Through basic science as well as animal and human clinical trials, the evidence is growing for the use of probiotics in the treatment of acne. Acne formation is dependent upon several processes, including follicular hyperkeratinization, excess sebum production, Propionibacterium acnes colonization and an inflammatory cascade. The antimicrobial properties of probiotics as well as the modification of the skin microbiome may decrease levels of P. acnes on the skin. Additionally, successful acne outcomes are influenced by compliance with topical regimens, which can commonly cause skin barrier disruption, leading to dryness and irritation. Consequently, calming inflammation as well as maintaining skin hydration and barrier repair is of primary importance when treating acne. In this chapter, we discuss how probiotics affect several factors in the pathophysiology of acne development and can improve the treatment outcomes.
Acne is an inflammatory disorder involving the pilosebaceous unit. A multifactorial cascade including excess sebum production, follicular hyperkeratinization, and bacterial overgrowth conspire to incite an inflammatory response. Acne therapies have focused on modulating this inflammatory response as well as targeting components of this cascade. Probiotics is an emerging area of research that continues to gain momentum for the treatment of acne. A probiotic is defined as a “live microorganism which, when administered in adequate amounts, confers a health benefit on the host” . Both oral and topical preparations of probiotics have shown promise in the treatment of acne.
2. The gut-brain-skin axis
The field of dermatology continues to investigate the interconnected relationships between the skin and other systems of the body. The unifying theory of the gut-brain-skin axis outlines the relationship between the skin, gastrointestinal (GI) system, and mental health. Notably, the role of the gastrointestinal (GI) system is an area of particular interest as it relates to inflammatory skin conditions. The gut microbiome reacts to various stimuli resulting in systemic responses. By altering the GI microbiome, it is possible to decrease systemic inflammation, and these results can improve the severity of inflammatory skin diseases such as acne.
2.1. History of the gut-brain-skin axis
The gut-brain-skin axis originated in 1930 when John H. Stokes and Donald M. Pillsbury reported their clinical observations and colleagues’ studies. They linked emotional states with gastrointestinal (GI) disorders through various mechanisms, including diet and neuronal responses. Stokes and Pillsbury reported cases of individuals with colitis who also suffered from urticaria and dermatographism. They purported that alterations of microflora increase gut permeability and lead to systemic inflammation. Higher levels of systemic inflammation result in altered cutaneous physiology. This association was further supported by the observation that hypochlorhydria is associated with multiple dermatologic conditions such as rosacea, eczema, pruritus, psoriasis, dermatitis herpetiformis, neurodermatitis, and acne .
Similarly, other case studies support the connection between gut physiology and cutaneous and psychological pathology. A psychopathic institute administered
Stokes and Pillsbury’s early concept of the gut being linked with the brain and skin started with anecdotal evidence and preliminary studies. They discovered that alteration of gastric acid levels and fluctuation of the gut microflora could have further effects beyond the GI system. From this evidence, they even proposed a treatment of Bacillus and cod liver oil, which is similar to present day probiotics and omega-3 fatty acids, to restore homeostasis in the gut. This early research has led to larger animal and human studies on the GI system, its microbiome, and its relation to the skin.
2.2. Theory of the gut-brain-skin axis
The negative impact of acne and other cutaneous diseases on the quality of life has been well-documented [6, 7, 8, 9, 10], and can cause long-lasting personality changes . It has been reported that 8.8% of patients with acne exhibit depression . Apart from psychological distress, acne patients often suffer from gastrointestinal disturbances at higher rates compared to the normal population . The gastrointestinal tract houses the largest population of commensal bacteria, and in this reservoir of bacteria lies the central theme to the gut-brain-skin axis.
Hypochlorhydria and small intestinal bacterial overgrowth (SIBO) are two conditions that demonstrate an association with cutaneous pathology and mental health. Alterations in gastric acid secretion, such as hypochlorhydria, increase the risk for SIBO. While increased rates of SIBO have long been associated with psychological disorders of anxiety, depression, and fibromyalgia, more recent evidence has demonstrated increased rates of SIBO in rosacea patients, as well, with one study reporting an SIBO rate of 50% in rosacea patients. Those patients were then treated for SIBO with the antimicrobial rifaximin, and most had significant improvement or clearance of their rosacea [13, 14]. Additionally, an Australian study used the probiotic
Intestinal permeability has also been linked to cutaneous pathology. As far back at 1916, acne patients have shown reactivity to stool-isolated bacteria using a serum complement test . Later, Juhlin and Michaelsson tested
2.3. Impact of the gut microbiome
The gut microbiome is dynamic; it changes with the stress on its environment and reacts to feedback from other systems. As stated previously, changes in the microbiome may influence levels of systemic inflammation. Acne is an inflammatory disorder that has demonstrated its response to systemic inflammation and oxidative stress. A Russian study found that not only is the intestinal microflora of acne patients altered, but therapy for the GI disruption reduced the duration of acne treatment .
