Follicular Skin Disorders, Inflammatory Bowel Disease, and the Microbiome: A Systematic Review.

Follicular skin disorders, including hidradenitis suppurativa (HS), frequently coexist with systemic autoinflammatory diseases, such as inflammatory bowel disease (IBD) and its subtypes, Crohn's disease and ulcerative colitis. Previous studies suggest that dysbiosis of the human gut microbiome may serve as a pathogenic link between HS and IBD. However, the role of the microbiome (gut, skin, and blood) in the context of IBD and various follicular disorders remains underexplored. Here, we performed a systematic review to investigate the relationship between follicular skin disorders, IBD, and the microbiome. Of the sixteen included studies, four evaluated the impact of diet on the microbiome in HS patients, highlighting a possible link between gut dysbiosis and yeast-exclusion diets. Ten studies explored bacterial colonization and HS severity with specific gut and skin microbiota, including Enterococcus and Veillonella. Two studies reported on immunological or serological biomarkers in HS patients with autoinflammatory disease, including IBD, and identified common markers including elevated cytokines and T-lymphocytes. Six studies investigated HS and IBD patients concurrently. Our systematic literature review highlights the complex interplay between the human microbiome, IBD, and follicular disorders with a particular focus on HS. The results indicate that dietary modifications hold promise as a therapeutic intervention to mitigate the burden of HS and IBD. Microbiota analyses and the identification of key serological biomarkers are crucial for a deeper understanding of the impact of dysbiosis in these conditions. Future research is needed to more thoroughly delineate the causal versus associative roles of dysbiosis in patients with both follicular disorders and IBD.

Insights into Gut Microbiome Composition in Hidradenitis Suppurativa: A Comprehensive Examination of Dietary Habits and Environmental Influences.

This study explores the relationship between dietary habits, environmental influences, and gut microbiome composition in individuals with hidradenitis suppurativa (HS), a chronic inflammatory skin condition. A cohort of 80 participants, equally divided into HS patients and healthy controls, was assessed through comprehensive questionnaires capturing demographics, dietary habits, and other health-related information. Fecal samples were collected and analyzed using next-generation sequencing to examine microbiome composition. Despite previous studies suggesting gut dysbiosis in HS, this research found no significant differences in alpha-diversity and Shannon diversity index between the groups. However, significant disparities in dietary habits were observed, with HS patients showing higher sugar and milk consumption. The study also identified a significant correlation between coffee consumption and the presence of certain bacterial genera. While the study did not reveal major differences in microbiome diversity, the findings on dietary habits and specific microbiome components suggest potential targets for therapeutic intervention. These results underscore the importance of further research into the gut-skin axis and its role in HS, aiming to enhance management strategies through dietary modifications and lifestyle interventions.

Gram-negative anaerobes elicit a robust keratinocytes immune response with potential insights into HS pathogenesis.

Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease with activated keratinocytes, tunnel formation and a complex immune infiltrate in tissue. The HS microbiome is polymicrobial with an abundance of commensal gram-positive facultative (GPs) Staphylococcus species and gram-negative anaerobic (GNA) bacteria like Prevotella, Fusobacterium and Porphyromonas with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome. Type strains of Prevotella nigrescens, Prevotella melaninogenica, Prevotella intermedia, Prevotella asaccharolytica, Fusobacterium nucleatum, as well as Staphylococcus aureus and the normal skin commensal Staphylococcus epidermidis were heat-killed and co-incubated with normal human keratinocytes. RNA was collected and analysed using RNAseq and RT-qPCR. The supernatant was collected from cell culture for protein quantification. Transcriptomic profiles between HS clinical samples and stimulated keratinocytes were compared. Co-staining of patient HS frozen sections was used to localize bacteria in lesions. A mouse intradermal injection model was used to investigate early immune recruitment. TLR4 and JAK inhibitors were used to investigate mechanistic avenues of bacterial response inhibition. GNAs, especially F. nucleatum, stimulated vastly higher CXCL8, IL17C, CCL20, IL6, TNF and IL36γ transcription in normal skin keratinocytes than the GPs S. epidermidis and S. aureus. Using RNAseq, we found that F. nucleatum (and Prevotella) strongly induced the IL-17 pathway in keratinocytes and overlapped with transcriptome profiles of HS patient clinical samples. Bacteria were juxtaposed to activated keratinocytes in vivo, and F. nucleatum strongly recruited murine neutrophil and macrophage migration. Both the TLR4 and pan-JAK inhibitors reduced cytokine production. Detailed transcriptomic profiling of healthy skin keratinocytes exposed to GNAs prevalent in HS revealed a potent, extensive inflammatory response vastly stronger than GPs. GNAs stimulated HS-relevant genes, including many genes in the IL-17 response pathway, and were significantly associated with HS tissue transcriptomes. The close association of activated keratinocytes with bacteria in HS lesions and innate infiltration in murine skin cemented GNA pathogenic potential. These novel mechanistic insights could drive future targeted therapies.

