Hair follicles and microbiota

The human body is colonized by trillions of microorganisms, collectively referred to as “microbiota”. In humans, microbiota inhabits diverse locations in our body such as the mouth, nasal cavities, skin, gastrointestinal tract, urogenital tract, respiratory tract, vagina, and other places. Due to advances in sequencing technologies in the last decade, a huge amount of research has demonstrated an important role of human microbiota in health and disease, particularly gut microbiota [1]. Here we will focus in hair follicle microbiota.

Human skin and hair follicles host a vast diversity of microorganisms including bacteria, viruses, fungi, and mites [2]. Microorganisms can be beneficial or pathogenic and the establishment of an equilibrium is crucial for health and disease of our skin and hair. Fortunately, the great majority of our skin and hair follicle residents are non-pathogenic and probably contribute to homeostasis by maintaining a constant dialogue with our immune system. However, stress and a variety of environmental factors are associated with microbiota imbalance.

Approximately 100,000 – 150,000 hair follicles are located in the scalp. Hair follicles are colonized by unique and complex microbiota. Fungi strain Malassezia and bacterial strains Propiobacterium, Cutibacterium, and Staphylococcus are among the most abundant microorganisms in human scalps. Compared to the skin, the hair follicle favors microbial growth because it is moist, well-perfused, relatively UV-protected and has a less acidic pH [3]. The hair follicle is an organ found in skin. There are three major segments of hair follicles: lower, middle and upper segments (Figure 1). The infundibulum covers most of the upper segment. The infundibulum is the funnel-shaped uppermost portion of the follicle. It is typically filled with sebum and debris. Due to its location, the infundibulum is a major interface zone between our skin and the environment, making it a microbiota rich place. Not surprisingly, the infundibulum is endowed with a specialized immune system. However, diverse studies have demonstrated that the infundibulum is involved in skin diseases such as acne, infundibular folliculitis, cysts, hidradenitis suppurative, keratosis pilaris, and a subtype of basal cell carcinoma [4]. An imbalance in the microbiota impacts the immune system and both are key elements in the pathogenesis of chronic scalp diseases.

Figure 1: A) Parts of a hair follicle. The infundibulum is the uppermost part of the hair follicle and is in contact with the environment. B) Zoom-in of the infundibulum, a funnel-shaped region rich in microbiota. Diverse microorganisms are depicted in colors. Figure adapted from [10].

A typical example of how alterations in the composition of hair follicle microbiota may impact diseases is observed in dandruff, a mild type of seborrheic dermatitis. Studies have shown that dandruff and seborrheic dermatitis are correlated with alterations in bacterial and fungal microbiota [5-8]. Similarly, microinflammation and infiltration of mononuclear cells and lymphocytes have been observed in infundibulum samples of patients with androgenetic alopecia [9]. However, further studies are needed to understand the relationship between the interactions of microbiota, hair follicle cells, and host immune system.

Microbiota varies from person to person and even within different body parts. We know that the hair follicle, especially the infundibulum is highly rich in microbiota and immune system cells. Alterations in microbiota concentrations and distributions may cause inflammation and damage to the infundibulum, deriving potentially in hair pathologies.

At CapilarFixTM we are experts at taking care of your hair follicles and your hair. We can recommend the best products that will help you maintain a balanced capilar microbiota.

References:

[1] Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R, Current understanding of the human microbiome. Nat Med. 2018; 24: 392-400

[2] Oh, J., Byrd, A. L., Deming, C., Conlan, S., NISC Comparative Sequencing Program, Kong, H. H., & Segre, J. A. (2014). Biogeography and individuality shape function in the human skin metagenome. Nature, 514(7520), 59–64.

[3] Lousada, M., Lachnit, T., Edelkamp, J., Rouillé, T., Ajdic, D., Uchida, Y., Di Nardo, A., Bosch, T. and Paus, R. (2020), Exploring the human hair follicle microbiome. Br J Dermatol. Accepted Author Manuscript. doi:10.1111/bjd.19461

[4] Schneider, M. R., & Paus, R. (2014). Deciphering the functions of the hair follicle infundibulum in skin physiology and disease. Cell and tissue research, 358(3), 697–704.

