Taking a More Holistic View of the Pathogenesis of Acne 

Dermatologists are facing an increasing number of acne patients, particularly adult females, who are searching for treatment options. The interest in complementary and alternative medical treatments (CAM) is on the rise, with more dermatology patients seeking out CAM practitioners.¹ CAM treatments can be used as monotherapy for those who desire alternatives to medications. More commonly, CAM treatments are used in conjunction with traditional medications or as maintenance therapy. As such, they may accelerate healing time, reduce the time spent on medications, or mitigate unwanted side-effects from acne medications including skin irritation, antibiotic resistance, and antibiotic-induced gastrointestinal upset. Despite increasing interest in alternative treatment options, current AAD guidelines of care for acne do not recommend herbal and alternative therapies due to limited data on their safety and efficacy.² Thus, there is a need to address research gaps in how CAM treatments can be used to treat acne in a more holistic way.

Although the full pathophysiology is still evolving, the development of acne is conventionally viewed as the result of four pathogenic factors that occur locally at the pilosebaceous unit (PSU): follicular hyperkeratinization, excess sebum production, Cutibacterium acnes (C. acnes) colonization, and a local immune response. Current therapeutics, therefore, have targeted these mechanisms. Comedolytics, antimicrobials, hormonal therapies including combined oral contraceptives (COCs) and anti-androgens aim to prevent follicular plugging, reduce sebum production, eliminate pathogenic microbes and/or prevent the associated inflammation locally. 

Although these are the established mechanisms for the development of acne, more recent studies have demonstrated there are other factors that drive or exacerbate acne in our patients.³ These factors are now being discussed as part of a broader picture as they influence the pathogenesis of acne by affecting the whole patient and not just the microenvironment of the PSU. Endocrine changes, diet, lifestyle, stress, and other system-wide factors are now being considered when treating acne patients.³ These factors give us additional therapeutic targets that may be amenable to treatment with CAM therapies.

Endocrine Changes

Almost all acne has an underlying hormonal component, with a consensus that androgens are the main player.⁴ The onset of acne is linked to an increase in the production of androgens that occurs in both sexes at puberty. Polycystic ovarian syndrome (PCOS), a condition that affects an estimated 6-12% of U.S. women of reproductive age, is strongly associated with acne.⁵ PCOS is often diagnosed by dermatologists as these patients present with cutaneous signs of hyperandrogenism. More commonly, adult women often complain of so-called “hormonal acne” that occurs around the time of menstruation. These flare-ups are due to an increase in progesterone and sebum production associated with the luteal phase of the menstrual cycle.⁶ Accordingly, managing hormonal fluctuations is a critical part of addressing acne in the adult female patient. Anti-androgens and COCs are often prescribed to female acne patients to target hormonal fluctuations but these medications are limited in that they cannot be used in women who are trying to conceive or who are currently pregnant.

Lifestyle Considerations

Lifestyle should also be considered when addressing acne especially in adult women. Busy schedules, stressful jobs and family obligations may exceed the bandwidth of adult females. Stress is known to be correlated with acne flares and is now considered to be a systemic driver of acne.³ Stress in acne feeds a vicious cycle for the adult female patient in that stress causes acne and acne flare ups cause more stress. Stress affects cutaneous health in general and can worsen inflammatory conditions such as psoriasis and eczema. Research shows that there is a correlation between mean stress severity and acne grade, as well as impaired wound healing, that may hinder resolution of acne lesions.⁷ On a systemic level, stress drives hormone fluctuations via the hypothalamic-pituitary-adrenal axis (HPA), with an associated release of corticotropin-releasing hormone (CRH) and increase in circulating cortisol.⁸ CRH stimulates sebaceous glands, steroidogenesis, and cytokine production by keratinocytes leading to the inflammation seen in acne. At the lesion site, it has been observed that peripheral nerves release substance P, a neuropeptide that accumulates locally around the sebaceous gland.⁹ Substance P stimulates mast cell proliferation, degranulation, and the release of pro-inflammatory cytokines.⁹ Taken together, the physiologic response to stress is both a systemic and local driver of inflammation associated with acne. 

