Scientific Connection Between Acne and Diet

Acne Current Concepts and Management, Updates in Clinical Dermatology

Acne is the most prevalent sebaceous glandrelated skin disease characterized by excessive sebum production, inflammation, altered keratinization, and overgrowth of Cutibacterium acnes [1, 2].

In the past, it was commonly believed that acne had no relationship with diet [3, 4]. It was generally believed that there was no relationship between acne severity and total calorie intake, carbohydrates, lipids, proteins, and so on. Chocolate was also presumed to be innocent [5]. But, the controversy about the correlation between acne and food continued [6, 7].

In one study, 32% of acne patients suggested diet as the third main cause of acne after hormones and genetic factors, and 44% of them considered foods as an aggravating factor for acne [8]. In another study, 11% of English teenagers responded that greasy food is the main cause of acne [9]. In addition, in a survey of final-year medical students in the University of Melbourne, 41% answered that diet is an important factor of acne exacerbation even though they learned from school that acne has no relationship with diet [10].

A pioneering observational study by Cordain et al. became a turning point in this long controversy and resulted in the change of paradigm.

In this article, authors suggested that acne is a disease of western civilization.

They performed cross-sectional studies for two tribal people: 1200 Kitavan islanders in Papua New Guinea and 115 Aché hunter-gatherers in Paraguay. They could not find any acne patients among these people with the age of 15–25 [11]. However, other tribal people living in more westernized civilization whose ethnic backgrounds are similar to these two tribes were reported to have much higher acne prevalence [12, 13]. Therefore, although genetic factors cannot be ruled out, the authors began to suspect the role of diet in acne development. The Kitavan islanders and Aché hunter-gatherers consumed dairy products, coffee, tea, oil, margarine, cereal, sugar in negligible amounts and their fat intake was considerably low.

Instead, they ingested carbohydrate in the form of low glycemic load diet like tubers, fruits, and vegetables [11].

Glycemic load, defined as a function of glycemic index and carbohydrate intake, is a measure of total glycemic response to a food or meal. Glycemic load is calculated as glycemic index multiplied by grams of carbohydrate in 100 g of food [14]. Glycemic index measures how much of a rise in circulating blood sugar level a carbohydrate can trigger compared to glucose which is set equal to 100 [15]. If the glycemic load of a food is more than 20, it is considered high and if it is less than 10, it is considered low. Western refined foods such as crisped rice cereal, jelly beans, rice cake, and table sugar have high glycemic loads which are more than 50.

On the contrary, unrefined food like parsnips, baked potatoes, fruits, and vegetables have low glycemic loads which are less than 10 [16, 17].

Hormonal cascade triggered by high glycemic load diet-induced hyperinsulinemia was suggested to explain the mechanism of acne development [17]. High glycemic load diet causes acute or chronic hyperinsulinemia which subsequently increases insulin-like growth factor-1 (IGF-1), a potent mitogen for all kinds of tissues [18, 19]. IGF-1 can promote keratinocyte proliferation, hyperkeratinization of hair follicles, and sebocyte growth, which play important roles in acne pathogenesis. Hyperinsulinemia also decreases IGFBP-3 directly or indirectly, which further increases the bioavailability of free IGF-1 in blood [15, 20].

In addition, insulin and IGF-1 can increase sebum production directly or indirectly by decreasing sex hormone binding globulin (SHBG) synthesis in the liver [21] and increasing synthesis of androgen in ovary and testicular tissues [22, 23]. There are several clinical evidences that support the role of endocrine factors in acne provocation and aggravation.

Women with post-adolescent acne maintain elevated serum concentrations of IGF-1, androgen, and insulin and they are mildly insulin-resistant [24].

Also, polycystic ovary syndrome (PCOS) patients show acne as a characteristic clinical feature. PCOS patients are:

• hyperinsulinemic, (means the amount of insulin in the blood is higher than what's considered healthy.)

• insulin-resistant, (when cells in your muscles, fat, and liver don't respond well to insulin and can't easily take up glucose from your blood.)

• and hyperandrogenic. (any state with an excess production of “male” hormones)

In these patients, IGF-1 serum level is elevated and SHBG level is decreased, which are consistent with hormonal cascade in acne development [25, 26].

Metformin, an anti-hyperglycemic agent, is used for the treatment of PCOS and also demonstrated to improve acne [27].

In native environments, non-westernized people were neither overweight nor hypertensive. They maintained low serum concentration of insulin, plasminogen activator inhibitor 1, and leptin. However, after they were adapted to westernized diet, they frequently became hyperinsulinemic and developed higher rates of type 2 diabetes [28]. More importantly, in dermatological aspect, acne began to occur.