[5] C. Clavaud, R. Jourdain, A. Bar‐Hen, M. Tichit, C. Bouchier, F. Pouradier, C. El Rawadi, J. Guillot, F. Menard‐Szczebara, L. Breton, J. P. Latge, I. Mouyna, Dandruff is associated with disequilibrium in the proportion of the major bacterial and fungal populations colonizing the scalp, PLoS ONE 2013, 8, e58203.

[6] L. Wang, C. Clavaud, A. Bar‐Hen, M. Cui, J. Gao, Y. Liu, C. Liu, N. Shibagaki, A. Gueniche, R. Jourdain, K. Lan, C. Zhang, R. Altmeyer, L. Breton, Characterization of the major bacterial-fungal populations colonizing dandruff scalps in Shanghai, China, shows microbial disequilibrium, Exp. Dermatol. 2015, 24, 398.

[7] R. C. Soares, P. H. Camargo‐Penna, V. C. de Moraes, R. De Vecchi, C. Clavaud, L. Breton, A. S. Braz, L. C. Paulino, Dysbiotic Bacterial and Fungal Communities Not Restricted to Clinically Affected Skin Sites in Dandruff, Front Cell. Infect. Microbiol. 2016, 6, 157.

[8] T. Park, H. J. Kim, N. R. Myeong, H. G. Lee, I. Kwack, J. Lee, B. J. Kim, W. J. Sul, S. An, Collapse of human scalp microbiome network in dandruff and seborrheic dermatitis, Exp. Dermatol. 2017, 26, 835.

[9] Mahé, Y. F., Michelet, J. F., Billoni, N., Jarrousse, F., Buan, B., Commo, S., Saint-Léger, D., & Bernard, B. A. (2000). Androgenetic alopecia and microinflammation. International journal of dermatology, 39(8), 576–584.

[10] Pisal, Rishikaysh & Dev, Kapil & Diaz, Daniel & Shaikh Qureshi, Wasay Mohiuddin & Filip, Stanislav & Mokrý, Jaroslav. (2013). Signaling Involved in Hair Follicle Morphogenesis and Development. International journal of molecular sciences. 15. 1647-70.

Vitamin D deficiency and hair loss

Vitamin D plays an important role in calcium homeostasis and bone health. It has been demonstrated that vitamin D is also associated with several autoimmune diseases such as lupus, type I diabetes mellitus, rheumatoid arthritis, multiple sclerosis, vitiligo, and psoriasis among others [Hewison, 2012].  Deficiencies in vitamin D may derive in abnormal autoimmunity responses [Arnson, 2007]. Furthermore, vitamin D and its receptor have been implicated in the pathogenesis of diverse forms of hair loss [Conic et al., 2018].

We obtain a small amount of vitamin D from our daily diet, however most of the vitamin D in our body is synthesized by keratinocytes in the epidermis after exposure to solar radiation. Vitamin D acts in human body cells through the vitamin D receptor (VDR), triggering a signaling cascade which modulates the transcription of target genes involved in regulating homeostasis. VDR is a nuclear receptor expressed in numerous cells and tissues in the human body including the skin. VDR is expressed in the two major cell populations conforming the hair follicle: epidermal keratinocytes and dermal papilla cells. Studies have demonstrated that absence of VDR leads to hair loss by hair cycle dysregulation [Mady et al., 2016].

The first evidence suggesting a role of VDR in hair cycle was derived from the observation of alopecia in patients with type IIA vitamin D-dependent rickets [Brooks et al., 1978]. Vitamin D-dependent rickets type IIA is a disorder in bone formation caused by a defect in the VDR gene. Interestingly most of the patients with this disorder also had alopecia. However, the molecular mechanisms by which vitamin D and its receptor VDR regulate hair cycle are still unknown.

Hair regeneration depends on the activation of hair follicle stem cells. The hair follicle is an organ that undergoes cyclic involution and regeneration throughout life [Paus et al., 1999]. The hair cycle consists in three cycling phases: anagen (growth), catagen (involution), and telogen (resting). In the telogen phase, the dermal papilla and the bulge come closer together and this approximation allows signaling between the dermal papilla and keratinocyte stem cells in the bulge, inducing a new proliferative anagen phase [Paus et al., 1999] as observed in the next Figure.