Primary skin abscess microbiota a systematic review.

An abscess is a collection of pus forming a cavity in the tissue, for example, the skin. They are generally perceived as the result of infection but infection is not mandatory for the diagnosis. Skin abscesses may occur independently (primary) or be part of other diseases such as the recurrent inflammatory skin disease hidradenitis suppurativa (HS). HS is noninfectious but nevertheless abscesses are a common differential diagnosis. The purpose of this study is to review the microbiome of bacteria positive primary skin abscesses in order to explore the reported microbiota. EMBASE, MEDLINER, and COCHRANE LIBRABRY were searched on 9th of October 2021 for microbiome, skin, and abscesses. Studies with more than 10 patients reporting the microbiome in human skin-abscesses were included and studies with abscess microbiota sampled from HS patients, microbiota not sampled from skin-abscesses, missing information on microbiome data, sampling bias, studies in other language than English or Danish, reviews and meta-analyses were excluded. In total 11 studies were included for further analysis. S. aureus is likely to dominate the microbiome of bacteria positive primary skin abscesses in contrast to the polymicrobial microbiome of HS.

Altered Skin and Gut Microbiome in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the formation of nodules, abscesses, and fistulae at intertriginous sites. The skin-gut axis is an area of emerging research in inflammatory skin disease and is a potential contributory factor to the pathogenesis of HS. A total of 59 patients with HS provided fecal samples and nasal and skin swabs of affected sites for analysis. A total of 30 healthy controls provided fecal samples, and 20 healthy controls provided nasal and skin swabs. We performed bacterial 16S ribosomal RNA gene amplicon sequencing on total DNA derived from the samples. Microbiome alpha diversity was significantly lower in the fecal, skin, and nasal samples of individuals with HS, which may be secondary to disease biology or related to antibiotic usage. Ruminococcus gnavus was more abundant in the fecal microbiome of individuals with HS, which is also reported in Crohn's disease, suggesting comorbidity due to shared gut microbiota alterations. Finegoldia magna was overabundant in HS skin samples relative to that in the healthy controls. It is possible that local inflammation is driven by F. magna by promoting the formation of neutrophil extracellular traps. These alterations in both the gut and skin microbiome in HS warrant further exploration, and therapeutic strategies, including fecal microbiota transplant or bacteriotherapy, could be of benefit.

Yin and Yang: A disrupted skin microbiome and an aberrant host immune response in hidradenitis suppurativa.

The skin microbiome plays an important role in maintaining skin homeostasis by controlling inflammation, providing immune education and maintaining host defense. However, in many inflammatory skin disorders the skin microbiome is disrupted. This dysbiotic community may contribute to disease initiation or exacerbation through the induction of aberrant immune responses in the absence of infection. Hidradenitis suppurativa (HS) is a complex, multifaceted disease involving the skin, innate and adaptive immunity, microbiota and environmental stimuli. Herein, we discuss the current state of HS skin microbiome research and how microbiome components may activate pattern recognition receptor (PRR) pathways, metabolite sensing pathways and antigenic receptors to drive antimicrobial peptide, cytokine, miRNA and adaptive immune cell responses in HS. We highlight the major open questions that remain to be addressed and how antibiotic therapies for HS likely influence both microbial burden and inflammation. Ultimately, we hypothesize that the two-way communication between the skin microbiome and host immune response in HS skin generates a chronic positive feed-forward loop that perpetuates chronic inflammation, tissue destruction and disease exacerbation.

