
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)13463-9
10.1016/j.heliyon.2024.e37432
e37432
Review Article
Fecal microbiota transplantation for the treatment of chronic inﬂammatory skin diseases
Wu Mingyang a1
Chen Xingyu a1
Lu Qianjin qianlu5860@pumcderm.cams.cn
bcd⁎⁎
Yao Xu dryao_xu@126.com
ad⁎
a Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
b Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
c Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
d Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
⁎ Corresponding author. Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, No.12 Jiangwangmiao Street, Xuanwu District, Nanjing, Jiangsu Province, China. dryao_xu@126.com
⁎⁎ Corresponding author. Institute of Dermatology, Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Sciences and Peking Union Medical College, No.12 Jiangwangmiao Street, Xuanwu District, Nanjing, Jiangsu Province, China. qianlu5860@pumcderm.cams.cn
1 these authors contribute equally to this work.

07 9 2024
30 9 2024
07 9 2024
10 18 e3743215 4 2024
2 9 2024
3 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
The regulation of immune functions and the maintenance of homeostasis in the internal environment are both integral to human gut microbiota (GM). If GM is disturbed, it can result in a range of autoimmune diseases, including chronic inflammatory skin conditions. Chronic inflammatory skin diseases driven by T or B-cell-mediated immune reactions are complex, including the most prevalent diseases and some rare diseases. Expanding knowledge of GM dysbiosis in chronic inflammatory skin diseases has emerged. The GM has some causal roles in the pathogenesis of these skin conditions. Targeting microbiota treatment, particularly fecal microbiota transplantation (FMT), is considered to be a promising strategy. FMT was commonly used in intestinal diseases by reshaping and balancing GM, serving as a reasonable administration in these skin inflammatory diseases. This paper summarizes the existing knowledge of GM dysbiosis in chronic inflammatory skin diseases and the research data on FMT treatment for such conditions.

Graphical abstract

Image 1

Keywords

Fecal microbiota transplantation (FMT)
Gut microbiota
Chronic inflammatory skin diseases
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pmc1 Introduction

A massive medical load has been caused by the prevalence of persistent inflammatory skin diseases, with atopic dermatitis (AD) and psoriasis being the most prevalent [1]. In addition, autoimmunity can be a contributing factor to conditions such as alopecia areata (AA), pemphigus and pemphigoid diseases, vitiligo, and chronic spontaneous urticaria, all of which are caused by T cells or B cells dysregulation. There are a few rare causes of chronic skin inflammation, including autoinflammatory diseases or rheumatic diseases, such as cutaneous lupus erythematosus (CLE), Sjögren's syndrome (SjS), and Behçet's disease (BD) [2].

Knowledge of gut microbiota (GM) dysbiosis in chronic inflammatory skin diseases has increased [3]. The interaction between intestinal epithelial cells and activation of immune cells has been suggested as a potential cause of various immune disorders attributed to GM dysbiosis [[4], [5], [6]]. Given the correlation of psoriasis phenotypes with gut microbes, there seems to be a powerful positive association between an increased abundance of Phascolarctobacterium species and proinflammatory cytokines, which could be pertinent to T-cell activation [7]. By regulating the proportion of T-cells and altering the composition of GM, Lactobacillus paracasei KBL382 isolated from healthy people has been shown to alleviate AD-like symptoms and symptoms of obesity [8]. Consequently, it is valuable to explore the relationship between gut microbiota (GM) dysbiosis and chronic inflammatory skin diseases, as well as consider fecal microbiota transplantation (FMT) as a proposed treatment for targeting these skin diseases. In our narrative review, the literature research was performed by searching the PubMed database, and adopting the search terms (fecal microbiota transplantation) OR (gut microbiota) AND (chronic inflammatory skin diseases).

2 FMT under clinical development for chronic inflammatory skin diseases

In humans, the intestinal microbiota is necessity for stimulating, educating and sustaining the immune system's equilibrium [9]. It is estimated that there are more than 1000 species-level phylotypes in human intestinal environments [10], of which Bacteroidetes and Firmicutes account for 90 percent [11]. As researchers delve into the links between GM composition and susceptibility to disease, as well as how commensal microbiota and their metabolites affect human health, they are being spurred on to investigate targeted microbiota-based therapies [12].

The first proposal for FMT in pseudomembranous colitis was made in 1958 [13]. The well-documented and effective GM-management strategy involves injecting healthy donor feces into the intestinal tract of the patient. Aiming to improve probiotic status, remodel a healthy GM, and reinstate its beneficial functions. For more than 40 years, FMT has been reported widely as a therapy for recurrent Clostridioides difficile infection [14], which is typically an antibiotic-induced dysbiosis.

