Fecal Short-Chain Fatty Acids to Predict Prediabetes and Type 2 Diabetes Risk: An Exploratory Cross-Sectional Study

<b>Background/Objectives:</b> Gut microbiota is profoundly influenced by dysglycemic states, including prediabetes (preDM) and type 2 diabetes (T2D). Although short-chain fatty acids (SCFAs) may serve as proxies reflecting these microbial changes, their predictive role remains elusive. This study aimed to evaluate the association between fecal SCFA concentrations and glycemic status (preDM and T2D), using individuals with normoglycemia (NonDM) as the reference group in a Mediterranean adult population. <b>Methods:</b> This study included a total of 88 participants from the [email protected] study who were classified into three groups according to the American Diabetes Association criteria: NonDM (45%), preDM (27%), and T2D (28%), respectively. We evaluated gut microbiota populations through massive sequencing and determined SCFAs concentration using gas chromatography-mass spectrometry. Adjusted multiple logistic regression models were used to estimate associations between SCFAs and metabolic status. <b>Results</b>: The mean age of subjects with preDM and T2D was approximately 68 years, older than that of NonDM participants (about 60 years). About 50% of the subjects in the NonDM and preDM groups were female, whereas in the T2D group, females represented about 25%. The analysis revealed that only fecal acetic acid was significantly reduced in T2D compared to NonDM (<i>p</i> = 0.036) and preDM (<i>p</i> = 0.018) groups. Remarkably, fecal acetic acid was negatively associated with T2D risk when taking preDM as the reference state (OR = 0.561 [95% CI: 0.371-0.846], <i>p</i> = 0.009). Intriguingly, fecal acetic acid was identified as a significant positive predictor of preDM risk, taking the NonDM group as reference (OR = 1.422; <i>p</i> = 0.028), while propionic acid was inversely associated with preDM (OR = 0.714; <i>p</i> = 0.028). <b>Conclusions</b>: Our analysis showed that fecal acetic acid levels were associated with a reduced risk of T2D but also with an increased risk of preDM; however, the biological relevance of these findings remains uncertain.