Volume 27, Issue 3 (Summer 2021)                   Intern Med Today 2021, 27(3): 342-357 | Back to browse issues page

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Rasheh S, Ahmadi M. The Effects of High-intensity Interval Training and Probiotic Consumption on Interleukin-10 and Interferon-gamma Gene Expression of Gut Tissue in an Animal Model of Fatty Liver. Intern Med Today 2021; 27 (3) :342-357
URL: http://imtj.gmu.ac.ir/article-1-3422-en.html
1- Department of Physical Education and Sport Science, Faculty of Human Sciences, Yadegar-e-Imam Khomeini (RAH) Shahre-rey Branch, Islamic Azad University, Tehran, Iran.
2- Department of Physical Education and Sport Science, Faculty of Human Sciences, Yadegar-e-Imam Khomeini (RAH) Shahre-rey Branch, Islamic Azad University, Tehran, Iran. , mahmadi1376@gmail.com
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1. Introduction
on-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common chronic liver disease that occurs in all age groups; this condition affects 17%-46% of the general population. NAFLD is a serious and growing clinical problem due to the prevalence of obesity and overweight [21]. The first damage to the liver is the accumulation of fat in the liver cells (steatosis), i.e., associated with the development of inflammation, leading to cirrhosis [3]. NAFLD is detected in 33.6% of patients with inflammatory bowel disease, often in the absence of metabolic risk factors [4]. Besides, in patients with severe intestinal inflammation, often steatosis has been reported on ultrasound [5].
Studies revealed that intestinal inflammation is associated with increased anti-inflammatory and pro-inflammatory cytokines in fatty liver disease [6, 7, 8]. Interleukin-10²(IL-10) is considered an anti-inflammatory cytokine that regulates inflammation in several organs and tissues under pathophysiological conditions [9]. IL-10 can significantly inhibit gene expression and the synthesis of proinflammatory cytokines [10]. IL-10, as a critical anti-inflammatory cytokine in immune responses, also presents a physiological effect on systemic inflammatory responses [11]. Furthermore, Interferon-Gamma (IFN-γ)³ exhibits anti-proliferative, immune, and pro-inflammatory activities; therefore, it is essential in immune-related mechanisms [1213]. IFN-γ also increases donor T cells and may be required for donor T cell differentiation. IFN-γ receptor is structurally related to the IL-10 receptor in the intestinal epithelium [14].
Limited pharmacotherapies have been proposed for fatty liver. Considering adverse effects, progressive weight gain and high cost, their continuous and regular use is not recommended. The standard treatment recommended for fatty liver consists of lifestyle modification, including diet modification and exercise [15]. Physical activity has been demonstrated to reduce the pathogenesis of NAFLD. Besides, aerobic exercise with and without weight loss reduces liver fat content and improves metabolic function in obese individuals, indicating the treatment or prevention of fatty liver disease [16]. Additionally, exercise, through its anti-inflammatory effects, plays beneficial roles in metabolic diseases [17]. There is conflicting information about the role of exercise in IL-10 as an inflammatory adipokine and its mechanism of action. In some studies, an increase in IL-10 levels has been reported after exercise [1819]; however, in some other studies, no significant change has been observed in IL-10 and IFN-γ levels after a training period [202122].
Studies considered using probiotics in treating fatty liver [2324]. In a study by Endo et al. (2013) in rats, probiotic administration could significantly stop or slow the progression of fatty liver [25]. Probiotics are living microorganisms with beneficial effects on the host body by improving the body’s microbial balance [26]. Among these beneficial effects on human health are the following: Provide an environment to prevent the growth of pathogens, strengthen the immune system, affect the flora of the intestinal tract, reduce and prevent intestinal tract infections, promote health, and regulate bowel movements. The mechanism of action of probiotics has been mentioned in 3 ways, including direct antimicrobial effects, strengthening the integrity of the mucosal defense barrier, and optimal changes in the immune system [28]. Numerous studies have reported the positive effects of exercise programs on the fatty liver; the type, intensity, and volume of exercise to recommend to patients with fatty liver remain unaddressed. Most studies have used conventional training methods, such as low to medium-intensity continuous training [16]. Few studies have examined the effects of other training, like High-Intensity Interval Training (HIIT). HIIT seems to present more beneficial effects on fatty liver treatment, compared to moderate and low-intensity exercises [29]. Compared to moderate physical activity, NAFLD patients who participated in strenuous activity presented a lower prevalence of liver fibrosis examined by biopsy, indicating the crucial role of strenuous physical activity [16]. There exists a wide prevalence of the fatty liver disease. It has interactions with inflammatory indicators. Thus, it is important to pay attention to the role of lifestyle changes, especially new methods of physical activity, and identifying different aspects of the treatment mechanism for this disease. Accordingly, we could choose the most effective intervention in this respect. Therefore, the present study intended to investigate the effects of intense HIIT and probiotic use on the expression of interleukin-10 and interferon-gamma genes in intestinal tissue in an animal model of fatty liver.
2. Materials and Methods
This was a fundamental and experimental study. The statistical population of this study consisted of all male Wistar rats of Pasteur Institute; from which, 40 male Wistar rats in the weight range of 200-200 g were randomly selected to participate in the study. The selected male Wistar rats were randomly divided into 5 groups of 8 subjects, including the healthy control group, fatty liver (steatosis), fatty liver (steatosis) + HIIT exercise, fatty liver (steatosis) + probiotics, and fatty liver group (steatosis) + HIIT Exercise + Probiotics. The study rats were kept in the research laboratory of Baqiyatallah University of Medical Sciences at a temperature of 20-23°C and a 12:12 light-dark cycle and relative humidity of 50% with standard access to water and food.
 Oral tetracycline at a dose of 140 mg/kg of body weight (dissolved in 2 mL of water) was fed to the examined rats by gavage for 7 days. The confirmation of fatty liver (steatosis) was established by measuring liver enzymes [30]. In the present study, an increase in liver enzymes was observed in the fatty liver groups. The advantages of using this model of fatty liver development include exploring the similarities of complications in animals with humans in a suitable time, as well as the possibility of controlling the test conditions. To prepare the serum, the obtained blood samples were centrifuged at 4°C and 5000 rpm for 10 minutes. Liver enzymes, including AST and ALT, were measured by Pars Azmoun diagnostic kits per the relevant protocols (Table 1).