Significantly, lower prevalence of acne was observed in tribes such as Inuit, rural villages of Kenya, Zambia and Bantu, Okinawa, Arequipa in Peru, and Purus valley in Brazil [29–31]. In fact, even in white races such as young Irish women, who were not adopting western diet, showed no or at least far less prevalence of acne [32].

They started to develop acne after they moved to the urban area [33].

Although chocolate was presumed to have no association with acne, debates are still ongoing over that issue. There are several studies which investigated the association between chocolate and acne.

In one study, a crossover single-blinded study was conducted to confirm the effect of chocolate on acne. Patients were assigned to eat either chocolate bar or control bar daily for 4 weeks and were assessed for the change of acne severity. The authors found out that acne severity did not change during the study periods and concluded chocolate is innocent [34]. However, the control bar used in this study was inappropriate because it contained similar total sugar and fat content as the chocolate bar [35].

In another study which investigated university students with mild to moderate acne, the authors also concluded that chocolates are innocent in acne development [36]. However, the sample size was only eight, and study participants consumed chocolate only on two successive days. In addition, although four subjects developed up to five new papules or pustules, the result was described as not significant change without statistical evaluation and controlled follow- up.

In 1971, university students with acne who identified dietary triggers were investigated. It was concluded that chocolate consumption and acne severity had no correlation [37]. However, there were also several limitations in this study: Sample size was not specified, no statistical evaluation, no control group, and follow- up of patients was not clear. These limitations made these articles unconvincing.

New evidences for the positive relationship between chocolate and acne have been published recently [38].

In a Korean study of investigating dietary patterns in acne patients, 783 acne patients and 502 controls were enrolled. Study participants answered the questionnaire about the association of acne and food which was verified for accuracy, reproducibility, and validity by specialists in nutrition and statistics [39]. According to their result, food intake was the major aggravating factor in male acne patients, and it was second to menstruation in female acne patients. Vegetables and green peas were eaten significantly higher in the control group than in acne patients, and glycemic loads of those foods were less than 10. On the other hand, compared to control group, significantly higher percentage of acne patients consumed junk foods such as donuts, waffles, carbonated drinks and instant noodles, which have glycemic load higher than 20. The intake of processed cheese, pork, chicken was also higher in acne patients. Especially, roasted pork and fried chicken consumption was more significantly associated with the aggravation of acne. Although these kinds of foods have no or very low carbohydrate, they have higher fat content so that increased consumption of such food can lead to acne aggravation.

There was also an article about the reduction in fat intake resulting in the decrease of androgen level [40].

After low fat diet, decrease in serum and urine androgen levels was observed.

In biochemical parameters, IGF-1 was significantly higher in acne patients aggravated by foods than in acne patients not aggravated by foods while IGFBP-3 was lower in acne patients aggravated by foods.

Conclusively, high glycemic load diet, dairy food intake, high fat diet, irregular dietary patterns were found to aggravate acne.

As for the possible association between the dietary dairy intake and acne, there was an interesting study that investigated more than 47,000 women [41].

The authors found significant association between acne and milk, sherbet, cheese, trans-unsaturated fat, and vitamin D supplement.

They divided milk into 4 kinds: whole milk, low fat milk, skim milk, and powdered milk. Especially skim milk had strong association with acne which made fat content of milk unlikely to cause acne. Instead, they suspected hormonal content of milk as a cause of acne [41].

In addition to estrogen and progesterone, milk contains androgen and its precursors which are involved in the process of comedogenesis [42]. It contains glucocorticoid and IGF-1 that can also act on sebaceous gland [43]. While processing milk to cheese, androstenedione is converted to testosterone, a more potent form of androgen. Skim milk processing may increase the bioavailability of bioactive molecules or change their interaction with binding proteins while whole milk contains more estrogen, which tends to reduce acne, than skim milk [44]. α-Lactalbumin, a primary transport protein in milk, has biologic effects similar to those of androgen and is added to low- fat and skim milk in processing [45].

Clinical relationship between acne and dairy products was confirmed again in a large case-control study [46].

Accumulated scientific evidences suggest signal transduction caused by IGF-1, insulin, and glucose in high glycemic load diet, high milk and dairy food intake. IGF-1 and insulin activates IRS-1/PI3K/Akt pathway, and this pathway plays an important role in acne pathogenesis [47].

Yoon et al. reported that epigallocatechin-3-gallate (EGCG), a constituent of green tea, improves acne by modulating intracellular molecular targets and inhibiting C. acnes.

In this study, EGCG inhibited IGF-1R, IRS-1, PI3K, Akt in AMPK- dependent manner in sebocytes (Fig. 7.1) [48].