The gut’s commensal bacteria can induce immune responses that ultimately reach T cells in the skin. Probiotics interact with the gastrointestinal mucosal immune system, altering levels of inflammatory cytokines in the blood . For instance, the levels of gamma-aminobutyric acid (GABA) are modified by intestinal bacteria [24, 25]. Microbial-fermented food enriched with GABA has been shown to improve atopic dermatitis in mice through a Th-1 mediated-immune response .
Major histocompatibility cell (MHC) class II complexes are found on antigen presenting cells, such as dendritic cells and macrophages, and interact with immune-regulating T cells. Gastrointestinal bacteria, including strains of probiotics, have been shown to bind to the MHC II complex and modify their expressions . A study that administered
The composition of the gut microbiome can inhibit or promote the release of substance P in both the skin and intestinal tract [33, 34]. When a specific strain of
The interconnected relationship described by the gut-brain-skin axis illustrates the significant role of the gut microbiome, and its alteration, for instance by probiotics, may play in the development of acne. Modification of local and systemic inflammatory profiles by GI flora presents a target for potential therapy.
3. Pathophysiology of probiotics and acne
It is quite evident that the gut-brain-skin axis plays a theoretically significant role in the formation of acne lesions. In the following sections, we will discuss the pathophysiology behind probiotics and their ensuing potential impact in the arena of acne treatment. As previously discussed, the early theories introduced by Stokes and Pillsbury conceptualized the functional interdependence of the gut-brain-skin axis. It was further proposed that alterations in the neural axis result in gastrointestinal dysfunction, thereby disrupting the local normal flora, and resulting in widespread inflammatory response . As we will see, the concept of systemic inflammatory response as well as oxidative stress is at the core of the rationale behind probiotics and their role in acne treatment.
The initial research during the era of Stokes and Pillsbury began with the discovery of concomitant hypochlorhydria in a significant portion of acne patients . Additionally, the expanded SIBO theory suggested that an increased pH in the stomach resulted in a migration of bacteria proximally, increased gut permeability, and significant resultant inflammation . This inflammation is the key starting point for the inflammatory cascade ultimately resulting in acne lesions.
The inflammatory state associated with acne has received much attention from dermatologic research studies and literature in recent years. While it was previously thought that events such as follicular keratinization and bacterial colonization preceded inflammation , it is now known that inflammation is actually the herald event .
The concept of acne as a result of inflammation is based upon the understanding that the immune system is designed to defend the human body against actual threats. However, in the acne patient, we are recognizing a chronic, low level of inflammation in the absence of threat . Ideally, probiotics would eliminate this chronic inflammatory state, and in turn, halt the development of acne lesions.
Subclinical microcomedones are established as the earliest lesions of acne, and even at this early stage, inflammatory cells have been observed to be already present in these primary lesions. A modern research study was performed comparing immunohistochemistry and immunofluorescence of early, inflamed papules less than 6 h old in acne patients to both uninvolved skin of acne patients and a nonacne control group. In papules less than 6 h old, a remarkable increase in K16 and K67 activity is observed . Uninvolved skin in acne patients exhibited increased expression of CD4+ T cells, and an even more significant upregulation of CD4+ T cells was observed in papules less than 6 h old . The presence of macrophages was found to be higher in both uninvolved skin of acne patients as well as papules less than 6 h old of acne patients compared to nonacne controls .
One of the strongest pieces of evidence supporting the theory of baseline inflammation in acne patients is the increased presence of interleukin-1-alpha (IL-1), a well-known pro-inflammatory cytokine. In the above study, an increased level of IL-1-alpha was observed in both early lesional skin and uninvolved skin of acne patients in comparison with the control group . IL-1 has been proposed as the signal that triggers the entire inflammatory cascade in the setting of a wound. In response to endothelial injury, IL-1 is the first cytokine to be produced, attracting lymphocytes to the area as well as activating endothelial cells to produce a hyperproliferative state . It is further proposed that increased expression of K6 and K16, TNF-alpha, and endothelial growth factors then occur as a result . Considering the above information, it may be deduced that IL-1 is a powerful inflammatory cascade that trigger in the setting of acne as well.
