Insulin resistance 1 modulates gut microbiota and incretin response remodeling after bariatric surgery in severe obesity

This study aims to assess the impact of insulin resistance (IR) on gut microbiota (GM) composition, incretin responses, and metabolic outcomes following sleeve gastrectomy (SG) in people with severe obesity who do not have diabetes. Methods: A prospective single-center study encompassed patients with severe obesity and normal glucose tolerance who underwent SG. Participants were stratified into two cohorts based on the magnitude of their insulin resistance state, as determined by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index: high-IR (Hi-IR; HOMA-IR 95th percentile) and low-IR (Lo-IR; HOMA-IR < 25th percentile). Body composition measurements, biochemical analyses, and microbiota assessments were performed before and six months post-surgery. Additionally, the responses to a standardized meal tolerance test (MTT) of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) were evaluated. Results: The study cohort consisted of 18 patients (9 with Hi-IR and 9 with Lo-IR), with a mean age of 48.8 ± 9.2 years and a mean body mass index (BMI) of 45.03 ± 4.82 kg/m². Six months post-surgery, the mean percentage of total weight loss (WL) was 26.5 ± 6%, with both groups exhibiting enhanced secretion of GLP-1 and GLP-2 following MTT. At baseline, participants exhibited distinct microbiota profiles; the Hi-IR group showed a higher relative abundance of Prevotella species, which are previously associated with adverse metabolic and inflammatory profiles. Post-surgery, both groups exhibited positive incretin responses and significant modifications in GM composition. Notably Hi-IR people experienced more 146 pronounced changes in microbial diversity, including increases in Akkermansia and Veillonella species and decreases in Prevotella species. Enhanced GLP-1 and GLP-2 responses were correlated with WL and metabòlic improvement, particularly in the Lo-IR population. Conclusions: These findings underscore the role of GM in metabolic changes and surgical outcomes after SG. Targeting gut microbiota may offer a promising avenue for improving obesity treatment strategies.