2.1 Atopic dermatitis

In recent years, a correlation has been found between changes in gut microbes and the occurrence of AD [15]. Specific characteristics of the GM in 3-month-old breast-fed infants showed greater abundance of Clostridium sensu stricto, which is thought to be related to AD [16]. This observation was the confirmation of similar alpha-diversity, partial differences in beta-diversity, and positive correlations in the abundance of Gemella species in allergic infants [17]. A cross-sectional investigation of 81 Brazilian children aged 5 to 11 revealed a correlation between AD and the greater numbers of Clostridium difficile, Bifidobacterium species, as well as lesser amounts of Lactobacillus species within their intestinal microbiota [18]. Patients with AD exhibited a reduction in GM diversity in comparison with healthy individuals, and the richness of conducive symbiotic microbes, such as Lactobacillus species and Bifidobacterium species, was notably diminished; however, the proportions of C. difficile, Escherichia coli, and Staphylococcus aureus were increased significantly [19]. One study showed that individuals with AD had a relative abundance of bacteria of the order Bacteroidales and Bacteroidia, phylum Bacteroidetes, and genera Romboutsia and Sutterella [20]. Similar to the skin, S. aureus was found to be abundant in the GM of patients suffering from AD [21]. According to a birth cohort study conducted in Sweden, S. aureus strains carrying specific superantigens and adhesins colonized the gut during early childhood would cause AD in those children later [22]. SCFAs are microbial metabolites in the human gut with anti-inflammatory effects. A significantly reduced risk of AD has been linked to a high concentration of SCFAs and copious amounts of butyrate-producing bacteria (BPB), such as Coprococcus eutactus, in fecal material [[23], [24], [25]]. Early life colonization and alteration of the GM occurs before the presentation of clinical manifestations, indicating that GM dysbiosis may be a contributing factor to AD [26,27].

Kim et al. initially put the emphasis on using FMT in AD therapy. It was shown that FMT had a potential therapeutic effect on AD-induced allergic symptoms in mice by restoring GM and immunologic balance (Th1 cells/Th2 cells) [28]. An oxazolone-induced AD mouse model was created. Mice were categorized into high-responding (HR) and low-responding (LR) donors determined by their dermatitis score, ear thickness, and concentrations of inflammatory cytokines. Feces materials from these AD mice were delivered into pregnant germ-free Swiss Webster dams and their progeny [27]. HR recipient mice exhibited higher clinical scores for dermatitis than LR recipient mice [29]. In a calcipotriol (MC903)-induced AD model, mice were treated with FMT from healthy mice for 7 days. The GM of the FMT group changed significantly during natural recovery, especially the increased Firmicutes: Bacteroidetes (F: B) ratio as well as BPB concentration. The mouse model of AD following FMT treatment, revealed a plethora of modifications in metabolic and immune pathways [30].

FMT was evaluated for the first time in humans at Tel Aviv Medical Center for adults with moderate to severe AD. The results showed a marked improvement from baseline in signs and symptoms of AD. Following each FMT, the average Scoring Atopic Dermatitis value decreased significantly at week 4. In the total of 9 participants, there were 7 and 6 patients achieved reduction of 50 % and 75 % at week 18 (after 8 weeks since the last FMT), respectively. However, two of the patients experienced quick relapse after treatment. The clinical results were hampered by the limited sample size, the lack of double-blinded design, and other factors that had to be taken into account [31]. For patients suffering from AD, FMT might be a safe and efficacious therapeutic intervention. Further explorations are required to confirm the immune response, gut metabolites, and AEs in clinical studies. There is a disruption in the gut barrier among AD patients, which makes them more vulnerable to the risks of FMT [32].The development of alternative GM-targeted therapies by combining appropriate microorganisms or microbial metabolites may therefore be a rational approach for treating AD in the future.

2.2 Psoriasis

GM in patients with psoriasis exhibits a diminished bacterial diversity and a variance in beta-diversity [33]. A greater decrease in biodiversity is observed in patients with moderate-to-severe psoriasis than in those with mild psoriasis [34]. GM composition is also distinct in patients, as Firmicutes, Actinobacteria, Verrucomicrobia, Faecalibacterium, Bacteroides, Bifidobacterium, Megamonas and Roseburia have higher abundances; whereas the phyla Bacteroidetes, Euryarchaeota, Proteobacteria and genera Prevotella, Alistipes, and Eubacterium are less abundant [35,36].