Collectively, several conclusions can be drawn from this information. These findings support the theory of acne as an inflammatory disease. Significant evidence reinforces the theory that inflammation precedes the overproduction of sebum, hyperproliferative state, and other physical manifestations of acneiform lesions. Taking into account the subtype of T cell activation observed, it is prudent to believe the inflammation is specific and antigenic in nature rather than an innate response .
Therefore, the anti-inflammatory actions of probiotics may be beneficial in the treatment of acne. Although the exact mechanism remains unclear, literature exists that suggests that
Further solidifying this concept, in a study aimed at examining the immunomodulatory effects of probiotics in subjects with food allergies, it was determined that probiotics do in fact increase production of anti-inflammatory cytokines such as IL-10, TNF-α, and INF-γ . This discovery may be re-enforced by looking back to the research involving rats and pretreatment with combined
Given the aforementioned research, it is once again reasonable to conclude that the addition of probiotics in the acne-prone patient would positively affect the causatory state of inflammation. It is clear that further research is needed to solidify the definitive effects of probiotics on the low-level inflammatory state and subsequent inflammatory cascade.
3.2. Oxidative stress
An alternative theory proposed by Allan L. Lorincz suggested that oxidative breakdown of lipids and squalene was a cause of acne rather than a consequence. The theory then goes on to suggest that this oxidative process is a trigger for the inflammatory condition seen in acne patients . Subsequent studies reinforced this theory. In 1975, A Tappel also supported the theory of inflammation stemming from the damaging effects of lipid peroxidation .
This is both important and relevant in the setting of acne as squalene, a key component in the formation of the comedone, is sensitive to oxidative stress. In an independent study, squalene, when exposed to UV radiation (a source leading to oxidative stress), became increasingly comedogenic .
It has thus been proposed that alongside inflammation, oxidative stress may play a significant role in the development of acne lesions. Reactive oxygen species (ROS) are produced by environmental factors as well as cellular metabolism byproducts. Higher levels of ROS encourage an environment that is more hospitable to bacteria such as
Faulty antioxidant response seen in acne patients provides yet another role for probiotics in the treatment of acne. Probiotics have been proven to assist in antioxidant activity. In a study performed on the probiotic,
In a separate study, researchers combined various strains of
Probiotics provide a mechanism to counter free radical damage and increase antioxidant activity, resulting in an environment that is less attractive for
4. Probiotics used for the treatment of acne
4.1. Oral probiotics
The idea of treating acne with probiotics dates back to the 1930s. During that time,
After Dr. Siver’s research was published, other researchers became interested in a correlation between oral probiotics and acne. Two studies, both published in a non-English language journal, continued to demonstrate a connection. In 1987, an Italian article was published by Marchetti et al., 20 of the 40 patients with acne were given 250 mg of freeze-dried
More recent studies have continued to confirm these results. In 2010, Kim et al. randomized 36 subjects with acne to receive either lactoferrin (a milk protein with anti-inflammatory, bactericidal, and fungicidal properties) added to fermented milk (experimental group) or fermented milk alone (control group). After 12 weeks, the experimental group experienced significant decreases in total lesion count (23.1%), inflammatory lesion count (38.6%), acne grade (20.3%), and sebum content (31.1%) compared to the control group. Although this study had the additional element of lactoferrin, both groups responded to the fermented milk and saw a reduction in total skin surface lipids. Furthermore, the addition of lactoferrin decreased a specific group of lipids called triacylglycerols, directly related to the decreased sebum content, acne lesion counts, and acne grade .
