The mammalian intestinal microbiota is an important factor that affects host nutrition, metabolic function, gut development, and maturation (14,37). The microbiota in the gut helps promote digestion and food absorption for host energy harvesting and storage, which is highly associated with energy utilization during exercise (15,33). Studies with germ-free (GF) and gut microbiota-lacking animals have revealed that gut microflora are required for the development of the gastrointestinal immune system and affect many physiological processes within the host (32). Bacteroides fragilis (BF) is a gram-negative anaerobic bacteria and is symbiotic in the lower gastrointestinal tract of humans and other animals. It has beneficial effects on host homeostasis (22,36).
The antioxidant enzyme system helps protect against intense exercise-induced oxidative damage and is related to the physical status of athletes (9). Antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) play an important role in preventing oxidative stress in vivo (1,25). In exhaustive and high-intensity exercise, the high production of reactive oxygen species (ROS) may induce oxidative stress and tissue damage (2,8,30), and antioxidant enzymes may alleviate exercise-induced oxidative stress and body fatigue. Enhanced antioxidant enzyme activity may prolong exercise performance and reduce physical fatigue (3). Additionally, supporting endogenous antioxidant systems with additional oral doses of antioxidants can prevent or reduce oxidative stress, decrease muscle damage, and improve exercise performance (3).
The host redox status is related to balanced microbiota and vice versa (40). Several studies showed that the microbiota composition could be affected by dietary intake or physical activity (21,26,29). Recent reports have shown high activity of antioxidant enzymes such as SOD in the intestinal tract mucosa of GF mice (10,11). Additionally, hepatic GPx level is low in GF rats (5). Also, probiotic supplements can affect the intestinal barrier and oxidation and influence the gut microbiota ecology in athletes (17,38).
No study has addressed the relationship between intestinal microbiota and exercise performance. Given the modulating effects of gut microbiota on antioxidant enzyme activity and the ability of antioxidant enzymes to augment recovery following extreme exercise or high-volume training, gut microbiota status may have various effects on antioxidant enzyme levels and exercise performance. We aimed to examine antioxidant enzyme activity and endurance exercise time in gut microbiota-lacking mice following an exhaustive exercise challenge. Our second aim was to examine the effect of colonization of GF mice with BF microbiota on exercise performance.
Experimental Approach to the Problem
We used GF mice to determine whether enteric bacteria alter antioxidant enzyme levels, exercise performance, and physical fatigue. In addition, we tested antioxidant enzyme activities, physical performance, and antifatigue function after monocolonizing GF mice with BF after an exercise challenge.
Animals and Sample Collection
We obtained 12-week-old male, specific pathogen-free (SPF) (n = 8), GF (n = 8), and BF gnotobiotic C57BL/6JNarl (n = 8) mice from the National Laboratory Animal Center (NLAC), National Applied Research Laboratories (Taipei, Taiwan). Mice were housed 4 per cage and maintained in a vinyl isolator in a room kept at a constant temperature (20–22° C) and humidity (55–65%) under an artificial 12-h/12-h light-dark cycle. Mice were fed a standard chow diet (3.42 Kcal·g−1, 24.6% protein, 5.5% fat, 50.1% carbohydrate, and 19.8% other; 5010 Lab Diet; Purina Mills, St Louis, MO, USA), and sterile water ad libitum. The Institutional Animal Care and Use Committee (IACUC) of NLAC approved all animal experimental protocols, and the study conformed to the guidelines of protocol IACUC2012M16 approved by the IACUC ethics committee to ensure the welfare of animals and the reliability of the experimental results.
All animals were killed with 95% CO2 asphyxiation 48 hours after they performed the exhaustive swimming test, and blood was withdrawn by cardiac puncture. The liver, spleen, muscle (including gastrocnemius and soleus muscles in the back part of the lower legs), brown adipose tissue (BAT), and epididymal fat pad (EFP) were removed and weighed. Liver and muscle tissue was frozen immediately in liquid nitrogen and stored at −80° C.
