DECIPHERING THE GUT MICROBIOTA OF VERY EARLY SYSTEMIC SCLEROSIS (VEDOSS) PATIENTS: A TAXONOMIC AND FUNCTIONAL CHARACTERIZATION

Background: In systemic sclerosis (SSc), the gastrointestinal (GI) tract is affected since the earliest disease stages. Gut microbiota (GM) has emerged as a crucial factor with a potential role in SSc pathogenesis, progression, and GI manifestations. Objectives: To evaluate and compare the faecal microbiota and its metabolites (i.e., short chain fatty acids (SCFAs) in patients with very early SSc (VEDOSS) and established SSc, and to investigate the relationship of GM composition and function with GI symptoms. Methods: 26 SSc patients (24 F + 2 M; mean age: 64.8±11.9 years; mean disease duration from the onset of Raynaud’s phenomenon (RP): 18.8±10.5 years), 18 VEDOSS patients (17 F + 1 M; mean age 51.7±16.1 years; mean disease duration from RP onset: 11.2±9.2 years) and 20 sex- and age-matched healthy controls (HC) were enrolled. For each subject, stool samples were collected and GM was assessed through 16S rRNA sequencing. SCFA abundances were measured through a dedicated gas chromatography-mass spectrometry method. GI symptoms were assessed with the UCLA-Gastrointestinal Tract (GIT) 2.0 questionnaire. Results: Concerning the GM composition, VEDOSS patients reported an increase in Bacteroidales and Oscillospirales orders, and a decrease in bacteria belonging to Bacilli class and Blautia, Romboutsia, Streptococcus, and Turicibacter genera compared to HC. Instead, on SSc patients we documented an increase in Acidaminococcaceae and Sutterellaceae families, as well as a decrease in Peptostreptococcaceae family and Anaerostipes, Blautia, Romboutsia and Turicibacter genera respect to HC. Regarding the SCFA profile, both SSc and VEDOSS patients showed lower abundances of butyrate and higher levels of acetate than HC. Notably, comparing the two groups of patients, VEDOSS showed an increase in Oscillospiracee family and Anaerostipes genus, and a decrease in Alphaproteobacteria class, Lactobacillales order, and Marinifilaceae family compared to SSc. Moreover, higher levels of acetate and lower levels of valerate were observed in VEDOSS patients. Interestingly, a positive correlation between faecal Alphaproteobacteria levels and reflux score at UCLA-GIT 2.0 questionnaire was found in the VEDOSS group (rho = 0.69, p = 0.030), while no correlations were detected for faecal SCFAs. Conclusion: For the first time we detected in VEDOSS patients a GM dysbiosis characterized by a loss of the probiotic/protective anti-inflammatory intestinal flora, mainly composed of butyrate-producing bacteria. In addition, VEDOSS patients presented a significant decrease of faecal butyrate. Such an early GM imbalance could foster the proliferation of pro-inflammatory noxious microbiome members, further exacerbating intestinal dysbiosis and inflammation since the earliest disease phases. Based on our data, further clinical research will be needed to disclose whether administration of butyrate since the very early disease phases might represent a new therapeutic strategy to reduce disease progression/symptomatology improving patient quality of life.