Bacterial Metabolites in the Plasma of Type 1 Diabetes Patients: Acetate Levels Are Elevated and Correlate with Glycated Haemoglobin and Para-Cresol Is Associated with Liver Disturbances and Hypertension

Type 1 Diabetes (T1D) is thought to result from the interaction of genetic and environmental factors, with different studies highlighting a potential role for the gut microbiota and its metabolites in modulating immune responses and disease development. We hypothesized that patients with T1D exhibited altered levels of circulating bacterial metabolites compared with healthy controls (HC), and that these metabolite profiles were associated with key demographic, clinical, and analytical features of the disease. A total of 91 T1D patients and 58 HC were recruited. Plasma samples were collected and analyzed with gas chromatography coupled to mass spectrometry for the detection of the metabolites: short-chain fatty acids (SCFAs: acetate [AA], propionate [PA], isobutyrate [IBA], butyrate [BA], isovalerate [IVA], valerate [VA], and methyl valerate [MVA]), medium-chain fatty acids (MCFAs: hexanoate [HxA] and heptanoate [HpA]) and para-cresol (p-cresol). We also calculated the ratios between the different SCFAs with AA. T1D patients showed significantly higher circulating AA levels than HC, along with reduced PA/AA and IBA/AA ratios, indicating an altered SCFA profile. SCFA diversity was lower in T1D patients, with reduced detection of BA, and total SCFA levels were increased mainly due to elevated AA. AA levels were higher and SCFA ratios lower in women with T1D compared with healthy women, while p-cresol levels were higher in men with T1D than in healthy men. In T1D patients, AA levels positively correlated with HbA1c, whereas PA/AA, IBA/AA, and BA/AA ratios showed negative correlations, particularly in women. MV/AA and non-AA/AA ratios were inversely associated with glucose levels, again, mainly in women. p-cresol levels correlated positively with age and ferritin and were higher in T1D patients with liver dysfunction or hypertension. Therefore, we can conclude that T1D is associated with a marked alteration in circulating gut-derived metabolites, characterized by increased AA levels, particularly in women, and an imbalance in SCFA ratios that correlates with glycemic control. These findings, together with the associations observed for p-cresol and metabolic comorbidities, support a role for the gut microbiota-host metabolic axis in T1D.