Exhaustive Swimming Test
Swimming was performed in plastic containers (22 × 22 × 24 cm) filled with water to 20 cm depth and maintained at 28 ± 1° C. Mice swam with no strings attached. The mice were considered exhausted when they failed to rise to the surface of the water to breathe after 7 seconds (6). Swim time to exhaustion was measured as the index of exercise performance.
Measurement of Blood Biochemical Variables and Biological Analyses
Blood collected by cardiac puncture was centrifuged at 2,500g for 10 minutes at 4° C, and sera was stored at −80° C for detection of glucose, blood urea nitrogen (BUN), uric acid (UA), lactate dehydrogenase (LDH), total cholesterol (TC), and triacylglycerol (TG) levels by use of an automatic analyzer (HITACHI 7080; Hitachi, Tokyo, Japan). Serum lactate level was determined by use of a lactate assay kit (Biovision, Mountain View, CA, USA). Liver and muscle glycogen content was determined by use of a glycogen assay kit (Biovision).
Antioxidant Activity in Tissue and Serum
Muscles were homogenized in commercially available buffer (pH 7.4) with use of a motor-driven homogenizer in an ice bucket. The supernatant was collected after centrifugation at 10,000g for 15 minutes at 4° C and stored at −80° C. Glutathione peroxidase, CAT, and SOD activity was determined with use of assay kits (Cayman, Ann Arbor, MI, USA).
Liver, kidney, muscle, and heart tissue was collected and fixed in 10% phosphate-buffered formalin, embedded in paraffin, sectioned at 4 μm, stained with hematoxylin-eosin and examined by light microscopy (BX-51; Olympus, Tokyo, Japan).
Data are expressed as mean ± SD. Results were analyzed by 1-way analysis of variance followed by least significant difference test. A p value of ≤0.05 was considered statistically significant.
Body, Tissue, and Proportional Weight of Tissue
The mouse genotypes did not differ in body or spleen weight (Table 1). Liver, muscle, BAT, and EFP weight was greater for SPF than GF mice (all, p ≤ 0.05). The proportional (%) weight adjusted for individual body weight was higher for SPF than GF and BF mice for liver (respectively, p < 0.0001 and p = 0.0001), muscle (p < 0.0001, p = 0.198), BAT (p = 0.0001, p < 0.0001), and EFP (p < 0.0001, p = 0.069).
Swim Time to Exhaustion
The swim-to-exhaustion times for SPF, GF, and BF mice were 81.6, 39.0, and 67.2 minutes, respectively (Figure 1). The time was shorter by 2.09-fold for GF than SPF mice (p < 0.0001) and was 1.72-fold greater for BF than GF mice but 1.21-fold lower than for SPF mice (p = 0.015). The time significantly differed among groups.
Levels of UA and BUN were lower for SPF and BF than GF mice (Table 2). Bacteroides fragilis mice showed the lowest levels of UA (2.18 ± 0.4 U·L−1) and BUN (26.5 ± 1.4 mg·dl−1), which was decreased by 34.7% (p = 0.011) and 23.1% (p < 0.0001), respectively, as compared with GF mice. Moreover, UA and BUN levels were lower by 26.7% (p = 0.038) and 0.9% (p = 0.744), respectively, in SPF than GF mice. Serum levels of TC and TG were lowest in BF mice as compared with SPF mice (p = 0.035, p = 0.466) and GF mice (p = 0.065, p = 0.520). Germ-free and BF mice showed significantly elevated glycogen stores in liver, increased 22.2% (p = 0.011) and 19.3% (p = 0.012), respectively, as compared with SPF mice. However, glycogen content in muscle did not differ among the genotypes. Likewise, LDH, lactate, and glucose levels did not differ among mice groups. However, LDH level was slightly lower in SPF than GF mice (p = 0.092) and BF mice (p = 0.164).
