with AV have an underrepresentation of Bifidobacterium and Butyricicoccus, which are primary producers of butyrate.50 Research suggests that butyrate may play a key role in improving the epithelial defense barrier, improving oxidative status, and relieving mucosal inflammation.53 It does so in part by providing energy to the gastrointestinal cells.52 Preclinical research indicates that butyrate may have a pro-apoptotic effect on the cell cycle, as well as effects on proliferation and differentiation.54 This is believed to be the underlying mechanism in its beneficial effects on hyperproliferative skin diseases such as psoriasis.54 In addition to directly providing energy and cell cycle control, butyrate may also activate regulatory T cells, which could be a connection to its anti-inflammatory properties.54
Hormones
Balancing androgen levels is used to treat AV in the clinic. Combined oral contraceptives mitigate the effect of hormonal fluctuation, improving AV in female patients.4 Spironolactone is a potassium-sparing diuretic with anti-androgenic properties.55 It is now used widely to treat female patients with AV and is considered an alternative to antibiotic therapy.4 Spironolactone is used at doses of 50-100mg/day for treating female patients with mild-to-severe AV but is contraindicated in patients who are pregnant or trying to conceive.55,56 While efficacious, these treatments are irrelevant to at least half the population or may come with unwanted side effects.4
Alternatively, botanicals have been used to mitigate mild effects of excess androgens in conditions such as menopause and PCOS. Maca (Lepidium meyenii), for example, is a Peruvian root used in high altitudes to maintain health and energy and address female-specific hormonal imbalances such as infertility and menstrual irregularities.57 In a double-blind, randomized, placebo-controlled study of early post-menopausal women, the oral intake of Maca tablets was significantly correlated to an increase in E2 production and suppression of FSH and LH.57 It also was linked to an increase in high density lipoprotein (HDL) levels and alleviated the frequency and severity of reported menopausal symptoms such as hot flushes and night sweats.57 Maca has also been associated with lower serum IL-6 levels and mitigated antidepressant-induced sexual dysfunction.58,59 All of this suggests that Maca could be a useful botanical supplement for addressing the underlying hormonal component of AV.
Selenium is also now being explored for its role in AV along with its androgen-modulating properties. Selenium levels in patients with AV have been reported as lower than in the general population.60 In a double-blind placebo-controlled study, women with PCOS who supplemented with selenium for 8 weeks showed significant improvement in AV.41 The study also noted a decrease in DHEA-S levels, an androgen that has been shown to be elevated in patients with AV.41 The oral intake of selenium was also associated with a significant decrease in C-reactive protein (CRP) and plasma malondialdehyde (MDA) levels, both markers for oxidative stress.41 When taking a patient-centric view, these findings suggest a link between decreased inflammation, oxidative stress, and AV improvement.
Oxidative Stress
While oxidative stress has not been specifically targeted by modern medicine in the clinic, many of the natural anti-aging phytochemicals with purported benefits in the skin in use today contain anti-oxidative properties. Lycopene, for example, in high concentrations in tomatoes, has been shown to inhibit oxidative markers that are generated in the skin during exposure to ultraviolet (UV) A and UVB.61 The oral intake of olive oil, long used for its supposed beneficial effects on the skin, was linked to a dose-dependent increase in HDL and the intracellular antioxidant glutathione peroxidase (GSH-Px), and a dose-dependent decrease in plasma oxidized LDL and other oxidized DNA and poly-unsaturated fatty acid (PUFA) markers.62 It was also associated with an increase in plasma concentrations of antioxidants such as tyrosol, hydroxytyrosol, and 3-O-methylhydroxytyrosol (MHT), a biological metabolite of hydroxytyrosol.62 In addition, a systematic review and meta-analysis concluded that ginger supplementation significantly reduced MDA levels as well as GSH-Px, both markers for oxidative stress.31
Sicilian orange, also known as blood oranges or Red Orange (Citrus sinensis, varieties Moro, Tarocco, and Sanguinello) has demonstrated high levels of antioxidative properties. A significant crop grown and exported in high-UV regions such as Italy and Egypt, blood oranges and their peels are rich sources of vitamin C.63,64 Their consumption for anti-aging properties is now being explored. An extract of these Sicilian Red Oranges has been shown to contain high levels of antioxidants such as anthocyanins, hydroxycinnamic acids, flavanones, and ascorbic acid.63 A recent study showed that consumption of this complex decreased UV-induced skin redness, in part by increasing the total antioxidant capacity of the skin.63 MDA levels were significantly lower in the active group, indicating a decrease in lipoperoxide levels due to UV stimulation.63 With the strong indications for UV damage and its role in AV development and epidermal integrity, antioxidants may be useful in the mitigation of this damage, which could improve skin health.
