Introduction

Hidradenitis suppurativa (HS) is a disabling chronic inflammatory disease with significant comorbidities that affects an estimated 1% of the Western population. A poor understanding of HS biology has limited the development of uniformly effective treatments. The characteristic lesions of HS in conjunction with disease improvement with broad spectrum antibiotic therapy have implicated bacteria in HS pathogenesis and suggested novel areas for consideration of therapeutic development.

Role of Bacteria in Hidradenitis Suppurativa Biology

HS is characterized by painful recurrent abscesses, malodorous purulent drainage, dermal tunnel formation, and disfiguring scarring involving intertriginous body sites including the axillae, breasts, groin, and buttocks. The clinical characteristics of HS lesions have implicated bacteria in HS biology, which has guided the variably successful use of broad-spectrum antibiotics for HS. Despite its clinical presentation, however, HS is not thought to be an infectious disease for several reasons. First, bacterial organisms common to all HS lesions have not been identified and proven to be pathogenic. Second, HS is not reproducible upon inoculation of an unaffected susceptible host. Third, HS responds to immunomodulatory therapy, including tumor necrosis factor (TNF) inhibitors and intralesional steroids, which would presumably worsen an infectious condition. Disease response to immunomodulatory therapies suggests an important role for immune dysregulation in HS pathogenesis.

Limited studies have implicated dysregulated immune responses in HS, including elevations in TNF, interleukin (IL)-1β, IL-12/23, and IL-17, and activation of the JAK pathway. Furthermore, TNF inhibitor adalimumab is currently the only US Food and Drug Administration-approved drug for HS, thus underscoring the important role of TNF in HS-related inflammation. Initial studies have also suggested a role for humoral immunity in HS pathogenesis. These findings have collectively guided the study of novel interventional treatments and the clinical use of biologic agents for HS.

Taken together, these observations suggest that chronic dysregulated immune responses to abnormal and pathogenic microbial colonization of the mucocutaneous surfaces, also known as microbial perturbations or dysbiosis , may result in persistent tissue inflammation in HS.

Bacteriology of Hidradenitis Suppurativa

Until the last decade, culture-based approaches were the standard for characterizing microbial diversity on the skin and at other body sites. Conventional culture-based methods for characterizing microbes are limited, however, because less than 1% of bacterial species are cultivatable under standard laboratory conditions. Fastidious growth requirements of some bacteria make isolation and cultivation difficult. This is underscored by the fact that historically, skin microbial research focused on investigation of a small number of cultivatable microbial species that were associated with common skin disorders. Resultantly, differential recovery of skin microbes using culture-based approaches can lead to misinterpretation of the true relative abundance of bacterial species in a given sample.

Although the presence of abscesses and malodorous drainage has implicated microorganisms in HS pathogenesis, no consistent organism has been cultivated from HS lesions using conventional culture-based methods. Polymicrobial flora, including coagulase-negative Staphylococci , mixed anaerobes, Staphylococcus aureus , and Corynebacterium species, have been identified in only approximately 50% of HS lesions using conventional culture-based methods. These findings have largely guided the use of broad spectrum topical and systemic antimicrobial therapy—including antiseptic washes and antibiotics—as first-line management for HS management.

Although antibiotic therapy can be effective for HS management, treatment strategies that rely on repeated and lengthy antibiotic courses may induce antibiotic-resistant bacterial species. In a single center study, antibiotic therapy with topical clindamycin, oral ciprofloxacin, and trimethoprim/sulfamethoxazole were associated with cultivation of antibiotic resistant organisms. These data caution antibiotic stewardship in the management of HS.

Biofilm in Hidradenitis Suppurativa

Biofilm is an architectural colony of microorganisms within a matrix of extracellular polymeric substance which they produce. Within biofilm, microbial cells adhere to one another and to a static surface, thereby sheltering themselves from clearance by host defenses and antibiotics. Biofilms are thought to play an important role in the maintenance of chronic HS dermal tunnels (also called sinus tracts) and have also been hypothesized to play a role in development of acute HS lesions.