Lactobacillus ramensus GG (PTCC1637) was obtained as lyophilized in standard vials from the Scientific and Industrial Research Organization of Iran (Tehran, Iran). Bacteria were cultured in MRS medium (Biogeya, Tehran, Iran), enriched with L-cysteine² ​​HCL, and incubated for 24 hours in an incubator at 37°C. To evaluate the effects of probiotics, the relevant groups received 10⁹ CFU/mL of Lactobacillus ramensus GG by gavage daily for 5 weeks and 5 days a week (there was no difference between the sample rats respecting receiving this substance) [31].
Initially, the examined rats were placed on a treadmill for 5-10 minutes for 3 to 5 weekly sessions for one week to get acquainted with the main exercise at a speed of 7-10 m/min and were forced to exercise. Then, an intense intermittent exercise program (5 sessions per week) and running on a treadmill for 5 weeks was performed according to the general principles of HIIT [31]. In this protocol, the HIIT program included warm-up and cool-down steps for 4-8 minutes with a running intensity of 40% of maximum speed. The protocol for performing training sessions is outlined in Table 2.

Accordingly, 48 hours after the last training session (10-12 hours fasting), the study rats per group were intraperitoneally injected with a mixture of ketamine 10% at a dose of 50 mg/kg and xylazine 2% at a dose of 10 mg/kg. The end of the small intestinal tissue (ilium) of rats was then sampled; after washing in physiological serum, it was immersed in 1.8 microtubes, containing RNAlaterTM¹ fluid with a ratio of 20% and transferred to the laboratory for genetic testing. The gene expression of the desired factors was measured from intestinal tissue by Real-time-PCR technique. After quantification, gene expression values ​​were analyzed by the formula 2-∆∆ ct. The PCR reaction was performed using (Applied Biosystems) PCR master mix and SYBR Green in the device (Applied Biosystems, Sequence Detection Systems. Foster City, CA) ABI Step One according to the manufacturer’s protocol. The sequence of used primers is listed in Table 3.

