肺-腸軸在肺纖維化中作用的研究進展_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

楊雪 , 江宇

重慶醫科大學附屬大學城醫院呼吸與危重癥醫學科（重慶 401331）;

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DOI：

10.7507/1671-6205.202502032

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1.	Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med, 2013, 188(6): 733-748.
2.	劉聲, 劉曉燕, 李立華, 等. “肺與大腸相表里”的組織細胞學基礎研究. 中華中醫藥雜志, 2012, 27(4): 1167-1170.
3.	Proctor DM, Relman DA. The landscape ecology and microbiota of the human nose, mouth, and throat. Cell Host Microbe, 2017, 21(4): 421-432.
4.	艾國平, 粟永萍, 程天民. 腸道粘膜免疫的構成與功能. 免疫學雜志, 2000(S1): 82-84.
5.	王劍, 田志剛. 呼吸道黏膜免疫及其相關疾病研究進展. 中國免疫學雜志, 2015, 31(3): 289-294.
6.	Tulic MK, Piche T, Verhasselt V. Lung-gut cross-talk: evidence, mechanisms and implications for the mucosal inflammatory diseases. Clin Exp Allergy, 2016, 46(4): 519-528.
7.	Ichinohe T, Pang IK, Kumamoto Y, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A, 2011, 108(13): 5354-5359.
8.	Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med, 2014, 20(2): 159-166.
9.	Hilty M, Burke C, Pedro H, et al. Disordered microbial communities in asthmatic airways. PLoS One, 2010, 5(1): e8578.
10.	Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med, 2020, 383(10): 958-968.
11.	Molyneaux PL, Cox MJ, Willis-Owen SA, et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2014, 190(8): 906-913.
12.	Molyneaux PL, Cox MJ, Wells AU, et al. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis. Respir Res, 2017, 18(1): 29.
13.	Han MK, Zhou Y, Murray S, et al. Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. Lancet Respir Med, 2014, 2(7): 548-556.
14.	O'Dwyer DN, Ashley SL, Gurczynski SJ, et al. Lung microbiota contribute to pulmonary inflammation and disease progression in pulmonary fibrosis. Am J Respir Crit Care Med, 2019, 199(9): 1127-1138.
15.	王凱, 殷松樓. 結締組織病相關間質性肺病的診治進展. 中國免疫學雜志, 2016, 32(10): 1562-1565,1569.
16.	Perelas A, Silver RM, Arrossi AV, et al. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med, 2020, 8(3): 304-320.
17.	Andréasson K, Alrawi Z, Persson A, et al. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther, 2016, 18(1): 278.
18.	Fretheim H, Chung BK, Didriksen H, et al. Fecal microbiota transplantation in systemic sclerosis: a double-blind, placebo-controlled randomized pilot trial. PLoS One, 2020, 15(5): e0232739.
19.	Park HJ, Yu D, Hong ST, et al. Bifidobacterium longum RAPO attenuates dermal and pulmonary fibrosis in a mouse model of systemic sclerosis through macrophage modulation and growth of short-chain fatty acid producers. Immune Netw, 2024, 24(6): e41.
20.	Xing Y, Liu Y, Sha S, et al. Multikingdom characterization of gut microbiota in patients with rheumatoid arthritis and rheumatoid arthritis-associated interstitial lung disease. J Med Virol, 2024, 96(7): e29781.
21.	Bae SS, Dong TS, Wang J, et al. Altered gut microbiome in patients with dermatomyositis. ACR Open Rheumatol, 2022, 4(8): 658-670.
22.	Jia XM, Wu BX, Chen BD, et al. Compositional and functional aberrance of the gut microbiota in treatment-na?ve patients with primary Sj?gren's syndrome. J Autoimmun, 2023, 141: 103050.
23.	Chen B, You WJ, Liu XQ, et al. Chronic microaspiration of bile acids induces lung fibrosis through multiple mechanisms in rats. Clin Sci (Lond), 2017, 131(10): 951-963.
24.	Bai L, Bernard K, Tang X, et al. Glutaminolysis epigenetically regulates antiapoptotic gene expression in idiopathic pulmonary fibrosis fibroblasts. Am J Respir Cell Mol Biol, 2019, 60(1): 49-57.
25.	Fang L, Chen H, Kong R, et al. Endogenous tryptophan metabolite 5-methoxytryptophan inhibits pulmonary fibrosis by downregulating the TGF-β/SMAD3 and PI3K/AKT signaling pathway. Life Sci, 2020, 260: 118399.
26.	Li JM, Yang DC, Oldham J, et al. Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis. Mol Ther, 2021, 29(4): 1487-1500.
27.	Gaugg MT, Engler A, Bregy L, et al. Molecular breath analysis supports altered amino acid metabolism in idiopathic pulmonary fibrosis. Respirology, 2019, 24(5): 437-444.
28.	Gorres KL, Raines RT. Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol, 2010, 45(2): 106-124.
