Journal of Exercise & Organ Cross Talk
Journal of Eexercise & Organ Cross Talk

The effect of a probiotic mixture combined with high-intensity interval training on the intestinal expression of FXR and PPAR-γ genes in diabetic rats

Articles in Press

Document Type : Original Article

Authors

Tahereh Jahandarlashaki
Hesam Parsa

Department of Exercise Physiology, Faculty of Sport Sciences, Bu-Ali Sina University, Hamedan, Iran.

10.22122/jeoct.2026.576456.1194
Abstract
This study investigated the effects of high-intensity interval training (HIIT) and a multi-strain probiotic mixture, on the intestinal expression of FXR and PPAR-γ in a rat model of type 2 diabetes mellitus (T2DM). Forty male Wistar rats were randomly assigned to five groups (n=8): Healthy Control (HC), Diabetic Control (DC), Diabetic+HIIT (DH), Diabetic+Probiotic (DP), and Diabetic+HIIT+Probiotic (DHP). T2DM was induced via a single intraperitoneal injection of nicotinamide (95 mg/kg) followed by streptozotocin (STZ, 55 mg/kg). The HIIT protocol was performed on a rodent treadmill for 8 weeks (5 sessions/week). The probiotic mixture (Lactobacillus rhamnosus GG, Lactobacillus casei, Lactobacillus reuteri; 1×10¹⁰ CFU/mL each) was administered daily via oral gavage. Diabetes induction significantly downregulated the intestinal expression of both FXR and PPAR-γ compared to healthy controls (p<0.001). HIIT and probiotic interventions, individually, significantly increased the expression of both nuclear receptors compared to the diabetic control group (p<0.001). Notably, the combined HIIT and probiotic intervention (DHP) produced the highest expression levels of FXR and PPAR-γ, which were significantly greater than either intervention alone (p<0.01) and restored FXR expression to levels comparable to healthy controls. Both HIIT and multi-strain probiotic supplementation effectively upregulate the intestinal expression of FXR and PPAR-γ in diabetic rats, with the combination exerting a synergistic effect. These findings identify a novel mechanism by which lifestyle interventions may restore intestinal metabolic function and inter-organ communication in T2DM, highlighting the therapeutic potential of targeting the gut through combined exercise and probiotic strategies.

What is already known on this subject?

The intestinal nuclear receptors FXR and PPAR-γ are critical regulators of metabolic homeostasis, and their expression is often downregulated in metabolic disorders like type 2 diabetes mellitus (T2DM).

High-intensity interval training (HIIT) and multi-strain probiotic supplementation are known to independently improve metabolic health and insulin sensitivity.

The "gut-muscle axis" is a key pathway for organ crosstalk, where intestinal health influences skeletal muscle metabolism and systemic insulin sensitivity.

 

What this study adds?

This study provides the first evidence that both HIIT and multi-strain probiotic supplementation individually upregulate the intestinal expression of FXR and PPAR-γ in a rat model of T2DM.

It demonstrates that a combined intervention of HIIT and probiotics produces a synergistic effect, leading to significantly greater upregulation of these nuclear receptors than either intervention alone.

The findings reveal a novel molecular mechanism—restoration of intestinal nuclear receptor signaling—through which combined exercise and probiotic strategies may enhance organ crosstalk and improve metabolic function in T2DM.

Keywords

Type 2 diabetes mellitus
High-intensity interval training
Probiotics
Gut-muscle axis
Organ crosstalk

Subjects

Acknowledgements

None.

Funding

None.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Compliance with ethical standards

Conflict of interest the authors declare that there is no conflict of interest in the present research.

Ethical approval All experimental procedures were approved by the institutional animal ethics committee and conducted in accordance with international guidelines for the care and use of laboratory animals.

Informed consent Animal study. 

Author contributions 

Conceptualization: T.J., Methodology: H.P., Software: T.J, H.P., Validation: T.J, H.P.,; Formal analysis: T.J, H.P.,; Investigation: T.J, H.P.,; Resources: T.J, H.P.,; Data curation: T.J, H.P.,; Writing - original draft: T.J, H.P.,; Writing–review & editing T.J, H.P, H.P.,; Visualization: T.J, H.P.,; Supervision: H.P.; Project administration: T.J, H.P.,.; Funding acquisition: T.J.    