Psoriasis has been associated with the GM in many studies [7,[37], [38], [39], [40]]. This is evidenced by the augmented F:B ratio, a sign of a weakened gut epithelial barrier of patients [37], which induces microbial movement from the gut to the bloodstream. Additionally, it has also been found that "leaky" bacterial DNA in the bloodstream of psoriatic patients, which is considered to derive from the intestinal lumen, contributes to the development of psoriatic plaques [38]. Psoriasis may be induced by GM variations, resulting in dysregulation of inflammation-related biomarkers and an abnormal immune response. In particular, IL-2 receptors interact positively with Phascolarctobacterium species and negatively with Dialister species. Therefore, the relative abundance of those strains could provide the clue of the severity of psoriasis in psoriatic patients [7]. The GM, in an experimental mouse model of psoriasis caused by TLR7 agonist imiquimod, augmented the Th17 response [39]. Broad-spectrum oral antibiotics administration could reduce the skin inflammation of mouse model by decreasing the Th17 immune response [40].

An experiment was conducted on mice that presented with psoriatic dermatitis and colitis. The imiquimod and dextran sulfate sodium (DSS) was administered to the rodents. Those given imiquimod experienced an abrupt onset of DSS-induced colitis, with a reduction in immunoglobulin (Ig)D+ and IgM+ B cells as well as a rise in noncytokine-producing macrophages in the gut. The GM composition of mice treated with imiquimod was significantly altered, with a decrease in the population of Lactobacillus species, which are implicated in causing severe DSS-induced colitis [41]. Further experiments demonstrated that IQI/Jic mice suffering from DSS-induced colitis experienced exacerbation when feces from imiquimod-treated mice were transplanted into them [41]. Conversely, the fecal microbiota of healthy individuals, when transplanted into imiquimod-induced mice, caused a remarkable reduction in skin inflammation, suggesting that the Tregs/Th17 cell imbalance observed in psoriasis could be remedied through this method [42]. Another study verified bacteria of the family Ruminococcaceae and genera Coprococcus_1 and Blautia were less plentiful in mice with psoriasis that received fecal microbiota from patients with psoriasis and their psoriasiform dermatitis took longer time to recover [43].

In a case, a 36-year-old Chinese man had been suffered with severe plaque psoriasis for a decade, as well as IBD for fifteen years, was the first to be described in a clinical case report regarding FMT application. During the five-week interval between administrations, FMT was administered twice through upper endoscopy and colonoscopy. At the endpoint, the serum concentration of TNF-α as well as Psoriasis Area and Severity Index were reduced in comparison to their baseline state, while histology and intestinal symptoms were both improved [44]. In 2015, the first proof-of-concept, a parallel-group, double-blind placebo-controlled, a single-center superiority trial was carried. The results showed that FMT is safe but not more effective than sham for active peripheral psoriatic arthritis. Thirty-one participants were enrolled. Serious AEs were not seen during the whole treatment peroid. The FMT group exhibited a significantly higher prevalence of treatment failure (defined as needing more than one intra-articular glucocorticoid injection, non-methotrexate conventional synthetic and/or biologic DMARD) than the sham group (transplant saline in the duodenum using an oral-duodenal tube), which was largely linked to AEs in gastrointestinal tract issues such as abdominal unease, flatulence, nausea, and vomiting [45]. Consequently, FMT is considered to be a safe administration for psoriasis, but the efficiency needs to be verified by larger sample size research.

2.3 Alopecia areata

A comparison of stool samples in AA and control groups did not reveal significantly different alpha- or beta-diversities in the GM. However, those with AA displayed an augmented abundance of bacteria of the families Erysipelotrichaceae, Lachnospiraceae, as well as Holdemania filiformis, Parabacteroides johnsonii, Clostridiales vadin BB60 group, Bacteroides eggerthii, and Parabacteroides distasonis [46]. In contrast to healthy controls, a survey of Chinese people demonstrated that the GM in the AA group showed markedly more abundance in the family Erysipelotrichaceae, the genera Blautia, Anaerostipes, Dorea, Collinsella, Megasphaera, and Achromobacter than those in healthy controls, while the family Fusobacteriales showed a lower abundance [47]. It is possible that the GM contributes to AA development either by preventing fiber intake or by lowering SCFA-producing bacteria. This could result in a decrease in bacterial SCFA synthesis, thus leading to a decreased Treg-associated peripheral tolerance [48,49]. Genetically susceptible individuals may be at risk for immune system stress caused by gut dysbiosis [50]. A pilot study found shifts in the GM in pediatric patients with AA and identified that Ruminococcus bicirculans abundance was reduced in children (4–17 years) with AA in comparison with the siblings without AA [51].

Preventive treatment of AA is not available. Hence, targeting the GM with FMT has become a candidate treatment for AA [52]. After FMT, hair regrowth occurred in two patients with recurrent C. difficile infection accompanied by alopecia universalis [53]. In a 86-year-old patient with patchy AA and noninfectious diarrhea, hair regrew in the affected areas, and gray hairs gradually turned black after FMT [54]. Therefore, FMT is considered a potential therapy for patients with AA. To authenticate the part FMT plays in AA, further extensive and specialized research is necessary.

