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高糖饮食重塑肠道菌群加重博来霉素诱导的肺纤维化
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Abstract:
目的：肺纤维化的确切病因尚不清楚，但它是一种慢性进行性疾病，可导致呼吸衰竭和肺组织破坏。高糖饮食被认为是促进肺纤维化的一个可能的危险因素，但高糖饮食影响肺纤维化的具体机制尚不清楚。在这项研究中，我们对高糖饮食对肺纤维化影响机制进行进一步探索。方法：C57BL/6小鼠给予博来霉素(BLM)建立了有效的肺纤维化动物模型。我们给予BLM引起肺纤维化的小鼠给予20%葡萄糖水或常规饮用水。通过苏木精–伊红染色法(HE)，马松染色(Masson)评估肺纤维化的严重程度。采用16s rRNA检测小鼠肠道菌群的改变。结果：高糖喂养的小鼠的血糖明显高于正常喂养的小鼠血糖(P < 0.05)。但是高糖喂养的小鼠的体重只是略微比正常喂养的小鼠体重升高(P > 0.05)。高糖喂养的小鼠的肺指数即肺脏体重/小鼠体重明显高于正常喂养的小鼠血糖(P < 0.01)。高糖喂养的小鼠的肺脏的肺纤维化评分(Score of Aschcroft)明显高于正常喂养的小鼠血糖(P < 0.01)。16s rRNA显示糖喂养的小鼠的α多样性和β多样性相比于正常喂养的小鼠具有显著差异(P < 0.05)。结论：高糖饮食可能通过重塑肠道菌群从而加重肺组织纤维化。我们的研究可能为临床肺纤维化的管理和预防提供新的视角和可能的治疗途径。
Purpose: The exact etiology of pulmonary fibrosis is unknown, but it is a chronic, progressive illness that can cause respiratory failure and the destruction of lung tissues. High-glucose diets are considered a possible risk factor for promoting pulmonary fibrosis, but the specific mechanisms by which high-glucose diets affect pulmonary fibrosis are not clear. In this study, we investigated the mechanisms underlying lung fibrosis and the means by which a high-glucose diet affects them. Methods: BLM administration in mice establishes an effective animal model of pulmonary fibrosis. Mice with BLM-induced pulmonary fibrosis were given either 20% glucose water or regular drinking water. Hematoxylin-eosin staining (HE) and Masson staining were used to evaluate the severity of pulmonary fibrosis. The changes of intestinal flora in mice were detected by 16s rRNA. Results: The blood glucose levels in mice subjected to a high-glucose diet were significantly elevated compared to those in mice on a standard diet (P < 0.05). Conversely, the body weight of mice on the high-sugar diet was only marginally higher than that of the control group (P > 0.05). The lung index, calculated as the ratio of lung weight to body weight, was significantly increased in the high-sugar diet group compared to the control group (P < 0.01). Additionally, the pulmonary fibrosis score, as assessed by the Ashcroft scale, was significantly higher in the high-glucose fed mice than in the normally fed mice (P < 0.01). Analysis of 16S rRNA revealed that both α diversity and β diversity in the gut microbiota of sugar-fed mice differed significantly from those in the control group (P < 0.05). Conclusion: High-glucose diet may aggravate pulmonary fibrosis by remodeling gut microbiota. Our study may provide new perspectives and possible therapeutic pathways for the management and prevention of clinical
| [1] | Hutchinson, J., Fogarty, A., Hubbard, R. and McKeever, T. (2015) Global Incidence and Mortality of Idiopathic Pulmonary Fibrosis: A Systematic Review. European Respiratory Journal, 46, 795-806. https://doi.org/10.1183/09031936.00185114 |
| [2] | Huang, Y., Oldham, J.M., Ma, S., Unterman, A., Liao, S., Barros, A.J., et al. (2021) Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells. American Journal of Respiratory and Critical Care Medicine, 204, 197-208. https://doi.org/10.1164/rccm.202008-3093oc |
| [3] | Serezani, A.P.M., Pascoalino, B.D., Bazzano, J.M.R., Vowell, K.N., Tanjore, H., Taylor, C.J., et al. (2022) Multiplatform Single-Cell Analysis Identifies Immune Cell Types Enhanced in Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 67, 50-60. https://doi.org/10.1165/rcmb.2021-0418oc |
| [4] | François, A., Gombault, A., Villeret, B., Alsaleh, G., Fanny, M., Gasse, P., et al. (2015) B Cell Activating Factor Is Central to Bleomycin-and IL-17-Mediated Experimental Pulmonary Fibrosis. Journal of Autoimmunity, 56, 1-11. https://doi.org/10.1016/j.jaut.2014.08.003 |
