Abstract
The composition and activity of the gut microbiota impacts several energy-regulating conditions including diabetes, obesity and metabolic syndrome; however, the specific mechanisms linking the gut microbiota with the host’s energy homeostasis remain elusive. Probiotics are health-promoting bacteria that when consumed, alter the composition and/or metabolism of resident microbiota conferring health benefits. To assess the role of a specific probiotic treatment on microbiota-derived impacts on energy homeostasis in the context of development, Drosophila melanogaster larvae were orally administered the probiotic Lactobacillus fermentum NCIMB 5221 or its metabolic product, ferulic acid: a potent anti-inflammatory and anti-oxidant hydroxycinnamic acid. In Drosophila larvae, both the probiotic and metabolite treatments advanced the nutritionally dependent stages of development in a dose-dependent manner while not affecting the hormonally controlled pupariation stage. These treatments correspondingly accelerated the developmental phase-dependent 20-hydroxyecdysone and insulin receptor gene expression surges and altered the phasic expression of downstream insulin signalling factors including dAkt, dTOR and dFOXO indicating a deep level of nutritionally dependent regulatory control. Administering Drosophila both ferulic acid and the TOR inhibitor rapamycin eliminated the physiological and molecular developmental advances indicating that microbial ferulic acid affects energy utilization in a dTOR-dependent manner outlining a potential mechanism of action of L. fermentum NCIMB 5221 on modulating microbiota dynamics to modulate energy homeostasis. TOR conservation from flies to humans indicates that probiotic therapy with L. fermentum NCIMB 5221 has a high therapeutic potential towards several human energy regulatory diseases such as obesity, diabetes and cancer.
Similar content being viewed by others
References
Jandhyala, S. M., Talukdar, R., Subramanyam, C., Vuyyuru, H., Sasikala, M., & Nageshwar Reddy, D. (2015). Role of the normal gut microbiota. World Journal of Gastroenterology, 21(29), 8787–8803.
Rosenbaum, M., Knight, R., & Leibel, R. L. (2015). The gut microbiota in human energy homeostasis and obesity. Trends in Endocrinology and Metabolism: TEM, 26(9), 493–501.
Mazidi, M., Rezaie, P., Kengne, A. P., Mobarhan, M. G., & Ferns, G. A. (2016). Gut microbiome and metabolic syndrome. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 10(2 Suppl 1), S150–S157.
Grewal, S. S. (2009). Insulin/TOR signaling in growth and homeostasis: A view from the fly world. The International Journal of Biochemistry & Cell Biology, 41(5), 1006–1010.
Mannaa, M., Kramer, S., Boschmann, M., & Gollasch, M. (2013). mTOR and regulation of energy homeostasis in humans. Journal of Molecular Medicine, 91(10), 1167–1175.
Layalle, S., Arquier, N., & Leopold, P. (2008). The TOR pathway couples nutrition and developmental timing in Drosophila. Developmental Cell, 15(4), 568–577.
Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124(3), 471–484.
Shingleton, A. W., Das, J., Vinicius, L., & Stern, D. L. (2005). The temporal requirements for insulin signaling during development in Drosophila. PLoS Biology, 3(9), e289.
Robertson, F. W. (1963). The ecological genetics of growth in Drosophila: The genetic correlation between the duration of the larval period and body size in relation to larval diet. Genetics Research, 4, 74–92.
Giannakou, M. E., & Patridge, L. (2007). Role of insulin-like signalling in Drosophila lifespan. Trends in Biochemical Sciences, 32(4), 180–188.
Dreyer, A. P., & Shingleton, A. W. (2011). The effect of genetic and environmental variation on genital size in male Drosophila: Canalized but developmentally unstable. PLoS ONE, 6(12), e28278.
Mirth, C. K., & Shingleton, A. W. (2012). Integrating body and organ size in Drosophila: Recent advances and outstanding problems. Frontiers in Endocrinology, 3, 49.
Koyama, T., Rodrigues, M. A., Athanasiadis, A., Shingleton, A. W., & Mirth, C. K. (2014). Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesis. Elife, 3, e03091.
Colombani, J., Bianchini, L., Layalle, S., Pondeville, E., Dauphin-Villemant, C., Antoniewski, C., et al. (2005). Antagonistic actions of ecdysone and insulins determine final size in Drosophila. Science, 310(5748), 667–670.
