Resveratrol Alleviated Intensive Exercise-Induced Fatigue Involving in Inhibiting Gut Inflammation and Regulating Gut Microbiota

Abstract

Resveratrol (trans-3,4',5-trihydroxystilbene, RES) is a stilbenoid naturally present in a variety of plants. Although there are several reports about its anti-fatigue activity, its impact on intensive exercise-induced fatigue and the underlying mechanisms are yet not well understood. In the present study, we established a swimming exercise protocol in mice that is similar to the fatigue condition induced by a long period of intensive exercise and explored the effect of RES on fatigue and the mechanisms from the perspective of intestinal injury and gut microbiota. The results revealed that RES significantly prolonged exhaustive swimming time in fatigued mice and improved the serum indexes associated with fatigue, including serum glucose, lactic acid (LA), urea nitrogen (BUN), lactate dehydrogenase (LDH), creatine kinase (CK), catalase (CAT), glutathione peroxidase (GSH-Px), and glycogen storage in liver and muscle. Meanwhile, RES increased the expressions of ZO-1, Occludin, and Claudin-1, thereby enhancing intestinal barrier integrity and inhibiting mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in the colon, thereby improving the pathological injury in the colon. Importantly, RES modified gut microbiota dysbiosis by increasing the diversity of gut microbiota, regulating microbiota associated with inflammation and fatty acid metabolism at the phylum (Bacteroidetes and Firmicutes), family (Erysipelotrichaceae, Enterobacteriaceae, and Prevotellaceae), and genus (Brevundimonas diminuta, Coprobacillus, Megasphaera, and Lactobacillus) levels, respectively. The results supplemented the anti-fatigue mechanism for RES from the perspective of intestinal injury and gut microbiota. The detailed mechanisms and associated metabonomics analysis remain for further study.

Keywords: 16S rRNA; exercise‐induced fatigue; gut microbiota; intestinal mucosal barrier; resveratrol.

FIGURE 1

Swimming protocol (A) and mice grouping and treatment (B) in the present study.

FIGURE 2

Effect of RES on exhaustive swimming time in EF mice. RES significantly prolonged exhaustive swimming time in EF mice, exhibiting an anti‐fatigue effect. Compared with CON group, *p < 0.05, **p < 0.01; Compared with EF group, #p < 0.01. n = 8.

FIGURE 3

Effect of RES on serum indexes associated with fatigue in EF mice. RES significantly increased the levels of blood glucose, CAT, and GSH‐Px and decreased serum LA, BUN, LDH, and CK in EF mice, which was beneficial for the improvement of EF. Compared with CON group, *p < 0.05, **p < 0.01; Compared with EF group, #p < 0.05, ##p < 0.01. n = 8.

FIGURE 4

Effect of RES on liver glycogen and muscle glycogen in EF mice. RES significantly increased liver glycogen and muscle glycogen in EF mice, indicating that RES could increase glycogen storage to improve EF. Compared with CON group, *p < 0.05, **p < 0.01; Compared with EF group, #p < 0.01. n = 8.

FIGURE 5

Effect of RES on pathological injury in colon of EF mice. RES significantly relieved colon injury induced by fatigue. Bars: 50 μm. n = 3.

FIGURE 6

Effect of RES on mRNA expressions of inflammatory factors in colon of EF mice. RES significantly inhibited TNF‐α, IL‐6, and IL‐1β expressions in colon of EF mice, suggesting that RES inhibited the inflammatory reaction in the colon induced by fatigue. Compared with CON group, *p < 0.05, **p < 0.01; Compared with EF group, #p < 0.01. n = 3.

FIGURE 7

Effect of RES on expressions of ZO‐1, Occludin, and Claudin‐1 in colon mucosa of EF mice. RES significantly increased expressions of ZO‐1, Occludin, and Claudin‐1 (A for representative images, and B, C and D for quantitative analysis) in colon mucosa of EF mice, thereby maintaining the integrity of the intestinal mucosal barrier destroyed by fatigue. Bars: 50 μm. Compared with CON group, *p < 0.01; Compared with EF group, #p < 0.01. n = 3.

FIGURE 8

Effects of RES on diversity of gut microbiota in EF mice. The Shannon index (A), Venn analysis of the diversity differences (B), and PCoA score plot based on unweighted in the β‐diversity analysis (C) revealed that RES increased the diversity of gut microbiota in EF mice. n = 5.

FIGURE 9

Effects of RES on enrichment of gut microbiota in EF mice at the phylum, family, and genus levels. RES decreased the Firmicutes to Bacteroidetes ratio at the phylum level (A for heatmap and B for bar graphs), decreased the enrichment of Erysipelotrichaceae and Enterobacteriaceae while increased that of Prevotellaceae at the family level (C for heatmap and D for bar graphs), and decreased the enrichment of Brevundimonas diminuta and Coprobacillus while increased that of Megasphaera and Lactobacillus at the genus level (E for heatmap and F for bar graphs). n = 5.