2.4 System lupus erythematosus

There was a significantly low F:B ratio observed in individuals with SLE in the first report on SLE-associated intestinal dysbiosis [55]. Except for two research groups that showed there was no alteration [56] or an ∼1-fold increase in the F:B ratio in patients with SLE [57], many studies subsequently revealed the same finding [58,59]. The genera Streptococcus, Campylobacter, and Veillonella had a positive correlation with SLE activity in the turbulent microbiota, whereas Bifidobacterium species had a negative association [58]. In Spain, bacteria of the genera Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium, Flavonifractora, and Incertae sedis were demonstrated to be clearly thrived among patients with SLE, whereas the Dialister species and Pseudobutyrivibrio species had a dramatic decline [60]. In southern China, the GM of individuals with SLE was observed to have a notable rise in the abundance of the phylum Actinobacteria and Ruminococcus gnavus [61]. Interestingly, a remarkable distinction in GM composition between male and female littermates at adult ages was observed in a mouse model with SLEs [62]. There was no change in the alpha-diversity of the GM among children with SLE, but a partial decrease in the beta-diversity [63]. There were lower alpha-diversities and altered beta-diversities in adult SLE patients and mouse models [56,60], which were directly paralleled with the SLE Disease Activity Index (SLEDAI) score [64]. Due to the translocation of Enterococcus gallinarum to systemic organs, autoimmune-prone patients and mice showed autoimmune reaction and lupus typical serological features [65].

Many experimental studies were conducted to investigate the effectiveness of FMT in treating SLE in mice [[66], [67], [68], [69]]. Consumption of acidic water drinking could correct the GM composition in mice with SLE, and transfer of this integrated GM via FMT could control SLE progression in mouse models [68]. Next-generation sequencing revealed that the fecal microbiota of germ-free mice that received transplants from donors with SLE had the exact same microbiota as their donors. The fecal microbiota of mice with SLE led to a significant rise in antibodies to double-stranded (ds)DNA. This, in turn, caused a noteworthy disturbance in the spread of immune cells, increased expression of SLE-susceptible genes, and accelerated the development of autoimmunity [70]. In MRL/MPJ-Faslpr (MRL-lpr) mice, a particular type of lupus-prone mouse model, the beneficial outcome was demonstrated through early and short-term FMT interventions. The richness of Prevotella species in the intestines of MRL/lpr mice with pristane-induced SLE was significantly increased, which was positively correlated with cyanogen amino-acid metabolism and many different metabolites [71]. FMT treatment following 1 week of short-term antibiotic exposure suppressed SLE progression. However, the therapeutic efficacy of prednisone was inhibited in mice aged 9–13 weeks when antibiotics or FMT were used for short-term before onset of SLE [66]. That result suggested that undertaking FMT treatment before SLE onset could decrease the severity and suppress the progression of SLE, but it should be considered cautiously for patients who are treated routinely with glucocorticoids.

Recently, the MRL/lpr mice provide new evidence that FMT, which is derived from prednisone-treated therapy mice to blank one, can reduce lupus activity. The efficiency is similar to prednisone, but no parallel adverse reactions. The finding may be due to the decreased abundances of Ruminococcus species and Alistipes species, whereas the abundance of Lactobacillus species remained unchanged [67]. Those data suggest that a combination of FMT and glucocorticoid therapy might be efficacious, but further study is needed. Germ free (GF) mice that accepted FMT from the one who suffered from SLE displayed a range of SLE-like characteristics, such as the augmented presence of autoimmune antibodies, abnormal release of cytokines, altered immune responses, and higher expression of SLE-related genes [69]. Environmental factors as well as the GM work in concert in the development of the sex-based bias seen in SLE. In female MRL/lpr mice, the GM is associated with higher SLE indices than in male mice. This has been linked to the presence of more bacteria of the genera Rikenella, Romboutsia, Turicibacter, and Escherichia-Shigella [72]. Recent findings have demonstrated upregulation of methylation at multiple sites after FMT treatment of SLE, thereby revealing a possible mechanism by which FMT therapy may restore abnormal hypomethylation [73]. Overall, those evidences describe an “ideal” role of FMT in recovering from the progress of SLE.