Diet

Diet and metabolism of macronutrients, vitamins, and minerals affect cutaneous health. The standard Western diet, high in simple carbohydrates and low in nutritional content, is thought to be a main contributor to acne. A high glycemic index diet affects multiple pathways that lead to immune activation and increased inflammation at the PSU.¹⁰ Glycemic load, blood glucose levels, insulin, and insulin-like growth factor (IGF-1) have been linked to increased sebum production at the PSU, hyperkeratinization, and cutaneous endocrine responses, as well as systemic immune activation. Accordingly, diet is now recognized as an important contributing factor to acne.¹⁰

Vitamins and minerals have long been recognized for their role in skin health as deficiencies in these nutrients result in conditions that are characterized by cutaneous findings. Lower levels of vitamin A, D, and folate, have been observed in acne patients, suggesting an association of vitamin levels and epithelial health.^11,12 Zinc, selenium, and vitamin D have all been found to be associated with acne and/or disease severity.^11,12 Taken together, we understand that nutrition status impacts acne and should be a part of the discussion when managing acne patients with a systems-wide approach.

Stress

Patients with acne are known to be under systemic and cutaneous oxidative stress.¹³ Reactive oxygen species (ROS) may be generated by environmental exposures or as a byproduct of mitochondrial energy production. Studies have demonstrated that patients with acne have an increase in circulating biomarkers for oxidative stress such as thiobarbituric acid reactive substance (TBARS) and malondialdehyde (MDA) and a decrease in both vitamin and enzymatic antioxidants.¹⁴ At the PSU, ROS accumulate causing oxidization of sebum lipids such as squalene.¹⁵ Squalene peroxide is comedogenic, pro-inflammatory, and facilitates colonization with C acnes.¹⁵C. acnes colonization also leads to neutrophil infiltration that further produce ROS.¹⁴ Thus, oxidative stress may be an early factor that drives the acne process. 

The role of the microbiome in the pathogenesis of acne continues to evolve. It is now understood that acne is not caused by an over proliferation of C. acnes per se, but instead results from dysbiosis caused by loss of diversity in C. acnes phylotypes.¹⁶ This dysbiosis triggers activation of the innate immune system, release of inflammatory mediators resulting in inflammation at the PSU.¹⁶ In addition, Staphylococcus epidermidis controls C. acnes growth and reduces inflammation caused by C. acnes.¹⁶C. acnes also inhibits growth of S. epidermidis by maintaining an acid environment in the PSU.¹⁶ On a broader scale, the role of bacteria in the pathogenesis of acne extends beyond the skin.¹⁷ Patients with acne exhibit lower gut microbiome diversity when compared to healthy controls.¹⁸ Gut dysbiosis compromises the intestinal barrier, triggers immune activation and results in the release of inflammatory mediators including lipopolysaccharide endotoxins into the systemic circulation.¹⁶ This systemic inflammatory response may play a role in triggering or exacerbating acne.

Other System-wide Factors

Finally, the compounding effects of these systemic drivers of acne leads to an aberrant or exaggerated immune response, that contributes to acne.¹⁹ Oxidative stress, microbial dysbiosis, emotional stress, and the other factors discussed here are associated with increased immune system activation and release of inflammatory mediators such as IL-1, IL-6, TNF, and substance P.²⁰ The local immune response at the PSU includes resident macrophages, mast cells, and other immune cells.²⁰C. acnes triggers immune responses through multiple pathways, including interaction with toll-like receptors, activating inflammasomes, inducing the production of matrix metalloproteases, and stimulating antimicrobial peptide activity.¹⁹ Neutrophil recruitment to the site of inflammation leads to damage of the sebaceous gland and epithelium. This cascade of events leads to inflammation, erythema, pain, and post-acne sequelae.

We currently have many tools for managing acne, although most are targeted to treat acne at the level of the PSU. There is mounting evidence that much of acne is the result of other contributing factors such as diet, lifestyle, environmental exposures, endocrinopathies, and other systemic metabolic processes leading to a generalized inflammatory response. Accordingly, targeting these factors using nutritional interventions, supplements, and lifestyle changes makes sense as part of a more comprehensive strategy for the adult acne patient. By using a more holistic approach, dermatologists can help patients achieve clearer skin, improved skin health, and overall well-being. n

Patricia K. Farris, MD, MS, is a dermatologist in private practice in Louisiana, and is a clinical associate professor at Tulane University. Dr. Farris is a co-founder and medical advisor at RegimenMD.