In a single study examining chronic HS lesions, biofilms were more commonly observed in lesional rather than perilesional skin, and specifically in sinus tracts and in the follicular infundulum. Active bacteria were noted in sinus tracts, which were associated with lymphocytic infiltration and giant cell reactions. In a subsequent study, biofilms were found in a minority of acutely inflamed hair follicles. These data together suggest that biofilms may play an important role in maintaining chronic HS lesions.

Skin Microbiota Alterations in Hidradenitis Suppurativa

In recent years, advances in high-throughput, culture-free, sequence-based genomic technologies have facilitated more comprehensive assessment of the diverse and uncultivatable microorganisms on the skin and mucosal surfaces of HS patients. Sequencing of the 16S ribosomal RNA gene, which is highly conserved in prokaryotes, has facilitated unbiased phylogenetic categorization of bacteria. Shotgun metagenomic sequencing consists of shearing the entire genomes of all microbes in a given sample, and then sequencing and assembling the fragments into a continuous sequence based on a reference or by forming larger contigs. This method allows not only for phylotyping but can also reveal functional information about microbial communities.

The health of microbial ecosystems is thought to be related to microbial diversity. Examining differences in microbial diversity can provide insights into microbial shifts within samples. Bacterial diversity can be measured by richness (the number of different species in a sample) and evenness (the extent to which species are evenly distributed). Alpha diversity is a measure of species richness within a sample, while beta diversity is a measure of differences in species composition across samples. The Shannon and Simpson diversity indices are mathematical measures that account for both the abundance and evenness of species in a given sample.

Gut Microbiome Alterations in Hidradenitis Suppurativa

HS has been associated with inflammatory bowel disease, a condition linked to perturbations in the gut microbiota. Additionally, HS patients anecdotally report variation in disease activity in response to dietary modifications. These data suggest that gut dysbiosis may be associated with HS. A single small case-control series of three patients and three controls has used 16S rRNA sequencing to examine the gut microbiome in HS patients and found that alpha diversity was increased in age- and sex-matched healthy controls as compared with HS patients. HS gut samples were also notable for reduced relative abundance of Firmicutes compared with healthy controls. Bilophila and Holdemania genera were more abundant and Lachnobacterium and Veillonella genera were less abundant in HS patients as compared with healthy controls. These findings are consistent with previous studies that report decreased gut microbiota diversity in inflammatory bowel disease (IBD) and obesity and increased relative abundance of microbes associated with metabolic dysfunction. Although these data are limited by small sample size, and the investigators did not control for tobacco smoking which is known to alter the gut microbiota, these preliminary data suggest that gut dysbiosis may be associated with HS. Larger controlled studies from diverse populations are needed to confirm these findings and their generalizability across the HS patient population.

Relevance to Therapy

The causal relationship between microbial perturbations and HS has yet to be clarified. Whether microbiome perturbations are drivers of disease or secondary to disease-associated patterns has not been elucidated. In other inflammatory diseases associated with microbiota shifts, previous proof-of-concept studies using high-resolution approaches have provided insights into the role of microbial perturbations and have led to development of novel therapeutic approaches. In atopic dermatitis, for example, relative abundance of S. aureus has been associated with disease flare, S. aureus has been shown to elicit inflammation and exacerbate eczema, and S. aureus -targeted treatment has been shown to reduce skin inflammation. These findings have led to the development of novel therapeutic strategies aimed at repopulating skin commensal bacteria. In inflammatory bowel disease, high-resolution approaches have provided insights into microbial shifts relevant to disease progression that have led to novel treatment approaches, including fecal microbiota transplants aimed at repopulating gut commensals.

Conclusion and Future Directions

Cross-sectional data from the skin and gut of HS patients have demonstrated microbial shifts that may have clinical relevance in HS. Longitudinal studies are needed to examine how microbiota perturbations shift over the course of waxing and waning disease and if these shifts portend disease development and progression. A deeper understanding of microbial drivers and microbial products that may have a role in immune dysregulation in HS may potentially lead to novel microbe-based interventions. Identification of microbiota clusters, or even specific microbial species, that may serve as biomarkers for disease prognosis or predictors of treatment response may potentially inform clinical practice. Finally, a deeper understanding of the functional impact of specific abundant or unique microbes in HS will be important to advance novel microbiota-based therapies.