Clinical trials of FMT as a treatment of SLE (e.g., ChiCTR2000036352) have been carried out since 2020 [74]. During a 12-week pilot study, 20 patients with active SLE received FMT as an additional treatment. For 3 consecutive weeks, these patients received encapsulated fecal microbiota by oral administration once a week. At the final evaluation period, there was a considerable reduction in SLEDAI-2K ratings and serum anti dsDNA antibody concentrations, and no noticeable serious adverse events were seen compared to the initial assessment. There was a significant rise in the population of bacteria that produce SCFAs, a significant decrease in bacteria that produce substances related to inflammation, a large amount of SCFAs in the gut led to a decrease in cytokine levels associated with inflammation, and a change in the ratio of CD4+ memory cells to naive cells in peripheral blood [74]. Subsequent single-cell analysis of peripheral blood revealed a decrease in T cells and an increase in natural killer cells. After FMT treatment, subcluster analysis revealed an overexpression of IL7R and CD28 in the total number of CD4+ T cells, as well as granzyme H (GZMH) and natural killer cell granule protein 7(NKG7) in CD8+ T cells. Additionally, interferon-associated genes expression was found to be decreased in CD4+, CD8+, double positive (DP), natural killer, and B cells [75]. There was a greater abundance of interferon-related pathways in patients who were unresponsive to FMT. The efficacy of FMT was negatively associated with interferon-related genes expressed in lymphocytes and myeloid cells. This preliminary clinical trial of FMT in patients with active SLE offers encouraging proof that it could be a novel, safe, and efficacious treatment for SLE.

2.5 Sjögren's syndrome

One hypothesis presumed a communication route called the “gut dysbiosis–ocular surface–lacrimal gland axis” in the pathogenesis of SjS [76]. A deeper analysis of the GM of patients with SjS through metagenomic sequencing revealed a remarkable reduction in the number of operational taxonomic units and Shannon alpha-diversity in comparison with those in healthy controls [77]. In comparison to controls, those with SjS had a greater relative abundance of bacterial genera Pseudobutyrivibrio, Escherichia/Shigella, Blautia, and Streptococcus, whereas the bacterial genera of Bacteroides, Parabacteroides, Faecalibacterium, and Prevotella were less plentiful abundant than that in controls [78]. In patients with SjS and dry eyes, Firmicutes are the most common phyla in the gut, followed by Bacteroidetes, Proteobacteria, and Actinobacteria [79]. In a study from China, the bacterial genera Biﬁdobacterium, Bacteroides, Escherichia-Shigella, Faecalibacterium, and Prevotella were notably prevalent in females with SjS [80]. Based on GM profiles of patients with primary SjS, diversity and richness were lower, and Bacteroidetes dominated at the phylum level, as one study described. The prevalence of opportunistic pathogens with proinflammatory activity was higher in patients with primary SjS and fewer beneficial bacteria or commensal bacteria produced butyrate. The peripheral area was affected by an increase in proinflammatory cytokines and a decrease in forkhead box P3 (FOXP3) mRNA expression due to this scenario [81]. Those with serious GM dysbiosis exhibited more intense disease activity, as assessed by the European Alliance of Associations for Rheumatology Sjögren's Syndrome Disease Activity Index and Clinical European Alliance of Associations for Rheumatology Sjögren's Syndrome Disease Activity Index scores. Additionally, they had a reduced complement component 4 and a high fecal calprotectin concentration [82].

Mice with SjS were treated with FMT in an experimental model of dry eye. A study delving into the part of commensal bacteria uncovered that germ-free mouse had transferable, spontaneous SjS-like lacrimal keratoconjunctivitis with a disruption of corneal barrier, fewer goblet cells and an abundance of total inflammatory cells and CD4+ T cells. Difference was not seen in stool microbiota composition between recipients and donors after FMT, while FMT inhibited proliferation of autoreactive CD4+ T cells in the lacrimal gland of vessels, reversed corneal epithelial barrier integrity, and restored goblet cell density [83]. Similarly, CD25-knockout mice spontaneously developed SjS-like inflammation. The dry-eye phenotype in germ-free CD25-knockout mice was reversed by fecal transplantation, and the formation of pathogenic CD4+ interferon-γ+ cells were reduced, suggesting that FMT treatment might reduce the onset and intensity of dacryoadenitis in SjS. Comparable corneal-barrier dysfunction, reduced density of goblet cells, and augmented lymphocytic infiltration were observed in these mice [84]. FMT from patients with SjS into germ free C57BL/6J female mice caused a disruption of corneal-barrier integrity and a decrease of CD4+ FOXP3+ cells in cervical lymph nodes. The progeny of SjS mice transplanted with FMT exhibited a comparable diminution in the amount of CD4+ FOXP3+ Tregs cells in their cervical lymph nodes. Above data implied that the GM traits of a parent could be passed down to offspring, potentially impacting the Treg cells growth of the progeny [77].