1. Landis ET, Davis SA, Feldman SR, Taylor S. Complementary and Alternative Medicine Use in Dermatology in the United States. The Journal of Alternative and Complementary Medicine. 2014-05-01 2014;20(5):392-398. doi:10.1089/acm.2013.0327

2. Reynolds RV, Yeung H, Cheng CE, et al. Guidelines of care for the management of acne vulgaris. Journal of the American Academy of Dermatology. 2024;doi:10.1016/j.jaad.2023.12.017

3. Del Rosso J, Farris PK, Harper J, Baldwin H, Hazan A, Raymond I. New Insights Into Systemic Drivers of Inflammation and Their Contributions to the Pathophysiology of Acne. J Drugs Dermatol. Feb 1 2024;23(2):90-96. doi:10.36849/JDD.8137

4. Bienenfeld A, Azarchi S, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR. Androgens in women: Androgen-mediated skin disease and patient evaluation. Journal of the American Academy of Dermatology. 2019;80(6):1497-1506. doi:10.1016/j.jaad.2018.08.062

5. Carmina E, Dreno B, Lucky WA, et al. Female Adult Acne and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee. J Endocr Soc. Mar 1 2022;6(3):bvac003. doi:10.1210/jendso/bvac003

6. Arora MK, Yadav A, Saini V. Role of hormones in acne vulgaris. Clin Biochem. Sep 2011;44(13):1035-1040. doi:10.1016/j.clinbiochem.2011.06.984

7. Jovic A, Marinovic B, Kostovic K, Ceovic R, Basta-Juzbasic A, Bukvic Mokos Z. The Impact of Pyschological Stress on Acne. Acta Dermatovenerol Croat. Jul 2017;25(2):1133-141. 

8. Pondeljak N, Lugović-Mihić L. Stress-induced Interaction of Skin Immune Cells, Hormones, and Neurotransmitters. Clinical Therapeutics. 2020;42(5):757-770. doi:10.1016/j.clinthera.2020.03.008

9. Toyoda M, Nakamura M, Makino T, Kagoura M, Morohashi M. Sebaceous glands in acne patients express high levels of neutral endopeptidase. Exp Dermatol. Jun 2002;11(3):241-7. doi:10.1034/j.1600-0625.2002.110307.x

10. Baldwin H, Tan J. Effects of Diet on Acne and Its Response to Treatment. Am J Clin Dermatol. Jan 2021;22(1):55-65. doi:10.1007/s40257-020-00542-y

11. Ozuguz P, Dogruk Kacar S, Ekiz O, Takci Z, Balta I, Kalkan G. Evaluation of serum vitamins A and E and zinc levels according to the severity of acne vulgaris. Cutan Ocul Toxicol. Jun 2014;33(2):99-102. doi:10.3109/15569527.2013.808656

12. Lim S-K, Ha J-M, Lee Y-H, et al. Comparison of Vitamin D Levels in Patients with and without Acne: A Case-Control Study Combined with a Randomized Controlled Trial. PLOS ONE. 2016;11(8):e0161162. doi:10.1371/journal.pone.0161162

13. Bowe WP, Patel N, Logan AC. Acne vulgaris: the role of oxidative stress and the potential therapeutic value of local and systemic antioxidants. J Drugs Dermatol. Jun 2012;11(6):742-6. 

14. Kardeh S, Moein SA, Namazi MR, Kardeh B. Evidence for the Important Role of Oxidative Stress in the Pathogenesis of Acne. Galen Med J. 2019;8:e1291. doi:10.31661/gmj.v0i0.1291

15. Ottaviani M, Camera E, Picardo M. Lipid Mediators in Acne. Mediators of Inflammation. 2010;2010:1-6. doi:10.1155/2010/858176

16. Dreno B, Dagnelie MA, Khammari A, Corvec S. The Skin Microbiome: A New Actor in Inflammatory Acne. Am J Clin Dermatol. Sep 2020;21(Suppl 1):18-24. doi:10.1007/s40257-020-00531-1

17. Sanchez-Pellicer P, Navarro-Moratalla L, Nunez-Delegido E, Ruzafa-Costas B, Aguera-Santos J, Navarro-Lopez V. Acne, Microbiome, and Probiotics: The Gut-Skin Axis. Microorganisms. Jun 27 2022;10(7)doi:10.3390/microorganisms10071303

18. Deng Y, Wang H, Zhou J, Mou Y, Wang G, Xiong X. Patients with Acne Vulgaris Have a Distinct Gut Microbiota in Comparison with Healthy Controls. Acta Derm Venereol. Aug 29 2018;98(8):783-790. doi:10.2340/00015555-2968

19. Firlej E, Kowalska W, Szymaszek K, Rolinski J, Bartosinska J. The Role of Skin Immune System in Acne. J Clin Med. Mar 13 2022;11(6)doi:10.3390/jcm11061579

20. Tanghetti EA. The role of inflammation in the pathology of acne. J Clin Aesthet Dermatol. Sep 2013;6(9):27-35.