Small intestinal compared with colonic short-chain fatty acid delivery drives distinct systemic concentrations and endocrine responses in humans: a randomized, crossover trial

1 ABSTRACT Background Through fermentation in the colon, dietary fiber produces short-chain fatty acids (SCFA), which modulate host physiology through endocrine actions in the gut and systemic effects on peripheral organs. Objective We hypothesized that delivering SCFA to the small intestine 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 small intestine). Methods 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 small intestine, the same dose targeted to the colon, or a placebo. We collected postprandial blood samples up to 8h to quantify total release of peptides GLP-1 and PYY (primary outcome), as well as circulating SCFA, glucose and c-peptide. Appetite was measured using VAS. Results The SCFA delivery site made a difference: consistent with our hypotheses, PYY release was greater following colonic compared to small intestinal delivery (iAUC, estimated difference (95% CI): β=111.46 (4.33, 218.59) pg/ml.h, p adj = 0.04) and circulating SCFA concentrations were highest after small intestinal compared to 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 following small intestinal compared to 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. Conclusion 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. Clinical Trial Registry This trial was registered as NCT06686888 at https://clinicaltrials.gov/study/NCT06686888