Antioxidant Enzyme Activity
Serum GPx activity was lower by 18.4% in GF than SPF mice (p = 0.031; Figure 2A), as was hepatic GPx activity (297.1% lower, p = 0.004; Figure 2B). Serum and hepatic GPx activity was slightly lower in GF than BF mice and lower by 13.7% (p = 0.084) and 79.6% (p = 0.134), respectively, than in SPF mice. Serum CAT activity was significantly greater in SPF than GF and BF mice (107.9% lower, p = 0.007; 71.9% lower, p = 0.025, respectively) (Figure 2C). Liver CAT activity did not differ between GF and SPF mice (p = 0.106; 12.8%) and BF mice (p = 0.253; 8.9%) (Figure 2D). Serum SOD activity was lower in BF than SPF mice (58.3% lower, p = 0.002) and GF mice (54.3% lower, p = 0.005) (Figure 2E). Liver SOD activity did not differ among the 3 mouse groups (Figure 2F).
Morphology of Liver, Kidney, Muscle, and Heart Tissue
Macroscopic observations of all organs were normal. Histological examination of organs showed no apparent tissue damage in any mice (Figure 3).
In this study, we aimed to examine antioxidant enzyme activity and endurance exercise time after an exhaustive exercise challenge in mice lacking gut microbiota. The absence of microbiota (GF conditions) decreased antioxidant enzyme activities and exercise performance. In addition, monocolonization of GF mice with BF prevented the decline in endurance exercise time. Therefore, different microbiota status may affect exercise performance and depends on GPx and CAT activity.
The EFP weight was greater in the SPF than GF mice. Therefore, gut microbiota can regulate different types of energy storage in the host (such as glycogen in GF mice and lipids in SPF mice) (7). Consistent with our previous study, total and relative liver and EPF weight were significantly higher in SPF than GF mice. In addition, BF colonization could increase the weight of liver, muscle, and EPF in BF gnotobiotic mice. The weight of the gastrocnemius and soleus muscles was higher in SPF and BF mice than GF mice. Previous study indicated that the exercise performance in activities such as swimming and long-distance running is not affected by skeletal muscle mass and size (39). Muscle weight may not be associated with exercise performance in mice with different microbiota status.
The swimming test is the most commonly used evaluation of antifatigue properties in animal models (35). Endurance swim time to exhaustion indicates the degree of fatigue. We found that swimming time was increased to 2.09-fold and 1.72-fold in SPF and BF mice, respectively, as compared with GF mice. Swimming capacity was weakest in GF mice. Monocolonization with BF could restore and enhance the exercise capacity. Previous studies have reported that treatment with probiotics could enhance antioxidant enzyme level, which subsequently neutralized excessive oxidative stress during intense exercise (17,20). Other researchers also demonstrated that probiotics including Lactobacilli and Bifidobacteria could enhance athletic exercise performance (17,20,38). Thus, gut microbiota with probiotics and also symbiotics may enhance exercise performance.
Increased UA levels might be a risk factor for renal damage and cardiovascular disease (12,19). Excessive oxidative stress plays an important pathophysiological role in hyperuricemia (16,27). We found higher UA level in GF than SPF and BF mice. This result was similar to our previous study showing low UA level related to reduced exercise-associated oxidative stress (39). However, we also found no association of BUN level and length of swimming time, which agrees with other reports (6,39). In addition, we found the lowest serum levels of TC and TG in BF mice as compared with SPF and GF mice. Lean humans and animals have a high proportion of intestinal Bacteroidetes, with a corresponding decrease in amount of Firmicutes in gut microflora (18). Bacteroides fragilis is the most symbiotic bacteria as a member of the genus Bacteroides. Therefore, serum levels of TC and TG might be affected by BF colonization but not related to exercise performance. Further research is required to determine the molecular signaling pathways involved in the regulation of TC and TG by BF colonization.
Glycogen is an important energy source during exercise. Deficiency of gut microbes affects the normal energy metabolism and promotes gluconeogenesis and glycogen synthesis, which results in accumulation of glycogen in the liver and lipolysis of adipose tissue (7). The concentration of glycogen in the liver is a fatigue index used to evaluate exercise performance (4). We found no association of liver and muscle glycogen content with exercise performance in any mouse group, and glycogen content in the liver was affected by different microbiota conditions. Tissue glycogen content may not be a suitable indicator for assessment of exercise capability in microbial status–related exercise research.
