Microbiome variation in autoimmune skin inflammation: insights into the gut–skin axis

Pemphigoid diseases (PDs) are autoimmune blistering disorders in which host–microbiome interactions remain poorly understood. Although alterations of the skin microbiota have been reported in bullous pemphigoid (BP), the gut microbiome of BP patients has been largely unexplored. This thesis investigated the gut microbiome in BP and BP-like experimental pemphigoid disease.

First, gut microbiome composition and functional potential were characterized in 66 BP patients and 66 matched controls using 16S rRNA gene sequencing and shotgun metagenomics. BP patients showed reduced alpha diversity and altered microbial composition. Disease-associated features included reduced Faecalibacterium prausnitzii and enrichment of pathways related to gamma-aminobutyric acid (GABA) metabolism.

Second, a passive transfer BP-like epidermolysis bullosa acquisita (EBA) mouse model was used to investigate the potential roles of microbiome in PD. Genetically identical mice from different breeding sources showed distinct baseline microbiota and disease severity. Co-housing led to partial gut microbiota homogenization and potential transfer, particularly from protected to more susceptible mice, accompanied by reduced disease severity in the latter.

Third, an active BP-like EBA model combined with longitudinal metagenomic and metatranscriptomic profiling was used to characterize microbiome dynamics during disease progression. Microbiome variation was driven mainly by time, and disease progression was accompanied by functional and transcriptional changes involving glutamate/GABA metabolism and flagellar assembly. Several features, including increased Flavonifractor plautii, decreased Lactobacillus-related taxa, and altered glutamate/GABA metabolism, overlapped with findings from BP patients and the passive transfer model. Distinct microbiome trajectories were also observed between EBA-resistant and EBA-susceptible mice.

Together, these studies provide evidence that BP and experimental pemphigoid-like disease are associated with alterations in gut microbiome composition, function, and temporal dynamics. While causal mechanisms remain to be established, the findings support further investigation of the gut–skin axis in PDs.