Staphylococcus aureus Carriage in Hidradenitis Suppurativa: Impact on Response to Adalimumab.

BACKGROUND: Several patients with hidradenitis suppurativa (HS) present flare-ups during treatment with adalimumab (ADA), the cause of which is not clear. ADA is the only FDA-approved biologic for the therapy of moderate-to-severe HS. A previous study of our group has shown that Staphylococcus aureus stimulation of whole blood affects the production of human ß-defensin 2 and modulates HS severity. It is, therefore, hypothesized, that carriage of S. aureus may drive HS flare-ups. OBJECTIVE: To explore the association between carriage of S. aureus and loss of response to ADA. PATIENTS AND METHODS: Among patients with moderate-to-severe HS without carriage of S. aureus at start of treatment with ADA, we investigated for carriage of S. aureus from the nares when flare-ups occurred. Flare-ups were pre-defined as at least 25% increase of inflammatory lesions (sum of inflammatory nodules and abscesses) from baseline. Samplings were also done after completion of 12 weeks of ADA treatment from all patients who did not present flare-ups. Clinical response to ADA was assessed by the HS Clinical Response score (HiSCR). RESULTS: Thirty-nine patients were studied; 24 with Hurley II stage HS and 15 with Hurley III stage HS. Twenty-nine patients achieved HiSCR after 12 weeks of treatment without any flare-ups; 10 patients had flare-ups and failed HiSCR. Three (10.3%) and 5 (50%) patients, respectively, had nasal carriage of S. aureus (odds ratio 8.67; 95% CI 1.54-48.49; p = 0.014). Among 32 patients reaching follow-up week 48, 20 patients achieved HiSCR and 12 had flare-ups leading to ADA failure; 2 (10%) and 5 (41.7%) patients, respectively, had positive culture for S. aureus (odds ratio 6.42; 95% CI 1.00-41.20; p = 0.05). CONCLUSION: Nasal carriage of S. aureus may be associated with loss of response to ADA. Findings need confirmation in larger series of patients.

Irrelevance of Panton-Valentine leukocidin in hidradenitis suppurativa: results from a pilot, observational study.

Panton-Valentine leukocidin (PVL) appears to be a virulence factor which, among others, can exacerbate the pathogenicity of Staphylococcus aureus infections, especially inducing severe necrotic, deep-seated skin infections, abscesses, and recurrences. These peculiarities have some overlaps with hidradenitis suppurativa (HS). Our main aim was to assess if S. aureus producing PVL could have some role in influencing clinical features and/or course of HS, specifically in the suppuration and recurrence of lesions. This pilot, mono-centric, observational study included all adult subjects affected with HS consecutively referring to our HS clinic over a 3-month period. Clinically evident suppuration and at least 2 weeks wash out from any antibiotic were the main inclusion criteria. Purulent material from HS skin lesions was collected with swabs in order to isolate micro-organisms, with specific regard to S. aureus. Detection of PVL was performed by real-time quantitative PCR (RT-qPCR). We also analyzed purulent material from suppurative skin lesions other than HS, as a control. Thirty HS patients were included; 29 purulent lesions (96.7%) harbored at least one bacterial species. Five (16.7%) swab samples were positive for S. aureus, none of which was positive for PVL genes. Among the 30 purulent disorders included as controls, 8 (26.3%) were positive for S. aureus; of these, 4 strains (50%) expressed LPV. The study results seem to exclude the pathogenetic involvement of S. aureus producing PVL in HS; as a result, PVL does not seem to represent a potential target in the future development of HS treatments.

