Xinyu Gao, Feifei Liao, Ziqi Cao, Wenzheng Tang, Jiahui Li, Qi Chen, Yingshuai Li
SCFA alterations were more evident in established T2DM than in pre-DM, with reduced butyrate emerging as the most consistent finding. Acetate showed a less consistent pattern, varying across glycemic comparisons and biological matrices. These findings highlight SCFAs as key metabolic correlates of T2DM and support further prospective and interventional research on their potential nutritional and metabolic relevance.
OBJECTIVE: Short-chain fatty acids (SCFAs) modulate insulin sensitivity, but evidence on their association with type 2 diabetes mellitus (T2DM) is inconsistent, possibly due to dynamic changes across the glycemic spectrum from normal glucose tolerance (NGT) to established T2DM. This systematic review characterizes stage-specific variation in SCFAs to assess their potential value as metabolic correlates of T2DM.
METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched up to December 2025 for observational studies on SCFAs involving participants with NGT, prediabetes (pre-DM), or established T2DM. Continuous/binary outcomes were expressed as standardized mean differences (SMDs)/odds ratios (ORs) with 95% confidence intervals (CIs). Newcastle-Ottawa Scale (NOS) and Agency for Healthcare Research and Quality (AHRQ) criteria assessed study quality. Data were pooled using fixed-effects or random-effects models according to I2 heterogeneity. Subgroup analyses, sensitivity analyses, and funnel plots were performed.
RESULTS: 17 studies (7,371 participants) were included. Based on 6 studies, butyrate was significantly lower in T2DM than in NGT (SMD: -0.49, 95% CI [-0.96, -0.01]), and the finding was robust in sensitivity analyses, whereas the observed increase in valerate was not. No significant differences in SCFAs were found between pre-DM and NGT except for propionate (1 study). Single-study analyses using either SMD or OR indicated lower acetate levels in T2DM than in pre-DM. Fecal, but not circulating, acetate and butyrate were significantly lower in T2DM than in NGT, with a significant sample-type subgroup difference only for acetate.
CONCLUSION: SCFA alterations were more evident in established T2DM than in pre-DM, with reduced butyrate emerging as the most consistent finding. Acetate showed a less consistent pattern, varying across glycemic comparisons and biological matrices. These findings highlight SCFAs as key metabolic correlates of T2DM and support further prospective and interventional research on their potential nutritional and metabolic relevance.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/. The Systematic Review Registration PROSPERO (No. CRD420251245821).