Antioxidant enzymes including GPx, CAT, and SOD are considered the first line of defense against ROS generated during exhaustive exercise (8). Glutathione peroxidase is the main enzyme of the enzymatic antioxidant defense system responsible for protecting against an increase in ROS production (24,28). Some studies suggest that GPx activity is increased in response to exercise training (3) and is the most important antioxidant enzyme induced with physical exercise (13,23). Intense physical activity disrupts the GPx activity balance by reducing its level in tissues, changing the redox status of cells (cell regeneration), and interfering in its production and transfer (31). We found lower serum and hepatic GPx activity in GF than SPF and BF mice. Loss of microbes might be associated with downregulated GPx activity, but existing microbes (SPF and BF mice) may enhance GPx activity to benefit exercise performance. This observation is consistent with that of Chen and Snyder (5) who found low GPx activity in GF rats.
Catalase is responsible for reducing H2O2 or organic hydroperoxides to water or alcohol, respectively. This antioxidant defense enzyme becomes weaker during chronic fatigue and intense exercise (34). Thus, improved CAT activity can help fight against fatigue. We found serum CAT activity higher in SPF than GF and BF mice. Gut microbiota may promote increased CAT activity to ameliorate exercise-induced fatigue. However, previous data suggested that gut microbiota could downregulate host SOD activity in the intestinal mucosa (10,11). We thought that downregulated SOD activity might be affected by BF colonization. Nevertheless, we did not find a relationship between SOD activity and exercise performance in the swim-to-exhaustion experiment (Figure 1). Previous studies demonstrated that high levels of ROS produced during exercise are associated with impaired muscle function and decreased exercise performance (8). Exhaustive exercise may augment the production of ROS to reduce exercise performance and increase fatigue. In contrast, an increase in antioxidant enzymes may ameliorate the effect of exercise-induced ROS and play a pivotal role in improving exercise performance. Our data demonstrate that intestinal microbiota can regulate antioxidant enzymes such as GPx and CAT but not SOD to modulate host exercise performance.
Previous study has shown that monocolonization of BF strain NCTC 9343 did not cause any signs of disease, including rectal bleeding and diarrhea (22). Our gross and histopathological examination showed that BF had no adverse effects on major organs such as the liver, kidney, skeletal muscles, and heart. Additionally, we found no abnormalities in SPF and GF mice on histological examination.
In conclusion, our results showed significantly decreased exercise performance and elevated serum UA levels in GF mice as compared with SPF and BF mice. In addition, GPx and CAT but not SOD levels and activity were lower in serum and liver of GF mice. Defective intestinal microflora might downregulate antioxidant capacity, which subsequently affects exercise performance.
This is the first study to show that intestinal microflora plays an important role in exercise performance. Different microbial status might regulate the antioxidant enzyme defense system to reduce physical fatigue and improve exercise performance. In general, intensive and sustained exercise training and high-level competition generate large amounts of free radicals that likely exceed the buffering capacity of the biological system, leaving athletes susceptible to oxidative stress. Supplementation with specific microbiota or probiotics may be a novel strategy for athletes, military personnel, and exercise enthusiasts who have to train at consistently high levels. Microbiota play important roles in immunity, energy harvest, and regulation of the oxidative defense system. The elite athlete's microbiota could be further compared with that from normal controls or different types of athletes for population/proportional analysis in future clinical trials. The human specific or potential microbiota strains could be further cultivated and supplemented to elucidate the regulation function of antioxidative effects for functional gain. Therefore, future study should seek to determine which specific microbe strains or commercialized probiotics and/or prebiotics are vulnerable to be considered ergogenic aids for practical supplementation.
We thank the Germfree and Gnotobiotic Section, Technical Services Division, National Laboratory Animal Center, National Applied Research Laboratories, for the kind gift of the germ-free and gnotobiotic mice; Laura Smales (BioMedEditing, Toronto, Canada) for her careful reading of the manuscript; and financial support from the Ministry of Science and Technology (MOST) of Taiwan, the successor to the National Science Council (grant NSC101-2320-B179-001 and NSC102-2628-B179-001-MY3). The publication of the results of the present study does not constitute an endorsement of any products used in the study by the National Strength and Conditioning Association. Y.-J. Hsu and C.-C. Chiu contributed equally to this study.
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