| [5] | Todd, N.W., Scheraga, R.G., Galvin, J.R., et al. (2013) Lymphocyte Aggregates Persist and Accumulate in the Lungs of Patients with Idiopathic Pulmonary Fibrosis. Journal of Inflammation Research, 6, 63-70. https://doi.org/10.2147/jir.s40673 |
| [6] | Keir, G.J., Maher, T.M., Ming, D., Abdullah, R., de Lauretis, A., Wickremasinghe, M., et al. (2013) Rituximab in Severe, Treatment‐Refractory Interstitial Lung Disease. Respirology, 19, 353-359. https://doi.org/10.1111/resp.12214 |
| [7] | Luo, Q., Deng, D., Li, Y., Shi, H., Zhao, J., Qian, Q., et al. (2023) TREM2 Insufficiency Protects against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization. International Immunopharmacology, 118, Article ID: 110070. https://doi.org/10.1016/j.intimp.2023.110070 |
| [8] | Huang, Y., Chen, Z., Chen, B., Li, J., Yuan, X., Li, J., et al. (2023) Dietary Sugar Consumption and Health: Umbrella Review. BMJ, 381, e071609. https://doi.org/10.1136/bmj-2022-071609 |
| [9] | Gähler, A., Trufa, D.I., Chiriac, M.T., Tausche, P., Hohenberger, K., Brunst, A., et al. (2022) Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma. Frontiers in Oncology, 12, Article 873293. https://doi.org/10.3389/fonc.2022.873293 |
| [10] | Goyal, M.S., Venkatesh, S., Milbrandt, J., Gordon, J.I. and Raichle, M.E. (2015) Feeding the Brain and Nurturing the Mind: Linking Nutrition and the Gut Microbiota to Brain Development. Proceedings of the National Academy of Sciences of the United States of America, 112, 14105-14112. https://doi.org/10.1073/pnas.1511465112 |
| [11] | Marsland, B.J. and Salami, O. (2015) Microbiome Influences on Allergy in Mice and Humans. Current Opinion in Immunology, 36, 94-100. https://doi.org/10.1016/j.coi.2015.07.005 |
| [12] | Peterson, L.W. and Artis, D. (2014) Intestinal Epithelial Cells: Regulators of Barrier Function and Immune Homeostasis. Nature Reviews Immunology, 14, 141-153. https://doi.org/10.1038/nri3608 |
| [13] | Atarashi, K., Tanoue, T., Oshima, K., Suda, W., Nagano, Y., Nishikawa, H., et al. (2013) Treg Induction by a Rationally Selected Mixture of Clostridia Strains from the Human Microbiota. Nature, 500, 232-236. https://doi.org/10.1038/nature12331 |
| [14] | Zhang, D., Liu, B., Cao, B., Wei, F., Yu, X., Li, G., et al. (2017) Synergistic Protection of Schizandrin B and Glycyrrhizic Acid against Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β1/Smad2 Pathways and Overexpression of Nox4. International Immunopharmacology, 48, 67-75. https://doi.org/10.1016/j.intimp.2017.04.024 |
| [15] | Yang, W., Pan, L., Cheng, Y., Wu, X., Tang, B., Zhu, H., et al. (2022) Nintedanib Alleviates Pulmonary Fibrosis in Vitro and in Vivo by Inhibiting the FAK/ERK/S100A4 Signalling Pathway. International Immunopharmacology, 113, Article ID: 109409. https://doi.org/10.1016/j.intimp.2022.109409 |
| [16] | Qu, Z., Dou, W., Zhang, K., Duan, L., Zhou, D. and Yin, S. (2022) IL-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis in Association with Inhibition of IL-17A in Mice. Arthritis Research & Therapy, 24, Article No. 280. https://doi.org/10.1186/s13075-022-02977-6 |
| [17] | Rao, L., Wang, Y., Zhang, L., Wu, G., Zhang, L., Wang, F., et al. (2020) IL-24 Deficiency Protects Mice against Bleomycin-Induced Pulmonary Fibrosis by Repressing Il-4-Induced M2 Program in Macrophages. Cell Death & Differentiation, 28, 1270-1283. https://doi.org/10.1038/s41418-020-00650-6 |
| [18] | Nossa, C.W. (2010) Design of 16S rRNA Gene Primers for 454 Pyrosequencing of the Human Foregut Microbiome. World Journal of Gastroenterology, 16, 4135-4144. https://doi.org/10.3748/wjg.v16.i33.4135 |