Immune Function
Considering that the systemic drivers discussed here and in Del Rosso et al71 have been linked to pathways that may drive generalized immuno-inflammatory activation, targeting and attenuating components of an irregular immune system could improve AV outcomes. Curcumin, the golden component of turmeric, is widely known for its use in Asian and Indian cuisine. It has also been used for centuries for its anti-inflammatory properties and is now being investigated for its use in inflammatory bowel disease, colon cancer, psoriasis, rheumatoid arthritis, and a multitude of other inflammatory conditions.65,66 New insights into molecular pathophysiology now indicate that curcumin may attenuate the generalized inflammatory response in part by lowering circulating levels of TNF-alpha and CRP, key inflammatory mediators released during injury or tissue damage.65 In fact, TNF-alpha inhibitors used to treat other inflammatory diseases are sometimes used off-label to treat cases of severe AV that are not responsive to other treatments.67 Curcumin may also prevent the onset and development of an inflammatory response by suppressing the transcription factor NF-kappaB, a key regulator of genes associated with generalized inflammation.68
Indirectly, curcumin mitigates a generalized inflammatory response through its protective effects as an antioxidant. Curcumin's polyphenolic structure acts as a free radical scavenger, which could improve antioxidant capacity in the skin to mitigate damage by UV and environmental assaults.68 It has also been shown to increase the cellular antioxidant GSH, which would prevent ROS-induced tissue damage.68 Studies specifically in fibroblasts and keratinocytes have shown increased protective effects of curcumin against H2O2.68
Important in AV, curcumin has also been shown to have anti-microbial properties against opportunistic microbes such as S. epidermis and C. acnes. With this, curcumin has been linked to the suppression of bacterial proliferation and the formation of biofilms by decreasing adhesion molecules of the microbes.68 Knowing that antibiotics have proven successful in the treatment of AV, these antimicrobial properties could also be a tool to improve outcomes in patients with AV.
Considering curcumin’s compelling therapeutic profile, much focus has been on improving its limited bioavailability in its natural form. Patented biotechnology has found that reconstituting 95% standardized curcumin in non-curcuminoid oil from turmeric improves bioavailability by almost 700% compared to curcumin alone.69 With this, the therapeutic potential of curcumin described for centuries can be incorporated into dietary intake.
Clinical Support for the Combination of a Standardized Acne Supplement
As reviewed here, several ingredients have been clinically studied to improve some of the underlying root causes of acne on their own. One would expect, then, that combining varying amounts of key ingredients could theoretically have better clinical results compared to single target ingredients that have thus been evaluated in patients with acne. A novel nutraceutical was recently formulated to include key ingredients to address multiple systems-wide root causes of acne (Table 1). This combination nutraceutical could potentially
enable less usage of any one specific ingredient and have the benefit of the multi-faceted approach.
The Standardized Nutraceutical was evaluated in a proof-of-concept study conducted in 51 adults with non-cystic acne. The study was approved by an Institutional Review Board (Advarra IRB, Columbia, MD) and conducted in accordance with accepted standards for Good Clinical Practices. All participants provided written informed consent prior to participating, consistent with the requirements in 21 Code of Federal Regulations (CFR) 50.25. This was a 12-week single-arm prospective study for women and men aged 18 to 50 years with facial acne ranging from mild to severe, excluding cystic acne. Participants discontinued all acne medications and topicals prior to the start
