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REVIEW ARTICLE |
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| Year : 2022 | Volume
: 67
| Issue : 6 | Page : 699-704 |
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| Hidradenitis suppurativa: Consequences of microbiome dysbiosis on immune dysregulation and disease severity |
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Minh G Chung, Ana Preda-Naumescu, Nabiha Yusuf
From the Department of Dermatology, School of Medicine, University of Alabama at Birmingham, AL, USA
| Date of Web Publication | 23-Feb-2023 |
Correspondence Address:
Nabiha Yusuf
1670, University Boulevard, VH 566A, Birmingham AL
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.ijd_623_21
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 Abstract | | |
Hidradenitis suppurativa (HS) is a chronic inflammatory condition characterized by the formation of nodules, abscesses, and sinus tracts with tunnels that primarily involves the skin folds. HS affects approximately 1% of the population, but its pathogenesis is unclear. Dysbiosis of skin microbiome is a major cause of HS and alterations of microbiome composition and diversity can be seen in the skin of patients with HS. These disruptions may contribute to the immune dysfunction seen in HS. Understanding these alterations and their contributions to the pathogenesis of HS could help guide future treatment. In addition to dysbiosis promoting immune dysregulation, HS may promote dysbiosis via differences in expression of antimicrobial peptides (AMPs). In this review, we have discussed the role of skin and gut microbiome in manifestation of HS and the consequences of dysbiosis on the immune system.
Keywords: Hidradenitis suppurativa, immune system, microbiome, skin
How to cite this article:
Chung MG, Preda-Naumescu A, Yusuf N. Hidradenitis suppurativa: Consequences of microbiome dysbiosis on immune dysregulation and disease severity. Indian J Dermatol 2022;67:699-704 |
How to cite this URL:
Chung MG, Preda-Naumescu A, Yusuf N. Hidradenitis suppurativa: Consequences of microbiome dysbiosis on immune dysregulation and disease severity. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 29];67:699-704. Available from: https://www.e-ijd.org/text.asp?2022/67/6/699/370331 |
| Introduction | |  |
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by the formation of nodules, abscesses, and sinus tracts with tunnels that primarily involves the skinfolds.[1] HS affects approximately 1% of the population; however despite the prevalence, the pathogenesis is not fully understood.[1] A well-established component of HS is cutaneous microbiome dysbiosis. Microbial communities reside in many parts of the healthy human body, including the skin and abdominal tract. HS skin shows disruption of this community via alterations in its composition and diversity. These disruptions may contribute to the immune dysfunction seen in HS.[1] Changes in levels of antimicrobial peptides (AMPs) in HS further support the involvement of the microbiome in this skin condition. Understanding these alterations and their contributions to HS pathogenesis could help guide future treatment.
| Proposed Pathogenesis | | |
The earliest identified events in the pathogenesis of HS include infundibular acanthosis with hyperkeratosis and immune cell infiltration.[1] While it is unclear which comes first, the outcome has been well characterized: plugging, and dilation of the hair follicle.[1] Additionally, cytokines from immune infiltration induce matrix metalloproteinases, which degrade the extracellular matrix and lead to thinning and weakening of the follicular basement membrane.[1] These combined actions result in the rupture of the hair follicle and its contents, including bacteria and cellular debris, which further aggravate the inflammation.[1] The subsequent chronic inflammation leads to the development of nodules, abscesses, tunnels, and scarring that have become almost pathognomonic for HS.
| Risk Factors and Associations | | |
Risk factors for HS include obesity, smoking, and certain genetic mutations. Approximately 60% of HS patients are obese, and approximately 90% have history of smoking.[1] Obesity increases body skinfold area and mechanical stress, which stimulates inflammation by creating an anaerobic environment well suited for bacteria.[1] Nicotine from smoking promotes acanthosis of the hair follicle, which facilitates formation of follicular plugs.[1]
Genetics are believed to play a considerable role in HS as one-third of patients have a family history of disease.[2] One mutation predisposing to HS involves the γ-secretase genes that code for a complex integral to the cleavage of Notch receptors.[2] Notch-deficient mice show T-cell abnormalities, including decreased interleukin (IL)-22 and T-helper cell activity.[1],[2] Similar cytokine profiles are seen in HS patients. Reduced IL-22 affects AMP activity, which may lead to pathologic alterations in the microbiome.[1] T-cell dysregulation further causes overproduction of proinflammatory cytokines, including IFN-γ and IL-17.