The safety of FMT for patients with SjS and immune-mediated dry eye was initially evaluated in an open-label, non-randomized clinical trial [85]. The study enrolled 10 individuals with dry eye meeting the diagnostic criteria for SjS. Patients received two FMT procedures obtained from one single healthy donor by enema with a 1-week interval. The GM profiles of all patients were markedly dissimilar to those of the healthy donor, with a decrease in the genera Faecalibacterium, Prevotella, and Ruminococcus, and increased abundance of the genera Alistipes, Streptococcus, and Blautia. AEs were not observed, with certain bacterial profiles similar to those of the donor for up to 3 months. Five patients reported detectable improvements in the symptoms of dry eye [85]. That clinical trial suggested that FMT might be an effective treatment for dry eye, but future studies must involve a larger sample size and further modification of the regimen.

2.6 Behçet's disease

The pathogenesis of BD involves infiltration of hyperactive neutrophils and immune-mediated inflammation caused by Streptococcus sanguinis or microbiota changes [86]. A peculiar dysbiosis in the GM of 22 BD patients' fecal microbiota compared to that of 16 healthy cohabiting controls, with a notable decrease in Roseburia and Subdoligranulum and butyrate production. This could be linked to a reduction in Treg responses and activation of immunopathologic responses of Teffector cells [87]. Subsequent research showed that the abundance of the genera Bifidobacterium and Eggerthella had clearly increased, whereas that of Megamonas and Prevotella had decreased. In addition, the phylum Actinobacteria, which includes Bifidobacterium species and the Lactobacillaceae family, had a greater presence in those with BD. No noteworthy difference in alpha-diversity between samples was observed, the beta-diversity did vary slightly [88]. Shimizu and colleagues revealed that the relative abundance of Eggerthella lenta, Acidaminococcus species, Lactobacillus mucosae, Bifidobacterium bifidum, Lactobacillus iners, Streptococcus species, and Lactobacillus salivarius was enhanced significantly in BD patients, whereas the relative abundance of Megamonas hypermegale, Butyrivibrio species, Streptococcus infantis, and Filifactor species was diminished compared with that in healthy controls. Analysis of functional annotation showed that gene functions for the “pentose phosphate pathway” and “inosine monophosphate biosynthesis” were prevalent in patients with BD. Studies revealed that those afflicted with BD had the capacity to modify their nucleic acid and fatty acid synthesis through gut microbes [89]. Moreover, Ye and coworkers revealed that patients with BD had a elevated concentration of sulfate-reducing bacteria such as Bilophila species., as well as a few opportunistic pathogens like Parabacteroides species. and Paraprevotella species, and a lower concentration of BPB like Clostridium species, and methanogens such as Methanoculleus species and Methanomethylophilus species [90]. Prevotella is the major dysbiotic bacterial genus in neuro-BD [91]. Analysis of samples from two cohorts of BD sufferers in both the Netherlands and Italy was conducted to determine if alpha-diversity in the GM remained constant, while beta-diversity did not show any distinct clusters between the healthy controls and patients However, principal coordinate analysis showed that patients by country of origin had a significant (p < 0.001) separation. Patients exhibited a decrease in the fecal abundance of Barnesiellaceae and Lachnospira species, yet IgA-coating of Bifidobacterium, Ruminococcus bromii, and Dorea species was augmented, implying that anti-inflammatory species were retained and pathosymbionts neutralized in BD [92].

Due to the autoinflammatory features, one study in Turkiye compared the microbial composition among Behçet's Syndrome patients with uveitis, patients with familial Mediterranean fever and patients with CD. They found that Succinivibrionaceae was the signature family, whereas Bacteroides species were not observed in the BD group [93]. In a detailed analysis of the GM, alpha- and beta-diversity levels were not different between the BD group and controls, which was different from the previous study. The abundance of the bacterial genera Actinomyces, Libanicoccus, Collinsella, Eggerthella, Enetrohabdus, Catenibacterium, and Enterobacter was significantly higher in the BD group, whereas that of Bacteroides, Cricetibacter, Alistipes, Lachnospira, Dielma, Akkermansia, Sutterella, Anaerofilum, Ruminococcease-UCG007, Acetanaerobacterium, and Copropaacter was lower in patients with BD. Further comparison of differences stratified by eye, mucocutaneous, and vascular involvement revealed the most significantly changed genera in each group, Lachnospiraceae NK4A136 in the uveitis group; Dialister, Intestinomonas, and Marvinbryantia in the mucocutaneous group; and Gemella in the vascular group [94]. The diversity of the GM was found to be modified to suit the environment by employing a mouse model. In a specific pathogen-free facility, mice exhibited more bacterial phyla diversity and lower prevalence of BD compared to conventionally maintained mice. Those data suggested that a normal microbiota could affect BD induction, and that increasing the number of bacterial phyla was linked with inhibition of BD development [95]. Upon oral administration of Eubacterium rectale, the mouse model of BD (induced by herpes simplex virus type 1) demonstrated a decrease in CD83+ cells and an inhibition of dendritic-cell activation and systemic inflammation [96].

