Acne vulgaris case management with sustainable, functional methods requires its recognition as a disorder of inflammation associated with loss of immune tolerance for a commensal skin bacteria. A paper published in the Journal of Clinical and Aesthetic Dermatology discusses how elucidating the role of inflammation in the pathology of acne is advancing our understanding:
“The conventional perspective of acne pathogenesis holds that Propionibacterium acnes, which is present on normal skin, colonizes the duct of the sebaceous follicle, causing an innate immune response and the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule. However, this viewpoint has come under increasing scrutiny over the last decade, as several lines of evidence have emerged suggesting that inflammation may exist throughout the lifecycle of the acne lesion, perhaps subclinically even before comedo formation. This evidence challenges the current nomenclature of noninflammatory versus inflammatory acne lesions and suggests that the nomenclature is both outdated and incorrect.”
Acne has always been considered an inflammatory disorder in its later stages, but emerging evidence indicates that acnes starts with inflammation.
“There has been little debate about the involvement of inflammation in the later stages of acne, manifested as clinically inflamed papules and pustules. Accumulating histological and immunological evidence, but increasingly also evidence derived from a clinical platform, supports the notion of inflammation as a fundamental process in the early development of acne lesions.”
In this regard…
“…relatively recent studies have suggested that inflammatory events may also occur very early in the development of acne lesions (microcomedones), even before the initial hyperproliferative changes. In these studies, the uninvolved skin from acne patients was found to contain elevated levels of CD3+ and CD4+ T cells in the perifollicular and papillary dermis and increased macrophage numbers similar to those seen in papules.
The role of Propionibacterium acnes
The association of P. acnes with acne vulgaris has been accepted for more than a century, but its central causative role is now being challenged.
“Although several early reports implicated P. acnes as the central causative factor in the development of inflammation in acne vulgaris, numerous observations are inconsistent with this notion. Leyden et al found a much higher density of Propionibacteria among patients with acne vulgaris compared with persons without acne, but failed to show an association between P. acnes density and severity of inflammation. Indeed, in this study, there was a lower density of P. acnes on the foreheads of patients with numerous large papules or pustules with or without nodulocystic lesions, than in individuals with no inflammatory lesions. Similarly, Leeming et al found no significant difference in the proportion of inflamed pilosebaceous units containing P. acnes when biopsied after 1 or 3 days of development, again failing to establish an association between P. acnes density and the development or progression of inflammatory lesions.”
Acne inflammation occurs even without P. acnes
Moreover, acne lesions can occur without the presence of P. acnes:
“Additionally, several independent studies have also shown that comedones are not universally colonized by P. acnes, supporting the argument that the micro-organism is not required for comedogenesis. Lavker et al studied follicular casts (“incipient or potential comedones”) taken from prepuberal children and children aged 9 to 12 years with open and closed comedones. They found no evidence of P. acnes colonization, raising the possibility that early events in comedo formation may occur in the absence of P. acnes. Given that a substantial proportion of comedones have been found to be sterile, it has been suggested that the micro-organisms found in inflammatory lesions are simply an extension of those already colonizing comedones and that their presence is not required for initiation of inflammation in acne…Considered collectively, these findings convincingly demonstrate that only a proportion of acne lesions, whether very early or clinically inflamed, contain micro-organisms. Thus, it appears that P. acnes is not required for the development of inflammation in acne lesions, regardless of the lesion type. That an inflammatory response can occur in the absence of P. acnes suggests that the inflammatory process is being driven via different immunochemical pathways independent of P. acnes. In this regard, accumulating evidence supports a significant role for the sebaceous gland in the development of inflammation in acne lesions.”