Allen, N. G., Higham, S. M., Mendham, A. E., Kastelein, T. E., Larsen, P. S., & Duffield, R. (2017). The effect of high-intensity aerobic interval training on markers of systemic inflammation in sedentary populations. European Journal of Applied Physiology, 117(6), 1249-1256. doi: https://doi.org/10.1007/s00421-017-3613-1  
Bindels, L. B., & Delzenne, N. M. (2013). Muscle wasting: the gut microbiota as a new therapeutic target? The International Journal of Biochemistry & Cell Biology, 45(10), 2186-2190. doi: https://doi.org/10.1016/j.biocel.2013.06.021  
Ding, L., Yang, L., Wang, Z., & Huang, W. (2015). Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharmaceutica Sinica B, 5(2), 135-144. doi: https://doi.org/10.1016/j.apsb.2015.01.004  
Dubuquoy, L., Rousseaux, C., Thuru, X., Peyrin-Biroulet, L., Romano, O., Chavatte, P., et al. (2006). PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut, 55(9), 1341-1349. doi: https://doi.org/10.1136/gut.2006.093484  
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., et al. (2015). Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nature Medicine, 21(2), 159-165. doi: https://doi.org/10.1038/nm.3760 
González, F. J., Jiang, C., & Patterson, A. D. (2019). An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology, 156(6), 1648-1655. doi: https://doi.org/10.1053/j.gastro.2016.08.057  
Keirns, B. H., Koemel, N. A., Sciarrillo, C. M., Anderson, K. L., & Emerson, S. R. (2020). Exercise and intestinal permeability: another form of exercise-induced hormesis? American Journal of Physiology-Gastrointestinal and Liver Physiology, 319(4), G512-G518. doi: https://doi.org/10.1152/ajpgi.00232.2020  
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016). From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell, 165(6), 1332-1345. URL: https://www.cell.com/cell/fulltext/S0092-8674(16)30592-X    
Koutnikova, H., Genser, B., Monteiro-Sepulveda, M., Faurie, J. M., Rizkalla, S., Schrezenmeir, J., & Clément, K. (2019). Impact of bacterial probiotics on obesity, diabetes and non-alcoholic fatty liver disease related variables: a systematic review and meta-analysis of randomised controlled trials. BMJ Open, 9(3), e017995. doi: https://doi.org/10.1136/bmjopen-2017-017995  
Lee, A. S., Johnson, N. A., McGill, M. J., Overland, J., Luo, C., Baker, C. J., et al. (2020). Effect of high-intensity interval training on glycemic control in adults with type 1 diabetes and overweight or obesity: a randomized controlled trial with partial crossover. Diabetes Care, 43(9), 2281-2288. doi: https://doi.org/10.2337/dc20-0342 
Mailing, L. J., Allen, J. M., Buford, T. W., Fields, C. J., & Woods, J. A. (2019). Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health. Exercise and Sport Sciences Reviews, 47(2), 75-85. doi: https://doi.org/10.1249/JES.0000000000000183   
Manoharan, I., Suryawanshi, A., & Manoharan, I. (2021). PPAR-γ in the regulation of intestinal homeostasis and inflammation. International Journal of Molecular Sciences, 22(15), 8036.  
Meissner, M., Havinga, R., Boverhof, R., Kema, I., Collado, M. C., & Kuipers, F. (2011). Exercise enhances whole-body cholesterol turnover in mice. Medicine & Science in Sports & Exercise, 43(8), 1460-1468. doi: https://doi.org/10.1249/MSS.0b013e3181cfcb02    
Moludi, J., Maleki, V., Jafari-Vayghyan, H., Vaghef-Mehrabany, E., & Alizadeh, M. (2020). Metabolic endotoxemia and cardiovascular disease: A systematic review about potential roles of prebiotics and probiotics. Clinical and Experimental Pharmacology and Physiology, 47(6), 927-939. doi: https://doi.org/10.1111/1440-1681.13250  
Motiani, K. K., Collado, M. C., Eskelinen, J. J., Virtanen, K. A., Löyttyniemi, E., Salminen, S., et al. (2019). Exercise training modulates gut microbiota profile and improves endotoxemia. Medicine and Science in Sports and Exercise, 52(1), 94. doi: https://doi.org/10.1249/MSS.0000000000002112  
Przewłócka, K., Folwarski, M., Kaźmierczak-Siedlecka, K., Skonieczna-Żydecka, K., & Kaczor, J. J. (2020). Gut-muscle axis exists and may affect skeletal muscle adaptation to training. Nutrients, 12(5), 1451. doi: https://doi.org/10.3390/nu12051451  
Rana, N. S., Vishvakarma, N. K., Sonkar, S. C., & Beg, M. M. A. (2026). Diabetes: A comprehensive review of the Indian landscape in contrast with global trends. World journal of diabetes, 17(2), 110701. doi: https://doi.org/10.4239/wjd.v17.i2.110701  
Shirvani H, Aslani J. The effects of high-intensity interval training vs. moderate-intensity continuous training on serum irisin and expression of skeletal muscle PGC-1α gene in male rats. Tehran Univ Med J 2017; 75 (7) :513-520 URL: https://www.sid.ir/paper/38841/en  
Ticinesi, A., Lauretani, F., Tana, C., Nouvenne, A., Ridolo, E., & Meschi, T. (2019). Exercise and immune system as modulators of intestinal microbiome: implications for the gut-muscle axis hypothesis. Exercise Immunology Review, 25, 84-95. URL: http://www.eir-isei.de/2019/eir-2019-084-article.pdf  
Wahlström, A., Sayin, S. I., Marschall, H. U., & Bäckhed, F. (2016). Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metabolism, 24(1), 41-50.  
Zheng, Y., Ley, S. H., & Hu, F. B. (2018). Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Reviews Endocrinology, 14(2), 88-98. doi: https://doi.org/10.1038/nrendo.2017.151  
 
 
 
 
Journal of Exercise & Organ Cross Talk

Articles in Press, Accepted Manuscript
Available Online from 30 March 2026

  • Receive Date 17 December 2025
  • Revise Date 15 February 2026
  • Accept Date 21 February 2026

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