ABSTRACT Objective This study evaluated whether two interventions with putative lipopolysaccharide (LPS)‐lowering properties, the phosphate binder sevelamer or a synbiotic, improve insulin sensitivity in humans. Methods We conducted a randomized, double‐blind, placebo‐controlled, three‐arm parallel‐group trial. Twenty‐two lean and twenty‐eight participants with obesity completed the trial. Participants were randomized to: (1) sevelamer; (2) synbiotic (oligofructose plus Bifidobacterium longum Rosell‐175); or (3) placebo, three times a day for 4 weeks. The primary outcome was change in peripheral insulin sensitivity (M) assessed by hyperinsulinemic (60 mU/m 2 min) euglycemic clamp versus placebo. Results In participants with obesity, sevelamer improved the M (+2.176 0.314, 4.038 mg/kg min vs. placebo; p = 0.022) and lowered LDL‐C (−29.675 −53.794, −5.556 mg/dL vs. placebo; p = 0.016). Synbiotic had no effect on insulin sensitivity or lipids in either group. No changes in markers of endotoxemia were observed with any intervention. Sevelamer increased plasma levels of metabolites linked to improved glucose and lipid metabolism, such as bile acids, amino acids (citrulline, betaine), NAD+ precursors (trigonelline), and xenobiotics (genistein, umbelliferone). Conclusions Sevelamer improves insulin sensitivity and LDL‐C in participants with obesity. Further investigation is warranted to elucidate sevelamer's metabolic mechanisms, potentially involving the mediation of bile acids and other host‐microbiome‐derived metabolites. Trial Registration ClinicialTrials.gov NCT02127125
Baeuerle et al. (2026) studied this question.