- •Previous methods to measure (intestinal) SCFA production might be inaccurate.
- •We assessed SCFA production with stable tracer pulse approach and compartmental modeling.
- •SCFA production and fluxes were reduced in aging but not affected by presence of COPD.
- •Non-compartmental SCFA production measurements underestimate production in inaccessible (intestinal) pool.
Production rates of the short-chain fatty acids (SCFA) acetate, propionate, and butyrate, which are beneficial metabolites of the intestinal microbiota, are difficult to measure in humans due to inaccessibility of the intestine to perform measurements, and the high first-pass metabolism of SCFAs in colonocytes and liver. We developed a stable tracer pulse approach to estimate SCFA whole-body production (WBP) in the accessible pool representing the systemic circulation and interstitial fluid. Compartmental modeling of plasma enrichment data allowed us to additionally calculate SCFA kinetics and pool sizes in the inaccessible pool likely representing the intestine with microbiota. We also studied the effects of aging and the presence of Chronic Obstructive Pulmonary Disease (COPD) on SCFA kinetics.
In this observational study, we designed a two-compartmental model to determine SCFA kinetics in 31 young (20–29 y) and 71 older (55–87 y) adults, as well as in 33 clinically stable patients with moderate to very severe COPD (mean (SD) FEV1, 46.5 (16.2)% of predicted). Participants received in the fasted state a pulse containing stable tracers of acetate, propionate, and butyrate intravenously and blood was sampled four times over a 30 min period. We measured tracer-tracee ratios by GC–MS and used parameters obtained from two-exponential curve fitting to calculate non-compartmental SCFA WBP and perform compartmental analysis. Statistics were done by ANCOVA.
Acetate, propionate, and butyrate WBP and fluxes between the accessible and inaccessible pools were lower in older than young adults (all q < 0.0001). Moreover, older participants had lower acetate (q < 0.0001) and propionate (q = 0.019) production rates in the inaccessible pool as well as smaller sizes of the accessible and inaccessible acetate pools (both q < 0.0001) than young participants. WBP, compartmental SCFA kinetics, and pool sizes did not differ between COPD patients and older adults (all q > 0.05). Overall and independent of the group studied, calculated production rates in the inaccessible pool were on average 7 (acetate), 11 (propionate), and 16 (butyrate) times higher than non-compartmental WBP, and sizes of inaccessible pools were 24 (acetate), 31 (propionate), and 55 (butyrate) times higher than sizes of accessible pools (all p < 0.0001).
Non-compartmental production measurements of SCFAs in the accessible pool (i.e. systemic circulation) substantially underestimate the SCFA production in the inaccessible pool, which likely represents the intestine with microbiota, as assessed by compartmental analysis.
Abbreviations:BMI (body mass index), COPD (Chronic Obstructive Pulmonary Disease), FEV1 (forced expiratory volume in 1 s), Fij (tracee flux from compartment j to compartment i [μmol·min−1]), FVC (forced vital capacity), kij (fractional tracer exchange rate from compartment j to compartment i [min−1]), Qi (tracee pool size in compartment i [μmol]), qi (tracer pool size in compartment i [μmol]), SCFA (short-chain fatty acid), TTR (tracer-tracee ratio), Ui (endogenous production in compartment i [μmol·min−1]), WBP (whole-body production [μmol·min−1]), WbRa (whole-body rate of appearance [μmol·min−1])
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Published online: January 12, 2023
Accepted: January 9, 2023
Received: October 22, 2022
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