Figure: Hair cycle phases anagen (growth), catagen (involution) and telogen (resting). [Chen et al., 2020]

The expression of VDR is increased in the hair follicle during the late anagen and catagen phases of the hair cycle; correlating with decreased proliferation and increased differentiation of keratinocyte stem cells [Demay et al., 2007]. VDR is essential for the start of a new anagen phase. Several mutations have been found which may interfere with VDR’s function increasing the risk of hair loss [Simon et al., 2010].

Additionally, levels of serum vitamin D have also been correlated to hair loss. Diverse studies have demonstrated insufficiency or significantly lower serum levels of vitamin D in patients with Alopecia Areata as compared to healthy controls [Yilmaz et al., 2012; Aksu et al., 2014; Ghafoor et al., 2017; Gade et al., 2018]. Supplementation with vitamin D has also been observed to protect hair follicles from chemotherapy-induced alopecia [Wang et al., 2006; Jimenez et al., 1996].

References:

Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf). 2012;76:315–25.

Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. 2007;66:1137–42.

Conic, R., Piliang, M., Bergfeld, W., & Atanaskova-Mesinkovska, N. (2018). Vitamin D Status in Scarring and Non-Scarring Alopecia. Journal of the American Academy of Dermatology, S0190-9622(18)30631-5.

Mady, L. J., Ajibade, D. V., Hsaio, C., Teichert, A., Fong, C., Wang, Y., Christakos, S., & Bikle, D. D. (2016). The Transient Role for Calcium and Vitamin D during the Developmental Hair Follicle Cycle. The Journal of investigative dermatology, 136(7), 1337–1345.

Brooks, M. H., Bell, N. H., Love, L., Stern, P. H., Orfei, E., Queener, S. F., Hamstra, A. J., & DeLuca, H. F. (1978). Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. The New England journal of medicine, 298(18), 996–999.

Paus, R., & Cotsarelis, G. (1999). The biology of hair follicles. The New England journal of medicine, 341(7), 491–497.

Demay, M. B., MacDonald, P. N., Skorija, K., Dowd, D. R., Cianferotti, L., & Cox, M. (2007). Role of the vitamin D receptor in hair follicle biology. The Journal of steroid biochemistry and molecular biology, 103(3-5), 344–346.

Simon, K. C., Munger, K. L., Xing Yang, & Ascherio, A. (2010). Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England), 16(2), 133–138.

Yilmaz N, Serarslan G, Gokce C. Vitamin D concentrations are decreased in patients with alopecia areata. Vitam Miner. 2012;1:105–109.

Aksu Cerman A, Sarikaya Solak S, Kivanc Altunay I. Vitamin D deficiency in alopecia areata. Br J Dermatol. 2014;170:1299–1304.

Ghafoor R, Anwar MI. Vitamin D deficiency in alopecia areata. J Coll Physicians Surg Pak. 2017;27:200–202.

Gade VKV, Mony A, Munisamy M, Chandrashekar L, Rajappa M. An investigation of vitamin D status in alopecia areata. Clin Exp Med. 2018;18:577–584.

Wang J, Lu Z, Au JL. Protection against chemotherapy-induced alopecia. Pharm Res. 2006;23:2505–14.

Jimenez JJ, Yunis AA. Vitamin D3 and chemotherapy-induced alopecia. Nutrition. 1996;12:448–9.

Chen, C., Huang, W., Wang, E.H.C. et al. Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration. J Biomed Sci 27, 43 (2020).

Is there a relationship between androgenetic alopecia and COVID-19?

We are currently in the midst of a pandemic situation orchestrated by the SARS-CoV2 (COVID-19) virus. The name SARS stands for Severe Acute Respiratory Syndrome and CoV2 indicates that the virus belongs to the family of Coronaviridae. Coronaviruses are characterized for having a surface covered with protrusions called spikes, giving them a crown-like appearance. Genomic sequence analysis suggest that the virus originated through natural selection in bats or Malayan pangolins and then jumped into humans, a process called “zoonotic transfer” [Lam et al., 2020].