After the normality of the data was established by the Shapiro-Wilk test, a One-way Analysis of Variance (ANOVA) was used for analyzing intergroup changes. Moreover, the Tukey post-hoc test was applied to examine the between-group differences. The obtained data were analyzed using SPSS at a significant level of P<0.05.
3. Results
 Data analysis indicated a difference concerning the mean expression of the IL-10 gene in intestinal tissue in the animal model of steatosis between different research groups (P=0.001). The results of the Tukey post-hoc test suggested that the expression of the IL-10 gene in intestinal tissue in the HIIT(P=0.001), probiotic (P=0.036), and HIIT - probiotic (P=0.001) groups were significantly lower than that in the fatty liver group. Furthermore, the expression of the IL-10 gene in intestinal tissue in the HIIT-probiotic group was significantly lower than that in the probiotic group (P=0.041); however, the expression of the IL-10 gene in intestinal tissue in the HIIT group, compared to the HIIT-probiotic group was not significantly different (P=0.934) (Figure 1).

 Data analysis indicated a difference between the mean expression of the IFN-γ gene in intestinal tissue in the animal model of steatosis between different research groups (P=0.001). The Tukey’s post-hoc test data revealed that the expression of the IFN-γ gene in intestinal tissue was significantly lower in HIIT (P=0.001), probiotic (P=0.002), and HIIT-probiotic (P=0.001) groups, compared to the fatty liver group. There were no significant differences in the expression of the IFN-γ gene in intestinal tissue in HIIT, probiotic, and HIIT-probiotic groups (P<0.05) (Figure 2).

