Whole wheat bread improves postprandial glucose tolerance in adults with prediabetes: a controlled-feeding randomized crossover trial with microbiome-associated variation in response.

BACKGROUND/HYPOTHESIS: Whole grain intake is associated with reduced risk of type 2 diabetes, yet inconsistent findings from randomized trials and substantial interindividual variability suggest that gut microbiota may influence glycemic responses. We hypothesized that whole wheat bread would improve glucose tolerance compared with refined white bread under controlled feeding conditions in adults with prediabetes, and that gut microbial features would be associated with variability in glycemic response. METHODS: In this randomized, controlled crossover trial, adults with prediabetes (n = 39; 34.7 ± 0.9 kg/m2) consumed fully controlled diets differing only in whole wheat (WHEAT) or refined white bread (WHITE) for 2-weeks each, separated by a 2-week washout. Fasting blood and stool samples were collected at baseline and post-intervention, and a 75 g oral glucose tolerance test was performed after each phase. RESULTS: Compared with WHITE, WHEAT reduced postprandial glucose excursion by 27% (p = 0.04), independent of body weight, inflammation, carbonyl stress, and fecal short-chain fatty acids (SCFAs). Fasting glucose and insulin improved over time irrespective of treatment (PTime < 0.05), whereas inflammatory biomarkers, plasma methylglyoxal, and fecal SCFAs did not differ between interventions. Gut microbial α- and β-diversity were unchanged. However, compositional analyses identified directional shifts in selected taxa during WHEAT, including higher relative abundances of Agathobacter, Agathobaculum, and Lachnospiraceae NK4A136 group and lower Streptococcus, Lachnoclostridium, and Mediterraneibacter (nominal p < 0.05). Moderation analysis revealed that baseline abundances of Lachnoclostridium and Lachnospiraceae NK4A136 group predicted postprandial glycemic responses in a diet-dependent manner, identifying distinct microbial profiles associated with greater metabolic benefit from WHEAT relative to WHITE (PInteraction < 0.05). CONCLUSION: Whole wheat bread improves postprandial glucose tolerance in adults with prediabetes while exhibiting microbiome-associated variation in glycemic response. These findings support whole wheat as an effective dietary strategy and highlight baseline gut microbial features as key contributors to inter-individual responses, advancing precision nutrition approaches to whole grain consumption. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT05318183.