Animals' experiments demonstrated that FMT with feces of patients with BD augmented the activity of experimental autoimmune uveitis significantly as well as increasing the level of inflammatory cytokines including IL-17 and interferon-γ [90]. As the community and functions of the GM in BD development become known, further clinical trials will become essential for BD treatment.

An overview of the published laboratory studies and clinical trials of FMT in chronic inflammatory skin diseases are given in Table 1, Table 2.Table 1 Animal studies using FMT against chronic inflammatory skin diseases.

Table 1Disorder	Source:	Outcome	reference	
AD	Healthy donor mice	The GM was restored to the donor state after FMT, and SCFAs levels increased.	[28]	
Mice with oxazolone-induced dermatitis	The CDS and ET of HR recipients were significantly higher before treatment.	[29]	
Non-sensitized mice	FMT could suppress release of AD-related inflammatory cytokines.	[30]	
Psoriasis	IMQ-treated mice	GF mice transplanted with IMQ-treated feces showed aggravated colitis.	[41]	
Healthy donors and patients with psoriasis	The symptom of psoriastic mice models administered with stools from psoriasis patient was worsened.	[42]	
Patients with moderate-to-severe psoriasis	After transplanting fecal microbiota from healthy human into a mice model of psoriasiform dermatitis, recovery was slowing.	[43]	
SLE	Normal C57/BL6 mice	FMT alleviated the severity of SLE, and suppressed SLE progression.	[66]	
Prednisone-treated MRL/lpr mice	Prednisone-regulated GM alleviated SLE.	[67]	
Patients and healthy controls	SLE-related phenotypic changes were induced in GF mice after being transferred with feces from patients with SLE.	[69]	
C57/BL6 mice and SLE-prone mice to GF mice	Fecal microbiome from mice with SLE led to an elevation in the number of anti-dsDNA antibodies.	[70]	
MRL/lpr mice and MRL/Mpj mice	FMT from MRL/lpr mice exacerbated the pristane-induced SLE mice model.	[71]	
SjS	Patients with SjS and healthy controls	Disruption of the corneal barrier in GF mice transplanted with fecus from SjS patients.	[77]	
Conventional C57BL/6J mice	The number of Th1 cells in the lacrimal gland of GF C57BL/6J mice with lacrimal keratoconjunctivitis was similar to SjS. FMT decreased the number of Th1 cells in the plasma and improved the corneal barrier.	[83]	
GF CD25KO mice	FMT improved recovery from a spontaneous dry eye phenotype and reduced the generation of pathogenic CD4+IFN-γ+ cells.	[84]	
BD	32 patients with active BD and 74 healthy	B10RIII mice transplanted with fecus from BD patients, disease activity was exacerbated.	[90]	
Abbreviations: AD: atopic dermatitis; SCFA: fecal short-chain fatty acid; GM: gut microbiota; Th: T helper cell; HR: high responding; CDS: Clinical Dermatitis Score; ET: ear thickness; GF: Germ free; IMQ: imiquimod; SLE: Systemic lupus erythematosus; SjS: Sjögren's syndrome; BD: Behçet's disease; dsDNA: double strains DNA; KO: knockout.

Table 2 Published clinical trials on use of FMT against chronic inflammatory skin diseases.

Table 2Disorder	Patient selection	Outcome details	Study type	reference	
AD	9 patients with moderate (n = 4) and severe (n = 5) AD	The average SCORAD decreased obviously. The GM became similar to that of the donor after FMT.	Concept, single‐blinded, placebo‐controlled cross‐over pilot study.	[31]	
Psoriasis	a 36-year-old male, diagnosed with severe plaque psoriasis for 10 years and IBS for 15 years, was treated twice FMT with interim of 5-week	Evaluation items were significantly improved, and IBS was completely relieved after 5 weeks of second FMT treatment. No adverse reactions were found.	Case Report	[44]	
Psoriasis	31 patients	No serious AEs or deaths were found in any group. Changes in HAQ-DI was decreased in the sham group than in the FMT group.	Double-blind, parallel-group, placebo-controlled, superiority trial.	[45]	
AA	A 38-year-old AA patient presented with abdominal pain and bloody diarrhea and a 20-year-old man with ileocolic CD	New hair grew was shown on the head, face, and arms during the FMT follow up period.	Case Reports.	[53]	
AA	A 86-year-old AA patient with noninfectious diarrhea, depressive disorder, and patchy	New hair was grown on the affected area of the scalp, and some gray hair gradually turned black after FMT.	Case Report.	[54]	
SLE	20 SLE patients with SLEDAI ≥6	No serious AEs or deaths were found. Serum level of anti-dsDNA antibody fell significantly.	12-week, single-arm pilot clinical trial.	[74]	
SjS	10 individuals with the symptoms and signs of dry eye received FMT	Five individuals had improved symptoms (gastrointestinal and dry eye) at the point of three months after FMT.	Open-label, nonrandomized clinical trial.	[85]	
Abbreviations: AD:atopic dermatitis; SCORAD: Severity scoring of atopic dermatitis; DLQI: Dermatology Life Quality Index; IBS: Irritable Bowel Syndrome; AEs: adverse effects; HAQ-DI: Health Assessment Questionnaire Disability Index; CD: Crohn's Disease; AA: alopecia areata; SLE: system lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; dsDNA: double strains DNA; CTR: clinical trial registration; NCT: nonrandomized clinical trial; SjS: Sjögren's syndrome.