| [19] | Xiong, J., Liu, Y., Lin, X., Zhang, H., Zeng, J., Hou, J., et al. (2012) Geographic Distance and Ph Drive Bacterial Distribution in Alkaline Lake Sediments across Tibetan Plateau. Environmental Microbiology, 14, 2457-2466. https://doi.org/10.1111/j.1462-2920.2012.02799.x |
| [20] | Zhang, D., Jin, W., Wu, R., Li, J., Park, S., Tu, E., et al. (2019) High Glucose Intake Exacerbates Autoimmunity through Reactive-Oxygen-Species-Mediated TGF-β Cytokine Activation. Immunity, 51, 671-681.e5. https://doi.org/10.1016/j.immuni.2019.08.001 |
| [21] | Soetikno, V., Andini, P., Iskandar, M., Matheos, C.C., Herdiman, J.A., Kyle, I.K., et al. (2023) α-Mangosteen Lessens High-Fat/High-Glucose Diet and Low-Dose Streptozotocin Induced-Hepatic Manifestations in the Insulin Resistance Rat Model. Pharmaceutical Biology, 61, 241-248. https://doi.org/10.1080/13880209.2023.2166086 |
| [22] | Ning, W., Xu, X., Zhou, S., Wu, X., Wu, H., Zhang, Y., et al. (2022) Effect of High Glucose Supplementation on Pulmonary Fibrosis Involving Reactive Oxygen Species and TGF-β. Frontiers in Nutrition, 9, Article 998662. https://doi.org/10.3389/fnut.2022.998662 |
| [23] | Tian, J., Zhang, M., Suo, M., Liu, D., Wang, X., Liu, M., et al. (2021) Dapagliflozin Alleviates Cardiac Fibrosis through Suppressing Endmt and Fibroblast Activation via AMPKα/TGF-β/Smad Signalling in Type 2 Diabetic Rats. Journal of Cellular and Molecular Medicine, 25, 7642-7659. https://doi.org/10.1111/jcmm.16601 |
| [24] | Park, S., Hahn, H., Oh, S. and Lee, H. (2023) Theophylline Attenuates BLM-Induced Pulmonary Fibrosis by Inhibiting Th17 Differentiation. International Journal of Molecular Sciences, 24, Article 1019. https://doi.org/10.3390/ijms24021019 |
| [25] | Park, S., Ryu, H.W., Kim, J., Hahn, H., Jang, H., Ko, S., et al. (2023) Daphnetin Alleviates Bleomycin-Induced Pulmonary Fibrosis through Inhibition of Epithelial-To-Mesenchymal Transition and Il-17a. Cells, 12, Article 2795. https://doi.org/10.3390/cells12242795 |
| [26] | Jia, Q., Li, Q., Wang, Y., Zhao, J., Jiang, Q., Wang, H., et al. (2022) Lung Microbiome and Transcriptome Reveal Mechanisms Underlying PM2.5 Induced Pulmonary Fibrosis. Science of the Total Environment, 831, Article ID: 154974. https://doi.org/10.1016/j.scitotenv.2022.154974 |
| [27] | Bhattacharya, S.S., Yadav, B., Rosen, L., Nagpal, R., Yadav, H. and Yadav, J.S. (2022) Crosstalk between Gut Microbiota and Lung Inflammation in Murine Toxicity Models of Respiratory Exposure or Co-Exposure to Carbon Nanotube Particles and Cigarette Smoke Extract. Toxicology and Applied Pharmacology, 447, Article ID: 116066. https://doi.org/10.1016/j.taap.2022.116066 |
| [28] | Gurczynski, S.J., Lipinski, J.H., Strauss, J., Alam, S., Huffnagle, G.B., Ranjan, P., et al. (2023) Horizontal Transmission of Gut Microbiota Attenuates Mortality in Lung Fibrosis. JCI Insight, 9, e164572. https://doi.org/10.1172/jci.insight.164572 |
| [29] | Cao, G., Wang, Q., Huang, W., Tong, J., Ye, D., He, Y., et al. (2017) Long-Term Consumption of Caffeine-Free High Sucrose Cola Beverages Aggravates the Pathogenesis of EAE in Mice. Cell Discovery, 3, Article No. 17020. https://doi.org/10.1038/celldisc.2017.20 |
| [30] | Liu, J., Zhou, H., Bai, W., Wang, J., Li, Q., Fan, L., et al. (2024) Assessment of Progression of Pulmonary Fibrosis Based on Metabonomics and Analysis of Intestinal Microbiota. Artificial Cells, Nanomedicine, and Biotechnology, 52, 201-217. https://doi.org/10.1080/21691401.2024.2326616 |