29.	Ren Y, Zhao J, Shi Y, et al. Simple determination of L-hydroxyproline in idiopathic pulmonary fibrosis lung tissues of rats using non-extractive high-performance liquid chromatography coupled with fluorescence detection after pre-column derivatization with novel synthetic 9-acetylimidazol-carbazole. J Pharm Biomed Anal, 2017, 142: 1-6.
30.	Gao HG, Fisher PW, Lambi AG, et al. Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse. PLoS One, 2013, 8(8): e71875.
31.	Ji Y, Dai Z, Sun S, et al. Hydroxyproline attenuates dextran sulfate sodium-induced colitis in mice: involvment of the NF-κB signaling and oxidative stress. Mol Nutr Food Res, 2018, 62(21): e1800494.
32.	Bernard K, Logsdon NJ, Benavides GA, et al. Glutaminolysis is required for transforming growth factor-β1-induced myofibroblast differentiation and activation. J Biol Chem, 2018, 293(4): 1218-1228.
33.	Hamanaka RB, O'Leary EM, Witt LJ, et al. Glutamine metabolism is required for collagen protein synthesis in lung fibroblasts. Am J Respir Cell Mol Biol, 2019, 61(5): 597-606.
34.	Fu A, Alvarez-Perez JC, Avizonis D, et al. Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation. Nat Metab, 2020, 2(5): 432-446.
35.	Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol, 2004, 4(8): 583-594.
36.	Kang YP, Lee SB, Lee JM, et al. Metabolic profiling regarding pathogenesis of idiopathic pulmonary fibrosis. J Proteome Res, 2016, 15(5): 1717-1724.
37.	Kitowska K, Zakrzewicz D, K?nigshoff M, et al. Functional role and species-specific contribution of arginases in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2008, 294(1): L34-L45.
38.	Li JM, Yang DC, Oldham J, et al. Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis. Mol Ther, 2021, 29(4): 1487-1500.
39.	B?cker U, Nebe T, Herweck F, et al. Butyrate modulates intestinal epithelial cell-mediated neutrophil migration. Clin Exp Immunol, 2003, 131(1): 53-60.
40.	Thorburn AN, McKenzie CI, Shen S, et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun, 2015, 23;6: 7320.
41.	Trompette A, Gollwitzer ES, Pattaroni C, et al. Dietary fiber confers protection against flu by shaping ly6c- patrolling monocyte hematopoiesis and CD8⁺ T cell metabolism. immunity, 2018, 48(5): 992-1005,e8.
42.	Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and "western-lifestyle" inflammatory diseases. Immunity, 2014, 40(6): 833-842.
43.	Mirkovi? B, Murray MA, Lavelle GM, et al. The role of short-chain fatty acids, produced by anaerobic bacteria, in the cystic fibrosis airway. Am J Respir Crit Care Med, 2015, 192(11): 1314-1324.
44.	Richards LB, Li M, Folkerts G, et al. Butyrate and propionate restore the cytokine and house dust mite compromised barrier function of human bronchial airway epithelial cells. Int J Mol Sci, 2020, 22(1): 65.
45.	Schulz-Kuhnt A, Greif V, Hildner K, et al. ILC2 Lung-homing in cystic fibrosis patients: functional involvement of CCR6 and impact on respiratory failure. Front Immunol, 2020, 11: 691.
46.	Sepahi A, Liu Q, Friesen L, et al. Dietary fiber metabolites regulate innate lymphoid cell responses. Mucosal Immunol, 2021, 14(2): 317-330.
47.	Noguchi S, Eitoku M, Moriya S, et al. Regulation of gene expression by sodium valproate in epithelial-to-mesenchymal transition. Lung, 2015, 193(5): 691-700.
48.	朱平, 邢順鵬, 徐僑翌, 等. 正丁酸抑制脂多糖誘導肺纖維化的作用及機制. 中華危重病急救醫學, 2016, 28(1): 8-14.
49.	Park HJ, Jeong OY, Chun SH, et al. Butyrate improves skin/lung fibrosis and intestinal dysbiosis in bleomycin-induced mouse models. Int J Mol Sci, 2021, 22(5): 2765.
50.	Lee HY, Nam S, Kim MJ, et al. Butyrate prevents TGF-β1-induced alveolar myofibroblast differentiation and modulates energy metabolism. Metabolites, 2021, 11(5): 258.
51.	Chen B, Cai HR, Xue S, et al. Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways. Respirology, 2016, 21(6): 1075-1080.
52.	Chiang JY. Bile acid metabolism and signaling. Compr Physiol, 2013, 3(3): 1191-212.
53.	Zhang L, Li T, Yu D, et al. FXR protects lung from lipopolysaccharide-induced acute injury. Mol Endocrinol, 2012, 26(1): 27-36.
54.	Savarino E, Carbone R, Marabotto E, et al. Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J, 2013, 42(5): 1322-1331.