Activation of this pathway inhibits TSC1/TSC2 which controls Rheb, a GTP-binding protein ubiquitously expressed in humans and other mammals. Consequently, IGF-1, insulin, and glucose upregulate Rheb which subsequently activates mTORC1 signaling pathway, and it leads to high protein, lipid synthesis, and increased sebocyte and keratinocyte growth and proliferation [49].

mTORC1 is a nutrient-sensitive kinase and integrates signals of cellular energy, growth factors like insulin, IGF-1, and protein-derived signals, predominantly leucine [50, 51]. It stimulates ribosome biogenesis, protein synthesis, cell growth, and proliferation while suppressing autophagy. Importantly, it is the central activator of lipogenesis. When mTORC1 is inactivated, lipin 1 in the nucleus prevents SREBP from being attached to promoter site of target gene. But when mTORC1 is activated, lipin1 is phosphorylated and stays in the cytoplasm, being unable to prevent SREBP binding to promoter site, which leads to lipogenesis [52].

Leucine, enriched in beef, cheese, and milk, is also an important factor in signaling pathway. In cooperation with Ras GTPase, leucine translocates inactive form of mTORC1 into lysosomal department which contains Rheb, turning mTORC1 into active form. Leucine also acts as a structural lipid precursor for de novo sebaceous lipid synthesis in the presence of insulin [49]. IGF-1 and insulin also controls FoxO1 by Akt signaling. FoxO1 is in the nucleus to prevent androgen receptor from being activated. When IGF-1R/IRS-1/PI3K/Akt pathway is activated, FoxO1 is phosphorylated and it moves into cytoplasm resulting in androgen receptor activation [53]. Other than that, FoxO1 has various functions. When FoxO1 expression is increased, it acts against the development of acne by inhibiting lipogenesis, cell proliferation, and androgen receptor activation.

Isotretinoin, one of the most widely used treatment option for acne patients, decreases cell proliferation and promotes apoptosis of sebocytes. Its mechanism is suggested to involve the increased function of FoxO1 which subsequently activates TSC1/TSC2 by way of AMPK [54, 55]. Activation of TSC1/TSC2 results in the downregulation of mTORC1 signaling.

From these findings, we can hypothesize that reduced glycemic load diet, less dairy products and less fat intake will be able to improve acne.

Kwon et al. investigated clinical and histological effect of high glycemic load diet in the treatment of acne patients. In their results, non-inflammatory and inflammatory acne lesions were significantly decreased at week 10 and 5, respectively, compared with the control group. Changes in glycemic load and acne lesion counts showed positive correlation in linear regression analysis.

In skin biopsy specimen, the size of sebaceous gland was significantly decreased after low glycemic load diet.

They also confirmed reduced expression of SREBP1 and IL-8, which altogether suggested the mechanism of improvement of acne in this 10 week clinical trial of dietary intervention [56]. There are some suggestions for best diet for acne.

According to Jung et al., the higher frequency of vegetables and fish intake seems to be associated with low prevalence of acne [39].

Also, there was an interesting article that dietary supplementation with omega-3 fatty acid and gamma-linolenic acid decreased inflammatory and non-inflammatory acne lesions significantly. In their results, patient subjective assessment of improvement showed similar results with objective assessment. In the skin biopsy of this clinical trial, reductions in inflammation and IL-8 were observed after supplementation.

Although the exact mechanism is yet to be studied more, omega-3-fatty acid was known to have anti- inflammatory effect, reduce sebum production, and decrease IGF-1 while increasing IGFBP-3.

Gamma-linoleic acid may ameliorate acne by producing prostaglandin E1 (PGE1) and 15-hydroxydihomo-γ-linolenic acid (15-OH-DGLA). These molecules showed the decrease of pro-inflammatory cytokines and eicosanoids, and the anti-proliferative effect on keratinocytes [57]. The mechanism involved in the scientific connection between acne and diet continues to expand.

In addition to high glycemic load diet and dairy products, saturated fat such as palmitate can activate mTORC1.

FoxO1 and mTORC1 are affected by many molecules through various signaling pathways, and they can also activate many other target molecules. Ultimately, they can activate inflammasome with IL-1β release and Th17 cell differentiation which are important in acne pathogenesis [58].

In conclusion, the relationship between acne and diet cannot be overemphasized in view of accumulating scientific evidences.

High glycemic load diet should be avoided. The ingestion of high amount of fat, leucine, milk, and dairy products may aggravate acne. Because we cannot test all foods, it would be appropriate to advise patients to avoid foods that they believe would worsen acne.

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