HS is also associated with several comorbid health conditions, including inflammatory bowel disease (IBD).[2] The association with IBD is particularly interesting as perturbations in the gut microbiome have been linked to the development of this disease. This link has opened investigations into the role the gut microbiome, and the human microbiome as a whole, might play in the development of HS.
| Cutaneous Disease and the Human Microbiome | | |
An understanding of the cutaneous microbiome is important as the physical and chemical features of human skin selects for microorganisms that likely play an important role in the immune system and the development, or prevention, of human disease. For example, cutaneous commensal microorganisms play a role in immune regulation by inhibiting the growth of pathogens through competition for resources and the production of antimicrobial compounds.[3] The human skin can be regarded as its own unique ecosystem, and disruption to this careful balance may be implicated in development of disease. Multiple studies have investigated the cutaneous microbiome in HS to better understand disease pathogenesis.
The cutaneous microbiome consists of bacteria, fungi, and viruses that are varied across as well as within individuals.[4] The microbial diversity of human skin differs based on anatomical location, and presence or absence of adnexal structures (i.e. pilosebaceous units, eccrine glands).[4] Extending as far down as the superficial subcutaneous tissue, it exists in homeostasis with the host immune systems and is involved in the production of regulatory cytokines, differentiation of keratinocytes, maintenance of the epidermal barrier, induction of local regulatory T-cell responses, and perpetuation of innate immune responses.[4] Perturbations to this carefully organized microbiome may contribute to the development of inflammatory skin disease.[5] For example, in atopic dermatitis an increased presence of Staphylococcus aureus (S. aureus) has been described. This bacterium releases toxins that propagate inflammation, including α-δ-toxin and proteases.[6] In mouse models, the addition of Gram-negative bacteria from healthy skin improved immune control of S. aureus and skin barrier function in atopic skin, suggesting a role of the microbiome in pathogenesis.[6] In acne vulgaris, Corynebacterium acnes colonization, secondary-to-increased sebum production and aberrant keratinization of pilosebaceous units, contribute to inflammation of acne.[6]
Connections between chronic skin inflammation and the human microbiome include perturbations in the gut microbiome. Much like the skin, the gastrointestinal tract is home to a wide variety of organisms. Metabolites produced by these organisms may be absorbed in the gut, traveling widely throughout the host's body.[7] In “leaky gut” syndrome, also known as increased intestinal permeability, decreased gut barrier integrity allows microorganism metabolites, including antigens and toxins, to enter the blood stream.[7] As these pathologic byproducts circulate throughout the body, inflammation occurs. In addition to increased production of toxic substances, gut microbiome alterations contribute to decreased levels of anti-inflammatory microbial products.[7] In patients with psoriasis, decreased numbers of the digestive tract bacterium, Faecalibacterium prausnitzii, an important producer of short-chain fatty acids (SCFAs) with anti-inflammatory and barrier-protection functions, contributes to gut dysbiosis.[7] In mouse studies, the gut microbiome induces Th17 activation, a major player in psoriasis pathogenesis.[6] Antibiotic treatment in these mice alters the gut microbiome composition and decreases disease severity.[6] Faecal analysis of atopic dermatitis patients also shows loss of intestinal biodiversity and decreased SCFAs, suggesting that treatments targeting the gut microbiome may be beneficial in the management of chronic skin conditions.[7]
| The Cutaneous Microbiome in HS | | |
There is increasing evidence linking skin microbiome dysbiosis to the development of inflammatory skin disease, with specific pathobionts identified and associated with various pathogenic processes.[5] In general, the most common bacteria found on the skin of patients with HS include S. aureus, other coagulase-negative Staphylococcus (CNS) species, and mixed anaerobes [Table 1].[8] Additionally, a prospective metagenomic study characterizing the cutaneous microbiome in HS found that the microbiology of HS lesions (i.e. abscesses, inflamed nodules) significantly differs from the microbiome found in the same patients' non-lesioned skin folds.[8],[9]
Dominant anaerobic Gram-negative rods Prevotella and Porphyromonas are highly associated with HS lesions, and as the severity of lesions changes so does the microbiota.[10] By contrast, the microbiota of non-HS skin contains Corynebacterium, Propionibacterium, and Staphylococcus.[6],[11] While no relationship has been found between the number of species and the duration, nor diameter, of HS lesions, the presence of certain microbes seems to be correlated to the severity of lesions in patients with HS.[10]
