00736705

June 15, 2021, 17:53

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TO THE EDITOR, We read the recent publication by Jang HR and Lee HY (World J Diabetes 2021 June 15; 12(6): 685-915) on the relationship of mechanisms linking intestinal microbial metabolites to insulin resistance published in this journal with great interest. Notably, based on compelling evidences of the host-microbiota and metabolic derangement crosstalk, substantial body of literature, either in preclinical models or in clinical studies (1-3), has linked intestinal microbiota in the pathophysiology of insulin resistance and type 2 diabetes. This present article elegantly highlights the potential role of specific microbiota-derived compounds in insulin-responsive tissues, acting as risk factors or protectors for the development of insulin resistance and the importance of the muscle-liver-adipose tissue axis interaction. Although so well demonstrated by the authors the potential role of some bacterial metabolites as regulators of metabolic functions in the body, such as short chain fatty acids propionate, butyrate, acetate, microbial products derived from phenolic acids and fatty-acids, in upregulating glucose homeostasis, the role of some bacterial metabolites in the host metabolism still need to be better understood. Despite mentioned the importance of succinate, a metabolite of the tricarboxylic acid cycle produced by both microbiota and the host (4), in the improvement of glucose homeostasis through activation of intestinal gluconeogenesis (5), Serena et al demonstrated that obese individuals exhibit high levels of this circulating metabolite (4). Furthermore, the imbalance of higher relative abundance of succinate-producing bacteria (Prevotellaceae and Veillonellaceae) and lower relative abundance of succinate-consuming bacteria Odoribacteraceae and Clostridaceae) may promote an increase in succinate levels and, ultimately, an impaired glucose metabolism. These authors also point out succinate as a potencial role in obesity and metabolic-associated cardiovascular disorder. Importantly, succinate acts as an immunogenic molecule, named damage associated molecular patterns (DAMPs). That molecular is recognized by immune cells and through its G-protein coupled receptor (succinate receptor 1/SUCNR1 or GPR19) stabilizes hypoxia-inducible factor-1α (HIF-1α), which promotes the pro-inflammatory differentiation of T lymphocytes, and synergizes the effects with Toll-like receptor ligands in dendritic cells for the production of cytokines (6,7). Collectively, these findings may promote an enhancement of insulin resistance and DM burden. In addition, broader investigations on the physiological implications of hydrogen sulfide (H2S) and the role of sulfur-reducing bacteria from the intestinal microbiota in better host glycemic control would be relevant (8). H2S metabolite may protect from oxidative stress by restoring reduced glutathione (GSH) and scavenging of mitochondrial reactive oxygen species, inducing pro-survival/angiogenesis signaling pathway (STAT3), and promoting immunomodulation (NF-κB) and vasodilation (KATP ion channel) (9). In conclusion, the modulation of the intestinal microbiota has emerged as a promising strategy in metabolic diseases, such as insulin resistance and diabetes. The intestinal microbiota is affected by several environmental aspects, and its response to these different stimuli must also be considered when studying the host-gut microbiota interactions (10). The interest in expanding the knowledge and understanding of the intestinal microbiota and compounds derived from this microbiota in human metabolism offers future perspectives for therapeutic purposes and opportunity for mitigating the impact of metabolic insults associated with those pathologies. Although there are many open questions to be explored in this growing field. Rosana M. C. Bastos1, Érika B. Rangel1,2 1Hospital Israelita Albert Einstein, São Paulo, SP, Brazil 2Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil REFERENCES 1. Wang H, Lu Y, Yan Y, Tian S, Zheng D, Leng D, et al. Promising Treatment for Type 2 Diabetes: Fecal Microbiota Transplantation Reverses Insulin Resistance and Impaired Islets. Frontiers in cellular and infection microbiology. 2019;9:455. 2. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55-60. 3. Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99-103. 4. Serena C, Ceperuelo-Mallafré V, Keiran N, Queipo-Ortuño MI, Bernal R, Gomez-Huelgas R, et al. Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. The ISME journal. 2018;12(7):1642-57. 5. De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Bäckhed F, Mithieux G. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis. Cell metabolism. 2016;24(1):151-7. 6. Garcia-Martinez I, Shaker ME, Mehal WZ. Therapeutic Opportunities in Damage-Associated Molecular Pattern-Driven Metabolic Diseases. Antioxid Redox Signal. 2015; 23(17): 1305-1315. 7. Rodriguez-Nuevo A, Zorzano A. The sensing of mitochondrial DAMPs by non-immune cells. Cell stress. 2019; 3(6): 195-207. 8. Pichette J, Fynn-Sackey N, Gagnon J. Hydrogen Sulfide and Sulfate Prebiotic Stimulates the Secretion of GLP-1 and Improves Glycemia in Male Mice. Endocrinology. 2017;158(10):3416-25. 9. Pal VR, Bandyopadhyay P, Singh A. Hydrogen Sulfide in Phsysiology and Pathogenesis of Bacteria and Viruses. IUBMB Life. 2018; 70(5): 392-410. 10. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nature reviews Microbiology. 2021;19(1):55-71.

First, thank you very much for your professional comments on the article published in World Journal of Diabetes. Second, we read your comments with great interest. You are welcome to format your valuable comments into a Letter to the Editor and submit it online to World Journal of Diabetes at https://www.f6publishing.com. There are no restrictions on the number of words, figures (color, B/W) or authors for a Letter to the Editor. In addition, the article processing charge will be exempted for this Letter to the Editor. As with all articles published by the Baishideng Publishing Group, the Letter to the Editor will be published online after completing peer review. The guidelines for a Letter to the Editor can be found at: https://www.wjgnet.com/bpg/GerInfo/219. Finally, we look forward to receiving your high-quality Letter to the Editor, which will promote academic communication and lead the development of this discipline.

05186196

June 15, 2021, 07:45

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The authors have submitted an interesting and well-written review on the mechanisms linking gut microbial metabolites to insulin resistance. In future reviews, the authors could also explore the contribution of oxidative stress to the microbiome-insulin resistance crosstalk. In addition, the potential benefits of prebiotics and probiotics in the management of insulin resistance could be discussed.

Thank you very much for your comments.