A systematic review and critical appraisal of metagenomic and culture studies in hidradenitis suppurativa.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease with still largely unknown pathogenesis. While infectious organisms have been identified in lesions of the disease since the 1980s, questions remain over the role that bacteria and microbiome play. Recent studies using 16S ribosomal RNA gene sequencing and larger culture-based studies have begun to paint a clearer picture of the microbial world of HS. With this systematic review, we summarize all the work that has been done to date in HS bacteriology, analyse potential pitfalls and limitations of the current studies, and address future directions of investigation. This systematic review attempted to collate and analyse all bacteriology studies done to date. This review was prospectively registered with PROSPERO (1670769) performed in line with the PRISMA checklist. Twenty two studies were identified comprising 862 individual HS patients for culture studies and 206 HS patients for 16S rRNA gene sequencing studies. Methodology tended to be varied, with different sampling, culturing and sequencing methods as well as amount of analysis and stratification of patients. Bacteria identified as elevated in HS lesions in sequencing studies as well as grown from HS lesions in culture studies are identified and discussed. These primarily included the anerobic Gram-negative bacilli Prevotella, Porphyromonas and Fusibacterium, the Gram-positive bacilli Corynebacterium, and the Gram-positive cocci Staphylococcus, Streptococcus and Parvimonas. Potential interactions, as well as work in other disease models with related bacteria are also discussed. Areas of further investigation include in vitro studies of interactions between bacteria and keratinocytes, gut and oral microbiome studies and deep sequencing studies for virulence and phage factors.

Hidradenitis Suppurativa and 1-Carbon Metabolism: Role of Gut Microbiome, Matrix Metalloproteinases, and Hyperhomocysteinemia.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition characterized by painful nodules which suppurate and later develop into scar tissues followed by the development of hypodermal tracts. Although the mechanisms behind HS are not fully understood, it is known that dietary factors play important roles in flare frequency and severity. We hypothesize that the high fat diet (HFD) causes dysbiosis, systemic inflammation, and hyperhomocysteinemia (HHcy) in susceptible individuals, which subsequently elevate inflammatory cytokines such as IL-1ß, IL-6, IL-17, and tumor necrosis factor alpha (TNF-α). This increase in dysbiosis-led inflammation coupled with a dysregulation of the 1-carbon metabolism results in an increase in matrix metalloproteinases MMP-2, MMP-8, and MMP-9 along with tissue matrix remodeling in the development and maintenance of the lesions and tracts. This manuscript weaves together the potential roles played by the gut microbiome, HHcy, MMPs, and the 1-carbon metabolism toward HS disease causation in susceptible individuals.

Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway-inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.

The pharmacology of antibiotic therapy in hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating skin disease. Several pharmacologic agents have been described to reduce lesion activity and inflammation in HS. In this study, we have reviewed the available antibiotic therapies for HS, analyzing the pharmacologic aspects of these kind of treatments. AREAS COVERED: The role of bacteria, infections, and superinfections in HS is still debated and controversial. Antibiotics are recognized as first-line treatments for hidradenitis suppurativa, but the data on their efficacy are limited. Antibiotics should not be replaced by new biological therapies and it is not necessary to make an efficacy classification: it is important for dermatologists to recognize the right patient and the right moment to prescribe an antibiotic therapy, together or in a rotational way with other therapeutic options. EXPERT OPINION: The HS treatment process for the physicians is often complicated by the disease's severity and several comorbidities. Fortunately, a better understanding of HS pathogenesis has been used to improve treatment strategies. Antibiotic therapy is an effective treatment of patients with HS but probably, in the next five years, many therapeutic options will be available, which will change the way we manage the disease, especially the moderate-to-severe forms of HS.

The Surface Microbiome of Clinically Unaffected Skinfolds in Hidradenitis Suppurativa: A Cross-Sectional Culture-Based and 16S rRNA Gene Amplicon Sequencing Study in 60 Patients.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the skin associated with specific lesional dysbiotic features. We studied the microbiome of clinically unaffected typical HS sites (armpits, inguinal folds, and gluteal clefts) in 60 patients with HS and 17 healthy controls. A total of 192 samples obtained by swabbing were analyzed by bacterial cultures. Of these, 116 randomly selected samples were studied by 16S rRNA gene amplicon sequencing. Patients and controls showed similar characteristics, except for smoking (87% vs. 6%, respectively). HS skinfolds were characterized by an increased abundance of anaerobes, predominantly Prevotella, but also Actinomyces, Campylobacter ureolyticus, and Mobiluncus, contrasting with a lower abundance of skin commensals such as Staphylococcus epidermidis, a major component of the skin microbiome; Kocuria; and Micrococcus luteus. The following three independent factors were associated with an abundance of high anaerobes by multivariate analysis: samples originating from patients with HS patients (P = 2.1 × 10-4); body mass index (P = 5 × 10-5); and the sampling site, the gluteal cleft being the most anaerobic area, followed by inguinal folds and axilla (P = 3 × 10-6). The microbiome of clinically unaffected HS skinfolds is reminiscent, albeit to a minor extent, of the microbiome of chronic suppurative HS lesions and may fuel inflammation at a preclinical stage of the disease.