Early epidemiologic reports have shown a disproportionate prevalence of COVID-19 severe cases between adult women and men (42% in males vs 58% in females) [Shi et al., 2020]. Furthermore, a bigger difference is observed in the number of severe COVID-19 cases between pre-pubescent children and adults [Lu et al., 2020]. In children, only 0.6% of COVID-19 cases are severe. In Mexico epidemiological reports are updated daily by Secretaria de Salud. Interestingly, as of July 22, 2020 only 34.8% of COVID-19 deaths were of women whereas 65.18% were men [https://coronavirus.gob.mx/]. An explanation for the skewed prevalence of severe COVID-19 cases between males and females is still unknown.

SARS-CoV-2 virus uses its spikes to target and anchor cells to infect. The main virus’ entry point in a host cell is a protein called ACE2. ACE2 is found on the surface of cells from a variety of human organs such as lungs, arteries, heart, kidneys, and intestines. Spikes need to be activated, process known as “priming”, for anchoring host cells. Spike activation is performed by the TMPRSS2 protein, also found on the surface of host cells [Hoffman et al., 2020]. Interestingly, when the androgenetic receptor (AR) is activated, it stimulates the production of TMPRSS2 protein which in turn activates more SARS-CoV2 spikes. Similarly, as in hair follicles, the androgenetic receptor (AR) requires of hormones called androgens (e.g. testosterone) to become activated. The next figure depicts the SARS-CoV2 molecular infection mechanism when encountered with a host cell.

Figure 1 – SARS-CoV2 infection mechanisms. Adapted from Hoffman en al., 2020.

In a study performed between March 23 and April 12, 2020 in three hospitals of Madrid, Spain, dermatologists classified 175 COVID-19 patients as “no alopecia”, “moderate androgenetic alopecia”, or “severe androgenetic alopecia” prior to hospitalization. Results demonstrate that 67% of the patients depict symptoms of moderate or severe androgenetic alopecia. Additionally, 79% of COVID-19 severe cases had androgenetic alopecia as well [Wambier et al., 2020]. These numbers show a clear trend; however, further epidemiological studies are required to assess a correlation between the degree of androgenetic alopecia and the severity of COVID-19 infection. It is worth mentioning that clinical trials highlighting the use of anti-androgen drugs are currently ongoing. These drugs aim at reducing androgen levels, thus decreasing the activation of androgenetic receptors in COVID-19 patients.

All these observations have led scientists to study the potential correlation between androgenetic alopecia with the severity of COVID-19 infection under the hypothesis that places androgens as the main cause of COVID-19 severity. The potential correlation between androgenetic alopecia and COVID-19 has been termed the “Gabrin Sign” in honor of Doctor Frank Gabrin, the first American physician who died of COVID-19 [Wambier et al., 2020]. Interestingly, Doctor Gabrin suffered from androgenetic alopecia and was victim of a severe COVID-19 infection.

At CapilarFix® we are not experts in COVID-19 however we are skilled in treating alopecia. Perhaps (we can’t be sure yet), by treating androgenetic alopecia we could indirectly be lowering the risk of severe COVID-19 infection.

References:

Lam, T.T., Jia, N., Zhang, Y. et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature 583, 282–285 (2020). https://doi.org/10.1038/s41586-020-2169-0

Shi Y., Yu X., Zhao H., Wang H., Zhao R., Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Crit Care. 2020;24(1):108.

Lu X, Zhang L, Du H, et al. SARS‐CoV‐2 infection in children. N Engl J Med. 2020.

Hoffmann M., Kleine-Weber H., Schroeder S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020:1–10.

Wambier, C. G., Vaño-Galván, S., McCoy, J., Gomez-Zubiaur, A., Herrera, S., Hermosa-Gelbard, Á., Moreno-Arrones, O. M., Jiménez-Gómez, N., González-Cantero, A., Fonda-Pascual, P., Segurado-Miravalles, G., Shapiro, J., Pérez-García, B., & Goren, A. (2020). Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: The “Gabrin sign”. Journal of the American Academy of Dermatology, 83(2), 680–682. https://doi.org/10.1016/j.jaad.2020.05.079