Circulating short-chain fatty acids and Mediterranean food patterns. A potential role for the prediction of type 2 diabetes risk: The Di@bet.es Study

Abstract

Background: Identifying nutritional patterns associated with developing type 2 diabetes (T2D) can facilitate more effective and personalized dietary interventions. Short-chain fatty acids (SCFAs), key metabolites derived from gut microbiota, are produced through the anaerobic fermentation of dietary fibers. This study aimed to evaluate whether circulating concentrations of SCFAs are associated with specific food consumption patterns and to assess their association with T2D development in at-risk subjects within a prospective cohort (The Di@bet.es Study). Methods: The Di@bet.es study is a prospective, population-based study utilizing random cluster sampling from the Spanish population aged over 18 years (n = 5,072). Among these participants, 4,347 were free of T2D at baseline. Follow-up losses were approximately 45%, resulting in a final re-screened sample of 2,408 subjects. A qualitative food frequency questionnaire evaluated Mediterranean diet (MedDiet) adherence and high-fiber food consumption. The risk of developing T2D was assessed using the FINDRISK. Metabolomics-driven analyses of SCFAs were conducted using gas chromatography-mass spectrometry. Results: Subjects who developed T2D after a median follow-up of seven years had higher baseline circulating concentrations of butyrate and isobutyrate. Circulating concentrations of SCFAs were associated with high-fiber food consumption at baseline. In multivariate analysis, baseline circulating concentrations of butyrate and isobutyrate were independently associated with incident T2D after adjusting for traditional clinical factors. The C-statistics for predicting T2D were 0.847 (95%CI:0.816-0.877) for butyrate and 0.843 (95%CI:0.812-0.875) for isobutyrate in adjusted models, similar to the reference model based on traditional clinical factors (0.840 [95%CI: 0.807-0.873]). Both models improved risk prediction compared to FINDRISK. Dietary patterns did not add predictive value. Sensitivity analysis excluding subjects with prediabetes at baseline confirmed these results. In addition, an association between baseline consumption of high-fiber foods with incident T2D emerged, suggesting a different behaviour between healthy and prediabetic subjects. Conclusions: Baseline circulating concentrations of SCFAs are associated with high-fiber food consumption and independently predict the development of T2D over seven years of follow-up. However, they offer limited improvement in risk prediction compared to traditional risk factors, though they enhance risk prediction as assessed by FINDRISK. Further studies are necessary to evaluate the impact of dietary interventions on SCFA.

The authors acknowledge the financial support provided through the project PI20/00312 (GL), funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, as well as through the project “XII Ayudas SED a Proyectos de Investigación Clínica en Diabetes dirigidos por jóvenes investigadores,” funded by the Sociedad Española de Diabetes (GL). Research conducted in the authors’ laboratory is supported by grants from the ISCIII (PI20/00338 and PI23/01133 to JV; PI18/0328 and PI21/01163 to DM) and the Spanish Ministry of Science and Innovation MCIN/AEI/https://doi.org/10.13039/501100011033 (RTI2018-093919-B-100 and PID2021-122480OB-584–100 to SFV, and PID2020-119030RJ-I00 to LC), all co-financed by the European Regional Development Fund (ERDF). Additional financial support was provided by the CIBER -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).