Betainized metabolites as biomarkers of whole grain wheat, not oat: insights from controlled crossover pharmacokinetic and daily feeding studies

Background: Betainized compounds are bioactive metabolites involved in 1-carbon metabolism and cellular osmoprotection. Whole grains (WGs) are important dietary sources of these compounds, but their postprandial and daily metabolic responses in humans remain understudied.

Objectives: To characterize the pharmacokinetic (PK) profiles and short-term accumulation of 16 betainized metabolites following WG wheat and OAT intake and to identify WG intake-specific biomarkers.

Methods: Two randomized, controlled crossover trials were conducted. The first was a 2-period PK study involving 12 healthy adults, who consumed WG wheat and OAT in a crossover design, with serial plasma and urine collection ≤24 h and 48 h, respectively. The second was a study with five 15-d controlled feeding periods separated by washout phases (∼8 mo total), in which 54 participants consumed wheat- or oat-based diets. Plasma and urine were collected on day 1 (baseline), day 8, and day 15 of each period. All samples were analyzed using LC-MS. PK parameters were calculated, and statistical analyses evaluated interindividual variability, temporal trends, and grain-specific effects.

Results: Valine betaine, isoleucine betaine, and glutamine betaine exhibited distinct PK profiles, peaking at 5 to 6 h after WG wheat consumption and coinciding with their major urinary excretion window. In the daily grain intake study, valine betaine increased from 1.2 ± 0.4 to 22.2 ± 1.8 nM in plasma and from 39.5 ± 2.2 to 218.5 ± 8.6 μmol/mmol creatinine in urine by day 15 (P < 0.05). Isoleucine betaine showed a similar trend, whereas glutamine betaine was only detected in urine, increasing from 5.7 ± 0.9 to 10.7 ± 0.6 μmol/mmol creatinine. These results demonstrate clear dose- and time-dependent accumulation consistent with their kinetic behavior.

Conclusions: Valine betaine, isoleucine betaine, and glutamine betaine are specific biomarkers of WG wheat intake, not WG OAT. Their distinct responses highlight the need for precision nutrition when evaluating the health benefits of WGs. This trial was registered at clinicaltrials.gov as NCT03783637 and NCT04104581.

betainized metabolites; biomarkers; controlled feeding study; pharmacokinetics; whole grain oat; whole grain wheat.