Gut microbiota and short-chain fatty acids: mechanisms of aerobic exercise regulation in type 2 diabetes

Abstract

BACKGROUND: Recent studies have shown that exercise modulates gut microbiota and glucose metabolism; however, the mechanism linking exercise to gut microbiota and short-chain fatty acid production in type 2 diabetes remains unclear. OBJECTIVE: To investigate the mechanism by which exercise modulates gut microbiota composition and short-chain fatty acid metabolism to treat type 2 diabetes. METHODS: Twenty male Sprague-Dawley rats were randomly divided into a control group (n=6) and a model group (n=14). The rats in the model group were fed a high-sugar, high-fat diet for 8 weeks to induce insulin resistance. Following 12 hours of fasting (water allowed), rats received a tail vein injection of 1% streptozotocin solution (35 mg/kg) to damage pancreatic β-cells and elevate blood glucose, establishing type 2 diabetes models. Following successful modeling, feeding protocols remained unchanged. Twelve type 2 diabetes rats were divided into a model group (n=6) and an exercise group (n=6), and the exercise group were subjected to 12 weeks of aerobic exercise. Following the final aerobic exercise intervention, blood samples were collected for glucose metabolism indicators, and fresh feces were collected for short-chain fatty acid measurement by gas chromatography. Total microbial DNA was extracted from fresh feces, PCR amplified, purified, and sequenced using NovaSeq high-throughput sequencing. Species annotation was performed using the SILVA database, differential flora screening based on linear discriminant analysis effect size, and MetaCyc functional pathway prediction to explore associations between exercise intervention and glycolipid metabolism pathways. Heatmaps and visualization network diagrams were used to analyze correlations between key flora and biochemical indicators. RESULTS AND CONCLUSION: After 12 weeks of aerobic exercise, the exercise group showed significant improvement in glycolipid metabolism disorders, reduced inflammation, enhanced insulin sensitivity, and significantly decreased fasting blood glucose (P < 0.01). α-diversity analysis showed that the exercise group had significantly higher richness (Chao index), coverage (Coverage index), diversity (Shannon index), and evenness (Simpson index) of gut microbiota compared to the model group (P < 0.05). Abundance statistics, correlation heatmaps, and network diagrams showed that exercise significantly increased the abundance of short-chain fatty acid-producing genera such as Colidextribacter and Intestinimonas within Firmicutes, positively correlated with hexanoic acid and valeric acid levels; while inhibiting pathogenic bacteria such as Klebsiella and Turicibacter within Proteobacteria, negatively correlated with short-chain fatty acid levels. Lactobacillus promoted the production of butyric acid and other short-chain fatty acids, and was negatively correlated with glycolipid metabolism and inflammatory markers, fasting blood glucose, and interleukin-6 (P < 0.05). KEGG and MetaCyc metabolic function prediction showed that aerobic exercise reshaped energy homeostasis by bidirectionally regulating microbial metabolic pathways: significantly downregulating pathways related to excessive glycolipid catabolism and pro-inflammatory metabolism, while upregulating key pathways for short-chain fatty acid synthesis and glycolytic homeostasis. This functional remodeling was highly synergistic with the restoration of short-chain fatty acid-producing genera in Firmicutes and inhibition of pathogenic bacteria in Proteobacteria (P < 0.05). These results suggest that the dynamic balance of microbial metabolic pathways and host glycolipid metabolism improvement and inflammation alleviation form a closed-loop regulation, indicating that microbiota, short-chain fatty acid synthesis, and metabolic function remodeling are core mechanisms by which exercise improves the pathological process of diabetes.

1. Introduction

Type 2 diabetes is a metabolic disease characterized by insulin resistance and pancreatic β-cell dysfunction, often accompanied by chronic low-grade inflammation. Recent studies have shown that gut microbiota dysbiosis is closely related to the occurrence and development of diabetes, with patients generally exhibiting reduced gut microbiota diversity, decreased abundance of short-chain fatty acid-producing bacteria, and characteristic microbial alterations. Short-chain fatty acids, produced by microbial fermentation of indigestible carbohydrates, can activate free fatty acid receptors 2/3 to regulate glucagon-like peptide-1 secretion, thereby influencing host metabolism and immune responses.

Studies have demonstrated that exercise can effectively lower blood glucose and lipid levels in diabetic patients. Different intensities and durations of exercise increase the relative abundance of beneficial bacteria, which are typically associated with anti-inflammatory, metabolic improvement, or cognitive function. Moderate-intensity aerobic exercise and high-intensity interval training both improve glycated hemoglobin levels, while high-intensity interval training has advantages in postprandial glucose control. Moderate exercise positively regulates gut microbiota, whereas excessive or high-intensity exercise may induce dysbiosis, increasing intestinal permeability and inflammation risk. Notably, moderate-intensity exercise specifically increases the abundance of butyrate-producing bacteria and enhances intestinal barrier function via the short-chain fatty acid-free fatty acid receptor 2 axis. These short-chain fatty acids, including acetate, propionate, and butyrate, not only provide energy for intestinal epithelial cells but also influence glycolipid metabolism by maintaining glucose homeostasis and insulin sensitivity.