After reviewing the contribution of proinflammatory agents inclduing the cytokines IL-1 and IL-8, protease-activated receptor-2 (PAR-2), b-defensin-1 and b-defensin-2, peroxisome proliferator activated receptors (PPARs), peptidases and neuropeptides the authors conclude:
“Emerging data indicate that acne vulgaris is a primary inflammatory disease, with histological, immunological, and clinical evidence suggesting that inflammation occurs at all stages of acne lesion development. The immunochemical pathways underlying the initiation and propagation of the inflammation in acne are complex and still being elucidated, but may involve P. acnes. However, given that an inflammatory response can also occur in the absence of P. acnes, in both early and clinically inflammatory lesions, other pathways of inflammation, in addition to those requiring P. acnes for activation or propagation, must exist. These include various inflammatory pathways activated within and around the sebaceous gland, and perhaps other as yet unidentified pathways. Thus, because inflammation is critical to all types of acne lesions and is multifactorial, anti-inflammatory drugs can be expected to exert effects against all lesion stages, albeit via distinct mechanisms of anti-inflammation.”
Interleukin-1 (IL-1) and the NLRP3 inflammasome in Acne
A study published recently in the Journal of Investigative Dermatology examines key inflammatory pathways in acne and highlights the role of IL-1β:
“Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1β mRNA and the active processed form of IL-1β are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte–macrophage NLRP3-inflammasome activation, IL-1β processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1β and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes—by activating the inflammasome—can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1β as possible therapeutic targets in acne.”
Key point: P. acnes is a commensal organism in the skin. The decisive factor is whether the immune system mounts an inflammatory reaction or not. This may be analogous to gastrointestinal disorders than ensue from the immune system having lost tolerance for commensal organisms in the gut.
The authors of a commentary in the same journal state:
“Such findings suggest that molecules targeting IL-1β and/or the NLRP3 inflammasome may constitute new treatment possibilities for acne vulgaris.”
Th17/IL-17 inflammatory cascade in acne
Inflammation driven by Th17 white blood cells and the cytokine interleukin-17 (IL-17) is a hallmark of autoimmunity. Evidence for their role in acne suggests that a loss of immune tolerance may be an important factor in developing an inflammatory reaction to P. acnes. Another study published last month also in the Journal of Investigative Dermatology offers details:
“Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4+ T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions.”
“We show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4+ subpopulation involved in inflammatory acne.”
The implication here is that the Th17/IL-17 inflammatory cascade is upregulated in people with acne by comparison.
The host response to P. acnes is decisive, not simply their presence
The authors of a study published in the Journal of Dermatological Science, while elucidating additional inflammatory agents, articulate the key point that Propionibacterium acnes can be present in skin without there being acne lesions—it is the host inflammatory response that determines whether or not they suffer from acne:
“The aim of the present study is to evaluate the importance of the immune response to P. acnes and the bacteriological factor in the pathogenesis of acne.”
To investigate they cultured P. acnes from both subjects with acne lesions and healthy volunteers, and examined the cytokine response of their peripheral blood mononuclear cells (PBMC) when stimulated with the viable P. acnes. Their was a clear difference:
“IFN-γ, IL-12p40, and IL-8 mRNA and protein production were significantly increased in PBMC from acne patients compared to that from normal donors. However, different P. acnes species isolated from acne lesions or normal subjects showed no difference in cytokines production from acne patients and normal subjects PBMC.”
In other words, the strain of the P. acnes did not matter at all, only the host inflammatory response. So the authors conclude:
“The inflammatory response of acne appears to be attributable to P. acnes-induced host immune response rather than P. acnes strains from normal skin or acne lesions.”
Immune regulating Vitamin A and Vitamin D ameliorate reaction to P. acnes
As might be expected for a condition characterized by a dysregulated immune inflammatory response—essentially loss of immune tolerance to P. acnes—with excessive IL-17 activity, the authors of another study published in the Journal of Investigative Dermatology found that Vitamin A and Vitamin D can help calm down the inflammatory reaction:
“Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs). P. acnes stimulated expression of key Th17-related genes, including IL-17A, RORα, RORc, IL-17RA, and IL-17RC, and triggered IL-17 secretion from CD4+, but not from CD8+ T cells…Furthermore, we found that the combination of IL-1β, IL-6, and transforming growth factor-β-neutralizing antibodies completely inhibited P. acnes–induced IL-17 production.”
