-fat foods may help decrease acne severity.
   3. Stress management: Psychological stress can worsen acne through hormonal imbalance; relaxation techniques may be beneficial.
   4. Hygiene practices: Avoiding excessive face touching, regular washing of pillow covers, and maintaining skin cleanliness help reduce bacterial load.
   5. Cosmetic selection: Use of non-comedogenic, oil-free cosmetics prevents pore blockage and acne aggravation.

5. Role of Microbiome and Oxidative Stress

Recent insights into AV highlight the crucial role of microbiome dysbiosis and oxidative stress in disease progression.

1. 1. Microbiome Dysbiosis

The skin microbiome, especially Cutibacterium acnes, comprises multiple phylotypes (IA1, IB, II, III) with varying pathogenicity. Acne is associated with a shift toward virulent strains (e.g., IA1) rather than increased bacterial load alone. These strains produce lipases, porphyrins, proteases, and CAMP factors, promoting inflammation and follicular damage.

C. acnes also form biofilms, enhancing persistence and antibiotic resistance. Reduced diversity of protective commensals like Staphylococcus epidermidis further disrupts microbial balance, amplifying TLR-2–mediated immune activation and inflammatory signaling.

ROS and Oxidative Stress

Reactive oxygen species (ROS) in excess from neutrophils and sebocytes induce lipid peroxidation of squalene, triggering comedogenesis and inflammation. ROS activate NF-κB and AP-1 pathways, increasing MMPs and cytokines (IL-1β, TNF-α) that cause scarring and tissue damage. Impaired antioxidant defenses further worsen inflammation.

1. 2. Integrated Impact

Microbiome imbalance and oxidative stress form a self-amplifying loop, driving progression from comedones to inflammatory lesions. Targeting these pathways (e.g., probiotics and antioxidants) offers promising therapeutic strategies [30].

6. Conventional Treatment of Acne vulgaris

Targeting the main pathogenic mechanisms of acne vulgaris, such as inflammation, microbial growth, follicular hyperkeratinization, and excessive sebum production, is the primary objective of treatment. Treatment strategies are selected based on disease severity, lesion type, and patient-specific factors, with a preference for combination therapy to enhance efficacy and reduce resistance.

1. 1. Topical Therapy

Topical medications minimize systemic exposure while delivering a high drug concentration to the pilosebaceous unit. They are the cornerstone of long-term maintenance therapy [31].

6.1.1 Topical Retinoids

The initial course of treatment for acne vulgaris, particularly for comedonal and mild to moderate inflammatory acne, is topical retinoids. They work by encouraging cell turnover, stopping the production of microcomedones, and restoring normal follicular keratinization.
By altering gene expression and lowering cytokine activity, they also demonstrate anti-inflammatory properties.

Common examples include adapalene, tretinoin, and tazarotene, available in gel, cream, or lotion forms. They are typically applied once daily, preferably at night. Although highly effective, they may cause skin irritation, dryness, and photosensitivity, which can be minimized by gradual introduction and use of moisturizers.

1. 1. 2. Benzoyl Peroxide (BPO)

One popular topical treatment for acne is benzoyl peroxide with strong antibacterial and anti-inflammatory effects. It releases oxygen free radicals that kill Cutibacterium acnes without causing resistance and also provides mild keratolytic action, reducing follicular blockage. It is available in 2.5–10% formulations (gels, creams, washes) and is often combined with antibiotics or retinoids for better efficacy. Typical adverse effects include dryness, irritation, and peeling, along with possible bleaching of fabrics.

1. 1. 3. Topical Antibiotics

Topical antibiotics are utilized because of their antibacterial and anti-inflammatory qualities. They work by lowering inflammatory mediators and preventing Cutibacterium acnes from growing. Clindamycin and erythromycin are common agents that are usually used as gels or solutions. To prevent antibiotic resistance, they are usually used with benzoyl peroxide or retinoids. There may be minor adverse effects including dryness or skin irritation [32].

6.1.3.1 Clindamycin:

Clindamycin is primarily administered topically (gel, lotion, solution) and acts locally at the pilosebaceous unit. It penetrates follicles and inhibits Cutibacterium acnes by blocking bacterial protein synthesis, while also reducing local inflammation. Its action is mainly bacteriostatic with additional anti-inflammatory benefits. However, prolonged use as monotherapy leads to significant bacterial resistance, including cross-resistance with macrolides. Therefore, it is commonly with benzoyl peroxide to boost effectiveness and stop resistance. Compared to erythromycin, clindamycin shows better follicular penetration and relatively lower resistance rates, making it more preferred in current acne therapy [33,34].

6.1.3.2 Erythromycin:

Erythromycin is administered both topically and orally, acting at the site of infection by inhibiting Cutibacterium acnes through suppression of protein synthesis. It reduces bacterial colonization and inflammation within the sebaceous follicles. However, its effectiveness is limited due to high levels of bacterial resistance, especially with long-term use. Resistance develops rapidly when used alone, making combination with benzoyl peroxide essential. Compared to clindamycin, erythromycin has higher resistance rates and reduced clinical efficacy. Although still used as an alternative when tetracyclines are contraindicated, its role in acne management has declined significantly in modern therapy [35].