The Role of the Cutaneous Microbiome in Hidradenitis Suppurativa-Light at the End of the Microbiological Tunnel.

The development of next generation sequencing, coupled with advances in bio-informatics, has provided new insights into the role of the cutaneous microbiome in the pathophysiology of a range of inflammatory skin diseases. In fact, it has even been suggested that the identification of specific skin microbial signatures may not only be useful in terms of diagnosis of skin diseases but they may also ultimately help inform personalised treatment strategies. To date, research investigating the role of microbiota in the development of inflammatory skin diseases has largely focused on atopic eczema and psoriasis vulgaris. The role of the microbiome in Hidradenits suppurativa (HS)-also known as acne inversa-a chronic auto-inflammatory skin disease associated with significant morbidity, has received comparatively little attention. This is despite the fact that antimicrobial therapy plays a central role in the treatment of HS. After briefly outlining the clinical features of HS and current treatment strategies, we move on to review the evidence of microbial dysbiosis in HS pathophysiology. We conclude by outlining the potential for metagenomic studies to deepen our understanding of HS biology but more importantly to identify novel and much needed treatment strategies.

Hidradenitis suppurativa/acne inversa: a prospective bacteriological study and review of the literature.

BACKGROUND: Hidradenitis suppurativa is a chronic inflammatory disease of the hair follicle that usually involves specific anatomic areas which are partially occluded, have a higher density of eccrine and apocrine sweat glands and a higher pH. These characteristics could promote the superinfection of certain group of bacteria. We aimed to describe the bacteria that can be isolated from hidradenitis lesions and to establish a correlation between bacteriological results and clinical data. METHODS: We prospectively enrolled forty-six patients presenting purulent or seropurulent discharge. Sixty samples were performed using swabs, which were deeply introduced in the lesions. RESULTS: Fifty-two percent of cultures resulted positive and fifteen bacterial species were isolated. The more prevalent species were Proteus mirabilis and Staphylococcus aureus. Samples from advanced cases were more likely to yield a positive bacterial growth. CONCLUSIONS: In our study the rate of positive cultures increased in more severe stages of the disease, thus bacterial superinfection of established lesions may contribute to maintain chronic inflammation. We could not find statistically significant correlation with the sampled anatomic area or specific group of bacteria. Larger prospective studies should be performed.

Clinical, microbiological, immunological and imaging characteristics of tunnels and fistulas in hidradenitis suppurativa and Crohn's disease.

Hidradenitis suppurativa (HS) tunnels and Crohn's disease (CD) fistulas are a challenge to treat. Although pathogenic similarities have been described between HS and CD, recent studies indicate that clinical, microbiological, immunological and imaging characteristics differ between these diseases. This review highlights the differences between HS tunnels and CD fistulas. Next-generation sequencing studies demonstrate a microbiome in HS tunnels dominated by Porphyromonas spp., Prevotella spp. whereas no specific bacteria have been associated with cutaneous CD. Immunologically, TNF has been found upregulated in HS tunnels along with various interleukins (IL-8, IL-16, IL-1α and IL-1ß). In CD fistulas, Th1, Th17, IL-17, IFN-ɤ, TNF and IL-23 are increased. US imaging is an important tool in HS. US of HS tunnels depict hypoechoic band-like structure across skin layers in the dermis and/or hypodermis connected to the base of a widened hair follicle. In CD, MR imaging of simple perianal fistulas illustrates a linear, non-branching inflammatory tract relating to an internal opening in the anus or low rectum and an external opening to the skin surface. An increased awareness of the immediate potential differences between HS tunnels and CD fistulas may optimize treatment regimens of these intractable skin manifestations.