Wheeler, D. E., & Nijhout, H. F. (2003). A perspective for understanding the modes of juvenile hormone action as a lipid signaling system. BioEssays, 25(10), 994–1001.
Beadle, G., Tatum, E., & Clancy, C. (1938). Food level in relation to rate of development and eye pigmentation in Drosophila melanogaster. The Biological Bulletin, 75(3), 447–462.
Rosenbaum, M., Knight, R., & Leibel, R. L. (2015). The gut microbiota in human energy homeostasis and obesity. Trends in Endocrinology & Metabolism, 26(9), 493–501.
Duca, F. A., & Lam, T. K. T. (2014). Gut microbiota, nutrient sensing and energy balance. Diabetes, Obesity and Metabolism, 16(Suppl 1), 68–76.
Everard, A., & Cani, P. D. (2014). Gut microbiota and GLP-1. Reviews in Endocrine and Metabolic Disorders, 15(3), 189–196.
Villanueva-Millan, M. J., Perez-Matute, P., & Oteo, J. A. (2015). Gut microbiota: A key player in health and disease. A review focused on obesity. The Journal of Physiology and Biochemistry, 71(3), 509–525.
Ley, R. E., Peterson, D. A., & Gordon, J. I. (2006). Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell, 124(4), 837–848.
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444(7122), 1027–1031.
Backhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I. (2007). Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the United States of America, 104(3), 979–984.
Hill, C., Guarner, F., Reid, G., Gibson, G. R., Merenstein, D. J., Pot, B., et al. (2014). Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology, 11(8), 506–514.
Cani, P. D., Hoste, S., Guiot, Y., & Delzenne, N. M. (2007). Dietary non-digestible carbohydrates promote L-cell differentiation in the proximal colon of rats. British Journal of Nutrition, 98(1), 32–37.
Sanz, Y., & Rastmanesh, R., & Agostoni, C. (2013). Understanding the role of gut microbes and probiotics in obesity: How far are we? Pharmacological Research, 69(1), 144–155.
Wang, J., Tang, H., Zhang, Y., Derrien, M., Rocher, E., van-Hylckama, J. E., Strissel, K., Zhao, L., Obin, M., & Shen, J. (2015). Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. The ISME Journal, 9(1), 1–15.
Tolhurst, G., Heffron, H., Lam, Y. S., Parker, H. E., Habib, A. M., Diakogiannaki, E., et al. (2012). Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes, 61(2), 364–371.
Ishimwe, N., Daliri, E. B., Lee, B. H., Fang, F., & Du, G. (2015). The perspective on cholesterol-lowering mechanisms of probiotics. Molecular Nutrition & Food Research, 59(1), 94–105.
Storelli, G., Defaye, A., Erkosar, B., Hols, P., Royet, J., & Leulier, F. (2011). Lactobacillus plantarum promotes drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing. Cell Metabolism, 14(3), 403–414.
Tomaro-Duchesneau, C., Saha, S., Malhotra, M., Jones, M. L., Labbe, A., Rodes, L., et al. (2014). Effect of orally administered L. fermentum NCIMB 5221 on markers of metabolic syndrome: An in vivo analysis using ZDF rats. Applied Microbiology and Biotechnology, 98(1), 115–126.
Ishii, N., Fujii, M., Hartman, P. S., Tsuda, M., Yasuda, K., Senoo-Matsuda, N., et al. (1998). A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature, 394(6694), 694–697.
Harrod, M. J., & Kastritsis, C. D. (1972). Developmental studies in Drosophila. II. Ultrastructural analysis of the salivary glands of Drosophila pseudoobscura during some stages of development. Journal of Ultrastructure Research, 38(5), 482–499.
Tomaro-Duchesneau, C., Saha, S., Malhotra, M., Coussa-Charley, M., Al-Salami, H., Jones, M., et al. (2012). Lactobacillus fermentum NCIMB 5221 has a greater ferulic acid production compared to other ferulic acid esterase producing Lactobacilli. International Journal of Probiotics and Prebiotics, 7(1), 23–32.
Zhang, J., & Liu, F. (2014). Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life, 66(7), 485–495.
Murphy, E. F., Cotter, P. D., Healy, S., Marques, T. M., O’Sullivan, O., Fouhy, F., Clarke, S. F., O’Toole, P. W., Quigley, E. M., Stanton, C., Ross, P. R., O’Doherty, R. M., & Shanahan, F. (2010). Composition and energy harvesting capacity of the gut microbiota: Relationship to diet, obesity and time in mouse models. Gut, 59(12), 1635–1642.