6.2 Combination Therapy in Acne Vulgaris

Combination therapy is the standard approach for effective acne management, as it targets multiple pathogenic factors simultaneously. It typically involves the use of topical retinoids along with antibiotics, benzoyl peroxide or the combination of topical and systemic treatments. This strategy enhances therapeutic efficacy, reduces lesion count more rapidly, and minimizes the risk of antibiotic resistance. Combination regimens are particularly beneficial in moderate to severe acne, where monotherapy is often insufficient [36].

1. 1. 1. Benzoyl Peroxide (BPO) Combination Therapy

Because of its potent antibacterial effect against Cutibacterium acnes and its capacity to avoid antibiotic resistance, benzoyl peroxide (BPO) is frequently employed in combination therapy.

• BPO + topical antibiotic (e.g., clindamycin + BPO): reduces bacteria and inflammation while limiting resistance.
• BPO + retinoid (e.g., adapalene + BPO): targets both comedones and inflammation by normalizing keratinization and killing bacteria.
• BPO + oral antibiotic (e.g., doxycycline + BPO): used in moderate–severe acne for enhanced efficacy and resistance control.

Overall, BPO combinations improve treatment outcomes and are first-line in acne therapy [37].

1. 1. 2. Salicylic acid:

Because of its keratolytic and comedolytic qualities, salicylic acid is frequently utilized in combination therapy for acne. It is frequently used in conjunction with topical retinoids, such as adapalene, to improve follicular exfoliation and stop the development of comedones or with benzoyl peroxide to improve antibacterial efficacy against Cutibacterium acnes. Additionally, formulations combining salicylic acid with niacinamide help reduce inflammation and regulate sebum production, making them suitable for mild to moderate acne. These combinations improve therapeutic outcomes by targeting multiple pathogenic mechanisms simultaneously while maintaining good tolerability [38].

1. 1. 3. Azelaic acid:

Because of its antibacterial, anti-inflammatory, and keratolytic qualities, azelaic acid is frequently used in combination therapy for mild to moderate acne. It is frequently used with topical retinoids (e.g., tretinoin or adapalene) to enhance normalization of follicular keratinization and improve comedone clearance. When used with benzoyl peroxide, it provides synergistic antimicrobial action against Cutibacterium acnes while reducing inflammation. Azelaic acid is also effectively combined with oral antibiotics in moderate acne to enhance lesion reduction and minimize resistance. Additionally, it offers the advantage of reducing post-inflammatory hyperpigmentation, making it particularly beneficial in patients with acne-associated pigmentation concerns [39].

1. 3. Systemic Therapy

Systemic therapy is used for moderate to severe AV, especially when unresponsive to topical treatment. It includes oral antibiotics (e.g., doxycycline) to reduce bacteria and inflammation, oral isotretinoin to target all major pathogenic factors, and hormonal therapy in females to control androgen effects. These treatments are effective but require monitoring due to potential side effects [40].

6.3.1 Oral antibiotics:

When lesions are large or do not respond to topical treatment, Moderate to severe inflammatory acne is often treated with oral antibiotics. Tetracyclines such as doxycycline and minocycline, are often given medications that have both antimicrobial activity against
The anti-inflammatory qualities of Cutibacterium acnes by preventing neutrophil chemotaxis and pro-inflammatory cytokines. These medications successfully enter the lipid-rich pilosebaceous unit, lowering inflammation and bacterial colonization. Erythromycin and other macrolides are substitutes, however because of growing antibiotic resistance, they are less favored. Since long-term usage is discouraged, oral antibiotics are usually recommended for a short period of time (8–12 weeks) and coupled and prevent resistance [41].

6.3.2 Oral isotretinoin:

A powerful vit. A derivative used to treat resistant or severe acne is oral isotretinoin. By decreasing sebum production, restoring keratinization, preventing Cutibacterium acnes, and having anti-inflammatory actions, it tackles all significant pathogenic causes. Although it offers long-term remission, adverse effects such teratogenicity, dryness, and lipid alterations necessitate close observation [42].

6.4 Hormonal Treatment of Acne Vulgaris

Females with acne linked to androgen excess, such as those with Polycystic Ovary Syndrome or persistent adult acne, are primarily treated with hormonal therapy. It functions by lowering androgen activity, which in turn lowers sebaceous gland stimulation and sebum production. Combination oral contraceptives, which contain both progestin and estrogen, decrease ovarian androgen production and raise sex hormone-binding globulin to lower free testosterone levels. Anti-androgens like spironolactone reduce inflammation and oil production by inhibiting androgen receptors in sebaceous glands. Hormonal therapy is frequently used in conjunction with topical therapies and is especially beneficial for acne on the jawline and lower face. After three to six months of treatment, clinical improvement is typically seen [43, 44].

6.5 Physical Procedures in Acne Vulgaris

Physical procedures are adjunctive treatments used to manage acne, especially in moderate to severe or resistant cases. These include comedone extraction, chemical peels (such as glycolic acid and salicylic acid), laser and light-based treatments, cryotherapy, and intralesional corticosteroid injections. Comedone extraction helps remove blackheads and whiteheads, while chemical peels promote exfoliation and reduce follicular blockage. Laser and light therapies (like photodynamic therapy and blue light) target Cutibacterium acnes and lessen inflammation. For nodules and cysts, intralesional corticosteroids are used to quickly reduce inflammation and avoid scarring. These procedures are often combined with medical therapy for enhanced clinical outcomes [45].

Table 2. Pharmacological Classification of Anti-Acne Drugs [46,47]