3 Conclusion and future perspective

The prevalence of chronic inflammatory skin disease is being linked to GM dysbiosis. As an essential method for reshaping and balancing GM, FMT serves as a reasonable administration in these diseases. A certain number of research evidence have indicated that FMT could alleviate persistent skin inflammation by restoring a healthy microbiota.

Although FMT has a very prospect for the treatment, it is still facing some challenges, such as infection risks and adverse reactions, and the compatibility of the microbiota of the donor and recipient remains a major concern. Nowadays, the widespread adoption of FMT as a standardized treatment is additionally hindered by regulatory factors and ethical concerns [97]. Engraftment of different donor strains has been ubiquitous across cohorts in studies. Administration route, antibiotic preconditioning and infectious diseases could also additionally interfere with the outcomes of FMT [98]. The risks of infectious transmission resulting from FMT are especially important [99]. Future standardized preparation of FMT with high quality and safety are urgently needed.

Due to the immune regulatory mechanisms of FMT, it has other potential values in the treatment for other skin conditions associated with GM imbalance, such as allergic contact dermatitis and melanoma. The efficacy of immunotherapy for melanoma is closely related to the gut microbiota [100]. FMT might assist the immunotherapy of melanoma by providing some favorable changes in immune and the tumor microenvironment, and it deserves further investigation. On the whole, it is imperative to address the existing knowledge gaps for future maximizing the potential of GM-targeted therapies and improving patient outcomes across a wider range of skin disorders.

Funding sources

National Key R&D Program of China (2022YFC3601800); CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1–059, 2022-I2M-C&T-B-096); The National 10.13039/501100001809 Natural Science Foundation of China (82373489, 82073446, 82273542, 82103735, 82304023); Non-profit 10.13039/501100022599 Central Research Institute Fund of 10.13039/501100005150 Chinese Academy of Medical Sciences (2021-RC320-001, 2020-RC320-003).

Data availability statement

Request on corresponding authors.

CRediT authorship contribution statement

Mingyang Wu: Resources, Investigation, Conceptualization, Writing – original draft, Writing – review & editing. Xingyu Chen: Writing – review & editing. Qianjin Lu: Writing – review & editing, Supervision, Conceptualization. Xu Yao: Conceptualization, Investigation, Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

FMT fecal microbiota transplantation

Tregs T regulatory cells

AD atopic dermatitis

SjS Sjögren's syndrome

AA alopecia areata

BD Behçet's disease

TNF tumor necrosis factor

DMARDs disease-modifying antirheumatic drugs

JAK Janus kinase

STAT signal transducers and activators of transcription

AEs adverse events

UC ulcerative colitis

CD Crohn's disease

FOXP3 forkhead box P3

IBD inflammatory bowel disease

SCFAs short-chain fatty acids

Th T helper

HR high responding

LR low responding

IL interleukin

TNF tumor necrosis factor

F:B ratio Firmicutes:Bacteroidetes ratio

DSS dextran sulfate sodium

HF hair follicle

SLE systemic lupus erythematosus

SLEDAI Systemic Lupus Erythematosus Disease Activity Index

BPB butyrate-producing bacteri

Acknowledgments

We acknowledge the 10.13039/501100012166 National Key R&D Program of China (2022YFC3601800 ); 10.13039/501100019018 CAMS Innovation Fund for Medical Sciences (CIFMS , 2021-I2M-1-059 , 2022-I2M−C&T−B−096 ); 10.13039/100014718 The National Natural Science Foundation of China (82373489 , 82073446 , 82273542 , 82103735 , 82304023 ); 10.13039/501100017287 Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021−RC320-001 , 2020−RC320-003 ).
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