An interesting open-label study was published in 2013 by Jung et al. concerning probiotics versus antibiotics in 45 women between the ages of 18 to 35 years old. The females were randomized into one of three groups: probiotics only (a mixture of
A 2016 clinical trial identified 57 patients with erythematous papulopustular facial rashes that were diagnosed as either acne, seborrheic dermatitis, or rosacea. The participants were started on a vegetarian diet and appropriate standard therapy for their disorder, including antibiotics, retinoids, and/or steroids. 37 patients of these patients were randomized to receive a daily oral probiotic supplement with
4.2. Topical probiotics
With the growing body of evidence for the role of systemic probiotics in the treatment of acne, the efficacy of topical probiotics is also generating interest and investigation. Similar to oral probiotics, the use of topical probiotics dates back to the early 1900s ; however, proper clinical trials were not conducted until much later. In 1999, Di Marzio et al. completed the first clinical trial evaluating topical probiotics and their effects on ceramide production in the skin. Ceramides are waxy lipid molecules that comprise 50% of the lipid matrix within the intercellular spaces of the stratum corneum. Along with cholesterol and long-chain fatty acids, they are essential to maintaining the water permeability of the skin barrier. Ceramides have been found to be low in patients with aged skin, xerosis, atopic dermatitis, psoriasis, and even acne; therefore, increasing their production may significantly impact these disorders . Initially, Di Marzio et al. conducted an
In the next phase of the study, Di Marzio tested this theory
Ceramides not only have a role in water permeability, but they also play a part in the antimicrobial and anti-inflammatory properties of the skin. The exact antimicrobial mechanism of ceramides has not been confirmed; however, there are many theories: reduction of bacteria adherence to epithelial cells, inhibition of bacterial protein kinases, and/or damage to the cell wall of the bacteria [59, 60]. Aware of their antimicrobial properties, Pavicic et al. performed a study in 2007 to evaluate the role of ceramides in patients with acne. The study consisted of both an
Topical probiotics may also help with stress-induced acne. It is known that acne can be exacerbated due to stress, primarily due to a release of a chemical called substance P. Sebocytes stimulated by substance P show higher levels of proinflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) tumor necrosis factor-alpha (TNF-alpha), and peroxisome proliferators activated receptors-gamma (PRAR-gamma), compared to a control . Studies by Gueniche et al. in 2010, using both
4.3. Future directions
Studies of topical and oral probiotics have demonstrated the beneficial anti-inflammatory and antibacterial properties of probiotics in the treatment of acne. Newer research is focusing on yet another treatment mechanism—the production of antimicrobial peptides (AMPs). AMPs are molecules produced by the innate immune system of a wide range of organisms, including humans, plants, and insects, that act as a first line of defense against natural antimicrobial agents . These peptides are extremely small, are anti-inflammatory, and have been shown to exhibit properties against bacteria, fungi, viruses, and tumors. They have even shown the ability to overcome bacterial resistance because it is difficult to develop complete resistance to AMPs, making them potential candidates for future therapeutic medications [64, 65]. Besides being produced by many eukaryotic organisms, numerous bacteria have been found to produce AMPs. These bacterial AMPs, called bacteriocidins, have been isolated from about 50 various bacterial species, especially lactic acid-producing bacteria [66, 67, 68]. Some researchers refer to bacteriocidins as only those produced by Gram-positive bacteria, which are further classified into two subgroups: lantibiotics (class I) and nonlantibiotics (class II). Many of the lactic acid bacteria produce AMPs in the nonlantibiotics group. AMPs produced by Gram-negative bacteria are sometimes referred to as microcins and classified further into two groups: class I and class II . For simplicity, the general term “bacteriocidins” will be used here.
Compared to AMPs produced by eukaryotic organisms, bacteriocidins have a narrower spectrum of activity, only capable of targeting a few species but have the advantage of being more potent. Bacteriocidins are active at pico- to nanomolar concentrations compared to micromolar concentrations required when produced by eukaryotes. Bacteriocidins are bactericidal, causing pore formation in cell membranes .
There have been multiple studies performed observing the effects of AMPs on many disorders, including acne vulgaris. In 2006, Bowe et al. discovered that a normal oral flora bacterium,
A similar study in 2009 by Kang et al. demonstrated the effects of the bacterium,
While these findings suggest that probiotics and the AMPs produced may benefit patients with acne, larger randomized controlled clinical trials are needed. Further studies will elucidate the most efficacious strains, preparations, and treatment regimens for the treatment of acne and potential uses in other conditions.
In summary, oral and topical probiotics are emerging as an exciting treatment option or adjuvant treatment for acne. Although additional research needs to be performed, the clinical trials conducted so far have continued to provide evidence that probiotics can improve acne, along with multiple other inflammatory disorders, with very limited adverse effects. In the upcoming years, probiotic formulations have the potential to be a fundamental component of acne treatment and may augment the efficacy of current treatments today.
Conflict of interest
No conflict of interest to be reported by the authors.