4. Discussion
 The present study results indicated that the expression of IL-10 and IFN-γ genes in the intestinal tissue of rats with steatosis in the fatty liver group was significantly higher than those in the other groups. Accordingly, fatty liver is associated with increased inflammation and high secretion of anti-inflammatory agents in intestinal tissue; it can increase the production of proinflammatory and anti-inflammatory cytokines, such as IFN-γ and IL-10 in intestinal tissue. HIIT also reduced IFN-γ and IL-10 gene expression in the intestinal tissue of the explored rats with steatosis. These findings highlight the effectiveness of HIIT in regulating IFN-γ and IL-10 gene expression in the intestinal tissue of rats with steatosis, i.e., consistent with some previous studies [32]. HIIT may be a time-consuming approach to reduce liver fat. Accordingly, several studies in animals and humans revealed that HIIT reduces the fat content of the liver and helps treat patients with fatty liver [33, 34]. Kistler et al. (2011) argued that patients who performed HIIT experienced a greater effect on reducing the risk of NAFLD and liver fibrosis, compared to moderate-intensity [29]. In the present study, HIIT significantly impacted changes in inflammatory factors, such as IFN-γ and IL-10. Exercise directly reduces pro-inflammatory factors by declining the production of cytokines in adipose tissue, muscle, and mononuclear cells, and indirectly, by increasing insulin sensitivity, increasing endothelial function, and weight loss. However, these effects on intestinal tissue remain unclear. Jahromi et al. (2014) examined endurance training effects on serum levels of interferon-gamma and TNF-α in inactive men. They presented a significant decrease in IFN-γ in the training group [35]. Intense intermittent exercise seems to play a significant role in reducing inflammation in fatty liver samples. IL-10 can inhibit the production of multiple cytokines, such as TNF-α, IL-1β, and IL-6 and reactive oxygen species [36]. According to molecular mechanisms, exercise, by negatively regulating the activity of NF-κB factor, regulates IL-10 secretion by monocytes and T cells through the Th2 pathway [37]. Another possible mechanism for regulating IL-10 secretion following regular exercise is the balance between Th1 and Th2-secreted cytokines; regular exercise can increase the production of cytokines secreted by Th2 cells and regulate the relative decrease in cytokines secreted by Th1 cells. Ultimately, this process leads to the modulation of inflammatory cytokines, including IL-10 [36]. The anti-inflammatory effects of exercise also depend on the duration and intensity of exercise. Therefore, it is possible that the intensity of exercise in the present study could induce anti-inflammatory properties in the exercise groups, and alter IL-10 gene expression in this group. The intensity of exercise may be among the influential factors; however, due to the anti-inflammatory role of IL-10, the most vulnerable environment might affect its changes [36].
 Contrary to the present study findings, Vahdat et al. (2018) stated that a 6-week periodic exercise significantly increased serum interleukin-10 levels in overweight men [38]. Chou et al. (2018) documented that 12 weeks of low-intensity training provided no significant effect on IFN-γ levels in splenic tissue among rats [39]. Ranjbar et al. (2016) signified that after 8 weeks of periodic training, the serum levels of interleukin-10 did not significantly change in women with type 2 diabetes [21]. The differences in the results of the studies can be attributed to the type of training interventions (duration, intensity, & the training period). Dornels et al. (2016) stated that inflammatory responses depend on the intensity of exercise. Their results reflected that IL-10 levels were found in overweight subjects immediately and 30 minutes after two intense training methods in overweight and obese individuals [40]. According to the present study data, the inconsistency of research results concerning the effect of exercise on cytokines can be related to the study population (healthy, sick, obese, etc.), different exercise protocols respecting duration, intensity, and type of activity, as well as the sampling tissue (plasma, gene expression, fat tissue, nerve tissue, etc.).
The beneficial effects of probiotics were reported on reducing the degree of fatty liver and other biochemical indicators in improving fatty liver [41, 42]. The present study results also confirmed the beneficial effects of probiotics on intestinal tissue in NAFLD disease. Consistent with these results, Savchenyuk et al. (2014), in the rat model, indicated that administrating various probiotics during the life of neonatal rats can significantly reduce the risk of fatty liver and obesity [41]. In another study by Ritz et al. (2014) in a fatty liver model of rats, the effects of probiotic administration were evaluated for 8 weeks. This treatment eventually led to a reduction in inflammation and liver enzymes [42]. As mentioned in our study, the improvement in IFN-γ and IL-10 gene expression in the intestinal tissue of steatosis mice was evident at the end of the intervention in the probiotic group. However, future studies considering the probiotic effects on inflammation seem necessary. A study on a mouse model concluded that probiotic administration can positively impact fat profile, insulin resistance, weight, and hepatic steatosis [43]. The exact mechanism of these effects remains unknown. It has been suggested that the positive effects observed due to using probiotics are related to increased intestinal wall integrity, reduced hepatitis, and reduced effects of pathogenic bacteria involved in NAFLD by their excretion or inhibition and production of short-chain fatty acids as antimicrobial agents. These factors prevent the damage of liver cells and the release of their enzymatic content into the blood [44]. However, in several studies, the intake of probiotics presented no beneficial effects on liver tissue [4546]. 
A potential reason for the difference in findings related to the effects of probiotics on the metabolic status of patients with NAFLD is the difference in the type of probiotics and the applied dose. Moreover, not all probiotics provide the same effect; there may be major differences in the desired effect on health and the associated possible adverse effects. Additionally, the status of the host is critical in terms of how it provides the conditions for the relationship between probiotic factors and intrinsic factors of the body, including the intestinal microbial flora [42]. Furthermore, the collected findings indicated that severe periodic exercises with probiotic consumption were more beneficial than probiotic consumption alone. Accordingly, these results suggested that synergistic periodic exercises to probiotics can be useful for intestinal tissue in fatty liver samples and present better results.
 Overall, studies emphasize the positive role of probiotics in improving the immune system. In the present study, intense intermittent exercise and probiotic use led to the modulation of the expression of genes involved in the innate immune system of fatty liver-induced intestinal tissue. However, due to the limited related studies, research on the effects of exercise and probiotic consumption on the factors involved in the immune system of intestinal tissue caused by fatty liver requires further studies. In the present study, other levels of proinflammatory cytokines (e.g., TNF-α) and inflammatory factors (e.g., CRP & IL-6) were not measured, i.e., a limitation of the present study. To evaluate the effects of tetracycline, it is suggested that the sham group be considered in future studies. Furthermore, a suitable solution for future studies is to compare different types of probiotics with variable doses. Further studies are required to understand the molecular mechanisms of the anti-inflammatory effect of exercise and the tissue or area where the action occurs.
5. Conclusion
 According to the obtained results, HIIT and probiotic consumption can modulate the expression of genes involved in the innate immune system of intestinal tissue caused by fatty liver. Therefore, HIIT and taking probiotics can probably help in the treatment of fatty liver.

Ethical Considerations
Compliance with ethical guidelines

This research was conducted following the approval of the Ethics Committee in Biomedical Research of the Institute of Physical Education and Sports Sciences (Code: IR.SSRC.REC.1399.069) and the Islamic Azad University, Imam Khomeini Memorial Branch in Rey. Also, all experiments were performed according to the policies of the Helsinki Convention.

This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
All authors equally contributed to preparing this article.

Conflicts of interest
The authors declared no conflicts of interest.

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Type of Study: Original | Subject: Gastroenterology and Hepatology
Received: 2019/11/16 | Accepted: 2021/03/1 | Published: 2021/07/1

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