In a pilot study by Naik et al.,[11] investigation into the relationship between overall disease severity and cutaneous bacteria in HS at sites of disease demonstrated increased bacterial diversity in HS skin when compared to healthy volunteers, and a correlation between worsening disease severity, increased relative abundances of anaerobes, and decreased relative abundances of major skin commensals. The presence of anaerobes Porphyromonas, Prevotella, Clostridiales, and Fusobacteria in lesions was found to be positively correlated with HS severity, while increased normal skin commensals Cutibacterium and Corynebacterium were negatively correlated.[6],[11] The most abundant taxon found to be associated with severe lesions is Fusobacterium.[9]
Outside of lesional skin, non-lesioned HS skin also significantly differs in comparison to the skin of healthy controls.[10] A cross-sectional study investigating the surface microbiome of clinically unaffected skinfolds in HS patients demonstrated decreased abundance of major skin commensals and an increased abundance of anaerobes.[5] This dysbiosis is reflective of the microbiome dysbiosis seen in HS lesions, albeit to a lower extent.[5] Non-lesional HS skin also has significantly fewer biofilms in comparison to healthy control skin.[12],[13]
A study conducted by Schneider et al.[14] found significant differences in microbiota, including species richness and distribution, between normal and HS lesional skin.[15] These differences likely have a functional impact on affected regions, as different microbiota are involved in different metabolic pathways. For example, several amino acid and vitamin metabolism pathways are significantly altered in HS skin, resulting in increased acidity of lesions.[15] The microbiome differences observed in HS skin reflects a general state of dysbiosis that may contribute to HS disease severity.
| Gut Microbiome and HS | | |
The role of diet in skin disease has long been recognized, with perhaps the most often cited example being celiac disease and dermatitis herpetiformis.[4] Research has attempted to link the gut microbiome to the development of HS, with one small-scale study demonstrating remission of lesions whilst practicing dietary avoidance of yeast and another, later study demonstrating that 70% of HS patients improved with a yeast-exclusion meal plan.[4] Investigation into the interplay between gut microbiome and HS has increased in recent years as IBD is recognized as a comorbid condition. A case-series exploring gut microbiome perturbations in HS showed decreased microbiome diversity compared to control gut microbiome while another study found that treatment/excision of HS lesions and dietary removal of brewer's yeast improved symptoms and quality of life.[15],[16] Upon resumption of eating food with brewer's yeast, HS recurred.[16] These findings suggest a relationship between diet, gut microbiome, and pathogenesis, as well as severity, of HS. Healthcare providers should keep in mind these associations when treating HS patients, as further research may reveal an important role of dietary modifications in disease management.
| Consequences of Microbiome Dysbiosis in HS | | |
It has been widely accepted that the pathogenesis of HS is not infectious in aetiology. However, the evidence of microbial dysbiosis suggests that bacteria play a role in propagating the development of disease. While the exact mechanisms are not fully understood, the prevalence of anaerobic bacteria in lesional skin can lead to bacterial multiplication, with subsequent rupture of the follicular unit.[1] Follicular rupture and inflammation activates pattern recognition receptors and release cytokines, including IL-1β and TNF-α, that propagate inflammation and immune dysregulation in HS.[1]
Cutaneous microbiome dysbiosis may contribute to disease severity as the overgrowth of anaerobic bacteria decreases skin commensals and allows the growth of pathogenic bacteria. Normal skin commensals, such as S. epidermidis and P. acnes, exhibit antimicrobial properties. These bacteria are decreased in HS and their absence may contribute to development as well as severity of disease.[6],[12] One study suggested that increased tryptophan degradation by bacteria such as Corynebacterium and anaerobes causes decreased secretion of aryl hydrocarbon receptor ligands by tryptophan-dependent bacteria such as Lactobacillus.[17] The aryl hydrocarbon receptor normally regulates immune response in the skin, so loss of their ligands may contribute to HS inflammation.[17]
Beyond the skin microbiome, changes observed in the gut microbiome of HS patients may also stimulate inflammation and alter immune responses [Figure 1]. For example, high fat diets reduce anti-inflammatory AMPs in the gut, resulting in increased release of cytokines that contribute to the pathogenesis of HS.[18] Some specific gut bacteria may be implicated in HS pathogenesis: Bilophila, increased in HS, is immunogenic in IBD and could also play an immunogenic role in HS.[15] Lachnobacterium, normally produces butyrate, an anti-inflammatory fatty acid, but HS patients show a decreased population of this bacteria in the gut.[15] | Figure 1: Proposed mechanisms of gut microbiome effect on HS inflammation. High-fat diets, increased gut Bilophila, and decreased gut Lachnobacterium may all contribute to increased inflammation.[15],[18] Created with BioRender.com
