Small intestinal compared with colonic short-chain fatty acid delivery drives distinct systemic concentrations and...

Through fermentation in the colon (Co), dietary fiber produces short-chain fatty acids (SCFAs), which modulate host physiology through endocrine actions in the gut and systemic effects on peripheral organs.

We hypothesized that delivering SCFAs to the small intestine (SI) instead of the colon would yield higher systemic SCFA concentrations (small intestinal cells do not metabolize SCFA), yet lower endocrine effects (density of enteroendocrine cells is lower in the SI).

To test our hypothesis, we conducted a randomized, single-blinded (participants), crossover trial in 28 healthy adults. On separate visits, we administered one of the following: a single, 230 mmol dose of SCFA targeted to the SI, the same dose targeted to the Co, or a placebo. We collected postprandial blood samples for 8 h to quantify total release of the peptides glucagon-like peptide 1 (GLP-1) and peptide YY (PYY; primary outcome), as well as circulating SCFAs, glucose, and C-peptide. Appetite was measured using the visual analog scale.

The SCFA delivery site made a difference: consistent with our hypotheses, PYY release was greater after colonic delivery compared with small intestinal delivery [incremental area under the curve (iAUC), estimated difference (95% confidence interval): β = 111.46 (4.33, 218.59) pg/mL.h, P_adj = 0.04], and circulating SCFA concentrations were highest after small intestinal delivery compared with colonic delivery [iAUC, acetate: β = 360.33 (226.50, 494.17) μM.h, P_adj < 0.001; propionate: β = 18.00 (11.62, 24.49) μM.h, P_adj < 0.001; butyrate: β = 7.21 (3.77, 10.66) μM.h, P_adj < 0.001]. Unexpectedly, GLP-1 release was higher after small intestinal delivery compared with colonic delivery [iAUC: β = 16.00 (1.31, 30.68) pM.h, P_adj = 0.03]. Nevertheless, the delivery site did not affect glucose or C-peptide concentrations. In all cases, SCFA administration reduced participant-reported appetite, but more so for small intestinal delivery.

Because circulating SCFA concentrations and SCFA-induced endocrine and appetite responses vary by delivery site, site-specific targeting is essential for optimizing SCFA-mediated physiological effects. This trial was registered at clinicaltrials.gov as NCT06686888. https://clinicaltrials.gov/study/NCT06686888.