Effect of Rifaximin Treatment on Endotoxemia and Insulin Sensitivity in Humans

Context: The gut microbiome is a source of inflammatory factors such as lipopolysaccharide (LPS; endotoxin) that influence metabolic homeostasis. Rifaximin is a well-tolerated antibiotic that may reduce LPS. Objective: We sought to develop a method to accurately assess postprandial endotoxemia and to determine whether rifaximin treatment improves metabolic homeostasis in obese humans with metabolic syndrome. Design and Setting: Plasma LPS, adipose inflammation, glucose and lipid metabolism, and insulin sensitivity were evaluated in a clinical research setting. Participants: Twelve obese human research participants with prediabetes or three features of metabolic syndrome participated. Intervention: The research participants were randomized to placebo control or rifaximin soluble solid dispersion (80 mg/d) treatment groups and treated for 12 weeks. Outcome Measures: We evaluated changes in insulin sensitivity with a euglycemic clamp; changes in lipid and glucose metabolism with oral lipid and glucose tolerance tests; changes in plasma LPS during the lipid tolerance test; and changes in adipose tissue and systemic inflammation by measuring inflammatory cytokines. Results: Rifaximin treatment slightly worsened insulin sensitivity (P = 0.03), did not improve glucose or lipid homeostasis, and did not significantly improve adipose tissue inflammation. Our efforts to accurately assess plasma LPS using limulus amebocyte lysate assays revealed that the majority of LPS is masked from detection by limulus amebocyte lysate assays, but can be unmasked using a pretreatment step with protease. Unmasked LPS increases during the lipid tolerance test, but rifaximin treatment did not reduce this. Conclusions: Rifaximin treatment did not lower plasma LPS or improve metabolic homeostasis in obese humans.