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Bariatric Surgery

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

International Journal of Obesity (2026)Cite this article

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Abstract

Background

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 6 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 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 metabolic 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.

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Fig. 1: GLP-1 and GLP-2 responses to MMT at baseline and 6 months in Lo-IR and Hi-IR.
Fig. 2: Baseline gut microbiota abundance and correlations with clinical and hormonal variables.
Fig. 3: Surgical-induced microbiota changes and associations between species and variables related to metabolic health status.
Fig. 4: Gut metagenomic signature predicts intervention success at 5-year follow-up.

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Data availability

The microbiome data presented in this study are available in the European Nucleotide Archive (ENA) at https://www.ebi.ac.uk/ena/browser/view/PRJEB48776, accession number PRJEB48776. The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Sr. Joan Badia for statistical analysis, the Bioinformatics and Biostatistics Unit at the IISPV, and the microbiome data analysis.

Funding

Research conducted in the authors’ laboratory is supported by grants from the ISCIII (PI14/00228, PI17/01503, PI20/00338 and PI23/01133 to JV, PI14/00633, PI17/00915, PI20/0114 and PI23/01289 to SP and PI14/01997; PI17/01556 and PI22/01773 to NV) and the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 (RTI2018-093919-B-100 and PID2021-122480OB-584-100 to SFV), all co-financed by the European Consorcio Centro de Investigación Biomédica en Red (CB07708/0012), ISCIII, Ministerio de Ciencia e Innovación, and by the “La Caixa” Foundation (ID 100010434) under grant agreement LCF/PR/HR20/52400013 (to SFV). SFV and JV also acknowledge support from the Agency for Management of University Research Grants of the Generalitat de Catalunya (2021 SGR 01409, 2021 SGR 0089).

Author information

Author notes

  1. These authors contributed equally: Rocío Puig, M-Mar Rodríguez-Peña.

  2. These authors jointly supervised this work: Joan Vendrell, Silvia Pellitero.

Authors and Affiliations

  1. Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Rocío Puig

  2. Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    Rocío Puig, Jose M. Balibrea & Manel Puig-Domingo

  3. Department of Endocrinology and Nutrition, Hospital Universitari Joan XXIII de Tarragona, Institut d’Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain

    M-Mar Rodríguez-Peña, Brenno Astiarraga, Sonia Fernández-Veledo & Joan Vendrell

  4. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    M-Mar Rodríguez-Peña, Brenno Astiarraga, Gemma Llauradó, Nuria Vilarrasa, Sonia Fernández-Veledo & Joan Vendrell

  5. Department of Endocrinology and Nutrition, Hospital Universitari de Bellvitge-Institut d’Investigació Biomèdica de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain

    Laura Hernández-Montoliu & Nuria Vilarrasa

  6. Clinical Nutrition Unit. Hospital Germans Trias i Pujol, Badalona, Spain

    Eva Martínez

  7. Department of General and Gastrointestinal Surgery. Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain

    Jose M. Balibrea, Jordi Tarascó & Albert Caballero

  8. CIBER Pathophysiology of Obesity and Nutrition (CIBEROBN), Córdoba, Spain

    Jose M. Balibrea

  9. Department of Endocrinology and Nutrition, Hospital del Mar, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

    Gemma Llauradó

  10. Department of Endocrinology and Nutrition. Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain

    Clara Joaquín, Manel Puig-Domingo & Silvia Pellitero

  11. Universitat Rovira i Virgili (URV), Reus, Spain

    Sonia Fernández-Veledo & Joan Vendrell

Authors
  1. Rocío Puig
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  2. M-Mar Rodríguez-Peña
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  3. Laura Hernández-Montoliu
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Contributions

RP, M-MR-P, JV, and SP contributed to the conception of the work and wrote the manuscript. LH-M and GLL contributed to the data analysis. BA performed the bioinformatics and statistical analyses. GLL, JB, JT, and AC participated in the study design. Gll, CJ, MP-D, NV, and SFV critically revised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Silvia Pellitero.

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The authors declare no competing interests.

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All participants provided informed consent, and the study was approved by the ethics committee of Germans Trias I Pujol Hospital (PI-14 103). All methods were performed in accordance with the relevant guidelines and regulations.

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Puig, R., Rodríguez-Peña, MM., Hernández-Montoliu, L. et al. Insulin resistance modulates gut microbiota and incretin response remodeling after bariatric surgery in severe obesity. Int J Obes (2026). https://doi.org/10.1038/s41366-025-01971-7

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