They too found that the host response is decisive:
“Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from normal donors.”
And that Vitamin A and Vitamin D, both known to help normalize immune tolerance, can help:
“Finally, vitamin A (all-trans retinoic acid) and vitamin D (1,25-dihydroxyvitamin D3) inhibited P. acnes–induced Th17 differentiation. Together, our data demonstrate that IL-17 is induced by P. acnes and expressed in acne lesions and that both vitamin A and D could be effective tools to modulate Th17-mediated diseases such as acne.
Acne and the gut-brain axis
As with other autoimmune inflammatory disorders the potential role of the gut-brain axis should be considered with acne. The authors of a review article published in the journal Beneficial Microbes articulate the gut-brain-skin theory and several mechanisms by which intestinal dysbiosis and altered gut permeaiblity may contribute.
“Acne vulgaris has long been postulated to feature a gastrointestinal mechanism, dating back 80 years to dermatologists John H. Stokes and Donald M. Pillsbury. They hypothesised that emotional states (e.g. depression and anxiety) could alter normal intestinal microbiota, increase intestinal permeability, and contribute to systemic inflammation. They were also among the first to propose the use of probiotic Lactobacillus acidophilus cultures. In recent years, aspects of this gut-brain-skin theory have been further validated via modern scientific investigations. It is evident that gut microbes and oral probiotics could be linked to the skin, and particularly acne severity, by their ability to influence systemic inflammation, oxidative stress, glycaemic control, tissue lipid content, and even mood. This intricate relationship between gut microbiota and the skin may also be influenced by diet, a current area of intense scrutiny by those who study acne.”
Diet and acne: refined carbohydrates do the most harm
Clarifying the issue of diet and acne, the authors of a paper published recently in the Journal of Drugs in Dermatology review the evidence and conclude that high glycemic carbohydrates are the main culprit:
“The prevalence of adult acne in the US appears to be increasing over the last few decades. But what’s behind the rise: is it nature or nurture? We are well aware that genetics can strongly influence a patient’s risk of developing acne. However, significant changes in germline genetic variants are unlikely to have occurred over the last 20 years. Consequently, we are forced to examine environmental variables, including diet.”
The authors acknowledge the confusion that had beset the topic of the role of diet in acne:
“The relationship between diet and acne, however, has been historically controversial. In the1930s through the 1960s, patients were regularly counseled regarding their dietary habits, as dietary triggers were thought to play a major role in acne. Following two critically impactful studies dietary restrictions were deemed no longer necessary. The idea that diet affected acne was relegated to myth. In 2007, one of the authors published a review in the JAAD re-implicating certain dietary factors in acne based on emerging evidence. This article concluded that refined carbohydrates and certain dairy products, in particular skim milk, appeared to be associated with acne. Since that review, several studies have been conducted, further elucidating which dietary factors play the largest role when it comes to acne. In this update, we present those studies and confirm our initial suspicion that refined carbohydrates are indeed the main dietary contributors to acne. This article is meant to serve as a follow up to that original JAAD publication, providing an update on the evidence linking diet and acne with a specific focus on carbohydrate intake.”
On extensive review of the evidence the authors conclude:
“Based on the data summarized here, dermatologists should encourage their acne patients to minimize their intake of high glycemic index foods.”
Celiac disease and acne
As might be expected considering the role in acne of a dysregulated immune inflammatory response with loss of tolerance to P. acnes, a study examining isoretinoin use found that acne risk is increased in subjects with celiac disease. The authors were first concerned about the pro-inflammatory effect of isoretinoin in the gut:
“Isotretinoin, a vitamin A analogue, can promote a pro-inflammatory milieu in the small intestine in response to dietary antigens. We hypothesized that oral isotretinoin exposure would increase the risk of celiac disease (CD).”
