A Specific Signature of Circulating Free Fatty Acid Discriminates Bullous Pemphigoid From Pemphigus Vulgaris and Healthy Controls

Bullous pemphigoid (BP) is an autoimmune skin disorder marked by antibodies targeting basement membrane proteins BP180 and BP230. Recent evidence suggests a role for the gut–skin axis and microbial metabolites, especially short-chain fatty acids (SCFAs), in modulating skin homeostasis and immune responses. In this study, we investigated the gut permeability and evaluated the circulating free fatty acids (FFAs) in BP patients, along with the assessment of the ability of each FFA to discriminate BP patients from both pemphigus vulgaris (PV) patients and healthy controls (HC). Thirty-six BP patients and 36 sex- and age-matched HC were enrolled. In addition, we used a previously examined cohort of 18 PV patients. FFAs were quantified through gas chromatography–mass spectrometry. Serum zonulin levels were measured by ELISA test and then correlated with FFA levels and clinical markers of disease activity. Receiver operating characteristic (ROC) curve analyses evaluated the diagnostic utility of individual FFAs. BP patients had significantly lower SCFA levels but higher medium-chain (MCFAs) and long-chain fatty acids (LCFAs) than HC. Zonulin levels were elevated in BP and correlated negatively with isovaleric acid. No clear associations emerged between FFAs, zonulin and clinical disease severity. Sparse partial least square discriminant analysis identified propionic, octanoic and octadecanoic acids as key discriminators between BP and both HC and PV serum FFAs. These metabolites achieved ROC AUCs > 0.9, showing a strong diagnostic value. Our findings reveal a pro-inflammatory shift in serum FFA profiles in BP—marked by decreased SCFAs and increased MCFAs/LCFAs—concurrent with elevated gut permeability. The strong diagnostic performance of propionic, octanoic and octadecanoic acids highlights their promise as biomarkers for BP.