Click here to view |
| Microbiome Dysbiosis and Immune Consequences | | |
Microbiome dysbiosis—for example the presence of Porphyromonas and Prevotella—in HS, contributes to inflammation and disease pathogenesis via upregulation of pro-inflammatory AMPs.[4] Antimicrobial peptides may be pro- or anti-inflammatory and are either produced constitutively or induced by infection and inflammation as a part of the human body's defense system towards pathogens.[19] These peptides are part of the innate immune system and are normally produced in impressive quantities by keratinocytes or epithelial appendages (i.e. eccrine sweat glands) in response to a microbial threat.[19] They exert an antimicrobial effect and influence cytokine production, neutrophilic chemoattraction, antigen presentation and wound healing.[20] Patients with chronic or recalcitrant HS demonstrate persistence of bacteria in affected skin—findings that are significant as they led investigators to speculate whether the persistent infection and inflammation seen in relapsing patients might be secondary to deficient or diminished AMP expression.[20]
AMPs produced by keratinocytes include, but are not limited to, human B-defensin-3 (HBD-3) and psoriasin.[20] Additionally, eccrine sweat glands and epithelial appendages produce the AMP dermcidin.[20] Circulating leukocytes also have the propensity to produce a variety of AMPs, one of which is human cathelicidin LL-37 [Figure 2].[20] | Figure 2: Keratinocytes and eccrine glands produce bactericidal psoriasin, HBD-3, and dermcidin. Circulating leukocytes and keratinocytes produce the pro-inflammatory human cathelicidin LL-37.[17],[18] Created with BioRender.com
Click here to view |
Studies have analysed the relationship between AMPs and HS pathogenesis, in particular the relationship between deficient AMP production and bacterial colonization in HS patients. Hofmann et al.[20] provided evidence for reduced induction of the immunosuppressive and anti-inflammatory AMP HBD-3 in patients with severe HS. Suppressed levels of HBD-3 are associated with higher chances of bacterial superinfection, as evidenced by research that show that decreased HBD-3 in the skin of previously healthy individuals is associated with more severe S. aureus skin infections.
They investigated other AMPs, dermcidin and psoriasin, for clues to their involvement in HS. Dermcidin is secreted in eccrine sweat and possesses microbicidal activity against a variety of pathogens, in addition to playing a role in skin immunity via induced cytokine expression by keratinocytes.[20] While Hoffman et al. found no evidence for differing patterns of dermcidin expression between healthy control subjects and those with HS, a more recent study showed downregulation of dermcidin.[21] Hoffman et al. found that psoriasin, an AMP involved in restricting bacterial growth, could not be induced in the skin of HS patients. These findings led the investigators to speculate whether a deficiency in the anti-inflammatory IL-22 that has been described in HS could be the cause.[20] IL-22 is important as it strongly induces cutaneous AMPs, including psoriasin, and its relative deficiency documented in HS patients could explain why psoriasin is not inducible in these patients.
In contrast to the decreased levels of AMPs described in HS literature, Thomi et al.[22] discusses cathelicidin LL-37, a peptide that is elevated in the skin of HS patients. LL-37 is produced by tissue-resident cells (keratinocytes, epithelial cells) and cells of the immune system (innate, adaptive) and has a wide range of proinflammatory actions, including T-cell (Th1/Th17) attraction and increased proinflammatory cytokine production [Figure 2]. LL-37 acts synergistically with other pro-inflammatory peptides, including IL-1β, to enhance pro-inflammatory responses.[22] Additionally, it has been linked to the development of other chronic inflammatory diseases, including obesity and insulin resistance.[22] These findings have led investigators to hypothesize that LL-37 is present in HS lesions early in the pathogenesis of the disease and persists in the chronic phase as it drives the pro-inflammatory state and the Th1/Th17 immune response.[22] Overall, these findings highlight possible treatment targets for HS patients.
| Conclusion | | |
Hidradenitis suppurativa patients show a wide range of disruptions in the skin microbiome. Microbiome composition varies among normal, HS non-lesional, and HS lesional skin, suggesting a relationship between dysbiosis and disease. While the full extent of the changes and their subsequent effects is still under investigation, studies appear to indicate that microbiome alterations may contribute to immune dysfunction and subsequently HS pathogenesis. In addition to dysbiosis promoting immune dysregulation, HS may promote dysbiosis via differences in AMP expression. With further study, both the microbiome and AMPs in HS could serve as future targets for HS treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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