When they examined the data for 26,739 individuals with CD in all 28 pathology departments in Sweden the link with acne emerged:
“Ninety-three individuals with CD (0.35 %) and 378 matched controls (0.28 %) had a prescription of isotretinoin. This corresponded to an odds ratio (OR) of 1.22. Risk estimates were similar in men and women, and when we restricted our data to individuals diagnosed after the start of the Prescribed Drug Registry. Restricting our analyses to individuals diagnosed aged 12–45 years did not influence the risk estimates (OR 1.38). Meanwhile, having a diagnosis of acne was positively associated with CD (OR 1.34).”
Acne and Bee Venom Therapy
Considering evidence for the use of bee venom therapy (BVT) in other autoimmune inflammatory disorders, the authors of a study in the Journal of Investigative Dermatology examined its ability to palliate the inflammatory response to P. acnes:
“Melittin is the main component in the venom of the honey bee (Apis mellifera). It has multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-inflammatory mechanisms of melittin have not been elucidated in Propionibactierium acnes (P. acnes)–induced keratinocyte or inflammatory skin disease animal models. In this study, we examined the effects of melittin on the production of inflammatory cytokines in heat-killed P. acnes–induced HaCaT cells. Heat-killed P. acnes–treated keratinocytes increased the expression of pro-inflammatory cytokines and Toll-like receptor 2. However, melittin treatment significantly suppressed the expression of these cytokines through regulation of the NF-κB and MAPK signaling pathways. Subsequently, the living P. acnes (1 × 107 CFU) were intradermally injected into the ear of mice. Living P. acnes–injected ears showed cutaneous erythema, swelling, and granulomatous response at 24 hours after injection. However, melittin-treated ears showed markedly reduced swelling and granulomatous responses compared with ears injected with only living P. acnes. These results demonstrate the feasibility of applying melittin for the prevention of inflammatory skin diseases induced by P. acnes.”
Acne and lauric acid in coconut oil—stronger than benzoyl peroxide
Coconut oil is thought to be beneficial for the skin. Lauric acid has known antimicrobial properties and accounts for about half the fatty acids in coconut oil. Authors of a study in the same journal investigated its use against P. acnes:
“The strong bactericidal properties of lauric acid (C12:0), a middle chain-free fatty acid commonly found in natural products, have been shown in a number of studies…This study evaluated the antimicrobial property of lauric acid against P. acnes both in vitro and in vivo. Incubation of the skin bacteria P. acnes, Staphylococcus aureus (S. aureus), and Staphylococcus epidermidis (S. epidermidis) with lauric acid yielded minimal inhibitory concentration (MIC) values against the bacterial growth over 15 times lower than those of benzoyl peroxide (BPO). The lower MIC values of lauric acid indicate stronger antimicrobial properties than that of BPO. The detected values of half maximal effective concentration (EC50) of lauric acid on P. acnes, S. aureus, and S. epidermidis growth indicate that P. acnes is the most sensitive to lauric acid among these bacteria. In addition, lauric acid did not induce cytotoxicity to human sebocytes. Notably, both intradermal injection and epicutaneous application of lauric acid effectively decreased the number of P. acnes colonized with mouse ears, thereby relieving P. acnes-induced ear swelling and granulomatous inflammation. The obtained data highlight the potential of using lauric acid as an alternative treatment for antibiotic therapy of acne vulgaris…In conclusion, we demonstrated the antimicrobial property of lauric acid against P. acnes in vitro and its therapeutic effects on P. acnes-induced inflammation in vivo using the ICR mouse ear model. The obtained data highlight the potential of using lauric acid as an alternative treatment option to the antibiotic therapy of acne vulgaris.”
Clinical note: Although the last two papers describe palliative measure, the main point is that case management of acne must address the underlying causes that contribute to the dysregulated inflammatory response to P. acnes, similar to management of any other disorder characterized by the loss of immune tolerance.