Broughton, S. J., Piper, M. D., Ikeya, T., Bass, T. M., Jacobson, J., Driege, Y., Martinez, P., Hafen, E., Withers, D. J., Leevers, S. J., & Patridge, L. (2005). Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proceedings of the National Academy of Sciences of the United States of America, 102(8), 3105–3110.
Brogiolo, W., Stocker, H., Ikeya, T., Rintelen, F., Fernandez, R., & Hafen, E. (2001). An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Current Biology, 11(4), 213–221.
Warren, J. T., Yerushalmi, Y., Shimell, M. J., O’Connor, M. B., Restifo, L. L., & Gilbert, L. I. (2006). Discrete pulses of molting hormone, 20-hydroxyecdysone, during late larval development of Drosophila melanogaster: Correlations with changes in gene activity. Developmental Dynamics, 235(2), 315–326.
Mirth, C. K., & Riddiford, L. M. (2007). Size assessment and growth control: How adult size is determined in insects. Bioessays, 29(4), 344–355.
Bian, Z., Furuya, N., Zheng, D.-M., Trejo, J. A. O., Tada, N., Ezaki, J., & Ueno, T. (2013). Ferulic acid induces mammalian target of rapamycin inactivation in cultured mammalian cells. Biological and Pharmaceutical Bulletin, 36(1), 120–124.
Koh, P.-O. (2013). Ferulic acid attenuates focal cerebral ischemia-induced decreases in p70S6 kinase and S6 phosphorylation. Neuroscience Letters, 555, 7–11.
Haissaguerre, M., Saucisse, N., & Cota, D. (2014). Influence of mTOR in energy and metabolic homeostasis. Molecular and Cellular Endocrinology, 397(1–2), 67–77.
Hietakangas, V., & Cohen, S. M. (2007). Re-evaluating AKT regulation: Role of TOR complex 2 in tissue growth. Genes & Development, 21(6), 632–637.
Mihaylova, M. M., & Shaw, R. J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biology, 13(9), 1016–1023.
Braco, J. T., Gillespie, E. L., Alberto, G. E., Brenman, J. E., & Johnson, E. C. (2012). Energy-dependent modulation of glucagon-like signaling in Drosophila via the AMP-activated protein kinase. Genetics, 192(2), 457–466.
Salih, D. A. M., & Brunet, A. (2008). FoxO transcription factors in the maintenance of cellular homeostasis during aging. Current Opinion in Cell Biology, 20(2), 126–136.
Puig, O., Marr, M. T., Ruhf, M. L., & Tjian, R. (2003). Control of cell number by Drosophila FOXO: Downstream and feedback regulation of the insulin receptor pathway. Genes & Development, 17(16), 2006–2020.
Kramer, J. M., Davidge, J. T., Lockyer, J. M., & Staveley, B. E. (2003). Expression of Drosophila FOXO regulates growth and can phenocopy starvation. BMC Developmental Biology, 3, 5.
Westfall, S., Lomis, N., & Prakash, S. (2018). Longevity extension in Drosophila through gut-brain communication. Scientific Reports, 8(1), 8362.
Ornoy, A. (2011). Prenatal origin of obesity and their complications: Gestational diabetes, maternal overweight and the paradoxical effects of fetal growth restriction and macrosomia. Reproductive Toxicology, 32(2), 205–212.
Wit, J. M., & Walenkamp, M. J. (2013). Role of insulin-like growth factors in growth, development and feeding. World Review of Nutrition and Dietetics, 106, 60–65.
Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274–293.
Blagosklonny, M. V. (2011). Rapamycin-induced glucose intolerance: Hunger or starvation diabetes. Cell Cycle, 10(24), 4217–4224.
Funding
This work was supported by NSERC and CIHR.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
This publication includes data filed in a US provisional patent (62/629832) through a company which SW and SP are co-founders. The authors received no funding from the company for completing this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Westfall, S., Lomis, N. & Prakash, S. Ferulic Acid Produced by Lactobacillus fermentum Influences Developmental Growth Through a dTOR-Mediated Mechanism. Mol Biotechnol 61, 1–11 (2019). https://doi.org/10.1007/s12033-018-0119-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12033-018-0119-y