Bullous diseases, including pemphigus and pemphigoid, are a set of autoimmune diseases that involve abnormal production of auto-antibodies targeting structural proteins of the skin or mucosae. Among them, pemphigus vulgaris (PV) and bullous pemphigoid (BP) are two of the most common diseases. Although BP and PV are both chronic autoimmune blistering skin diseases mainly caused by IgG autoantibodies, they have distinct pathophysiology and clinical characteristics [1]. BP mainly occurs in the elderly population with the most typical clinical manifestation–edematous erythema and tense blisters with a negative Nikolsky sign [2]. Subepidermal blistering with inflammatory infiltration of eosinophils and lymphocytes is the characteristic pathological sign of BP [3]. In BP, abnormal auto-antibodies bind to the destruction of BP180 and BP230, two structural proteins that constitute hemidesmosomes, leading to subsequential inflammation. PV, on the other hand, affects a relatively younger population than BP [2]. Suprabasilar blisters formed by PV are easy to break and spread, resulting in a positive Nikolsky sign. PV is caused by auto-antibody interacting with desmoglein (Dsg)1 and/or 3 (Dsg3), which involves a loss of function of desmosome structure and leads to intraepidermal blistering [3].

Gut microbiota was proven to regulate both local and systemic immune responses through activating immune cells, releasing metabolites and endotoxins, and bacteria translocation [4], [5], [6], [7]. The gut-skin axis was proven to be involved in many skin diseases [8]. Some dermatologists agreed that the skin has common features with the epithelium of the gastrointestinal tract, since they are similar in histological structure, with a certain level of secretory and immune functions as well as protective functions [9]. The gut microbiota can have immunomodulatory effects on the skin, which in turn may affect the occurrence and prognosis of a variety of skin conditions. Therefore, the dysbiosis of gut microbiota is presumed to be explainable in some autoimmune skin diseases [8]. Gut microbiota and their metabolites could regulate skin inflammation and were involved in the pathogenesis and development of psoriasis, acne vulgaris, and atopic dermatitis [8], [10], [11], [12]. Prebiotics and probiotics could effectively relieve skin lesions through modulating gut microbiota and were considered as a potential therapy for skin diseases [8].

BP180 and BP230 are both proven to be expressed in the intestinal epithelium and BP was tightly related to inflammatory bowel disease (IBD) which has been proven to be induced by gut microbiota [13]. Therefore, considering the essential influence of gut microbiota on the host immune system, we want to delve into the function of gut microbiota in the occurrence and development of bullous diseases. However, only few studies focused on the dysbiosis of gut microbiota in BP or PV patients. Scaglione et al. compared the gut microbiota of BP and PV patients and demonstrated the composition of gut microbiota in BP and PV patients was different from the healthy population, while BP and PV share similarities [14]. However, the sample number was small (n = 17 in total) and this study only discussed the alteration at the phylum level of gut microbiota. Huang et al. examined the gut microbiota of patients with PV and found a reduced abundance of thick-walled Bacteroides and a greater enrichment of the Enterobacteriaceae family and Escherichia-Shigella genus in patients with PV [15]. The dysbiosis of gut microbiota had a strong correlation with inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-7, suggesting intestinal dysbiosis may promote the development of PV. However, all participants in both researches have received treatment and thus the changes in gut microbiota may be affected by the treatment. Wang et al. further investigated the gut microbiota in PV patients without glucocorticoid treatment and found a significant gut dysbiosis in PV patients. Escherichia coli was dominant in PV patients and was related to the treatment response [16]. In the BP part, the skin microbiota composition has been proven to be substantially different from the healthy people and a novel indicator of disease [17]. Compared with healthy population, the relative abundance of Lachnospiraceae significantly decreased, while Bacteroidaceae and Ruminococcaceae increased in BP patients[18].

However, the correlation and differences in microbiota between BP and PV have not been thoroughly investigated, and whether the gut microbiota is involved in the pathogenesis and development of bullous diseases still needs more studies. Our study aims to explore the potential role of gut microbiota in bullous diseases by comparing the gut microbiota of BP patients, PV patients, and HC; and to provide some directions for future treatments.