1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med, 2013, 188(6): 733-748.
2. 劉聲, 劉曉燕, 李立華, 等. “肺與大腸相表里”的組織細胞學基礎研究. 中華中醫藥雜志, 2012, 27(4): 1167-1170.
3. Proctor DM, Relman DA. The landscape ecology and microbiota of the human nose, mouth, and throat. Cell Host Microbe, 2017, 21(4): 421-432.
4. 艾國平, 粟永萍, 程天民. 腸道粘膜免疫的構成與功能. 免疫學雜志, 2000(S1): 82-84.
5. 王劍, 田志剛. 呼吸道黏膜免疫及其相關疾病研究進展. 中國免疫學雜志, 2015, 31(3): 289-294.
6. Tulic MK, Piche T, Verhasselt V. Lung-gut cross-talk: evidence, mechanisms and implications for the mucosal inflammatory diseases. Clin Exp Allergy, 2016, 46(4): 519-528.
7. Ichinohe T, Pang IK, Kumamoto Y, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A, 2011, 108(13): 5354-5359.
8. Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med, 2014, 20(2): 159-166.
9. Hilty M, Burke C, Pedro H, et al. Disordered microbial communities in asthmatic airways. PLoS One, 2010, 5(1): e8578.
10. Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med, 2020, 383(10): 958-968.
11. Molyneaux PL, Cox MJ, Willis-Owen SA, et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2014, 190(8): 906-913.
12. Molyneaux PL, Cox MJ, Wells AU, et al. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis. Respir Res, 2017, 18(1): 29.
13. Han MK, Zhou Y, Murray S, et al. Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. Lancet Respir Med, 2014, 2(7): 548-556.
14. O'Dwyer DN, Ashley SL, Gurczynski SJ, et al. Lung microbiota contribute to pulmonary inflammation and disease progression in pulmonary fibrosis. Am J Respir Crit Care Med, 2019, 199(9): 1127-1138.
15. 王凱, 殷松樓. 結締組織病相關間質性肺病的診治進展. 中國免疫學雜志, 2016, 32(10): 1562-1565,1569.
16. Perelas A, Silver RM, Arrossi AV, et al. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med, 2020, 8(3): 304-320.
17. Andréasson K, Alrawi Z, Persson A, et al. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther, 2016, 18(1): 278.
18. Fretheim H, Chung BK, Didriksen H, et al. Fecal microbiota transplantation in systemic sclerosis: a double-blind, placebo-controlled randomized pilot trial. PLoS One, 2020, 15(5): e0232739.
19. Park HJ, Yu D, Hong ST, et al. Bifidobacterium longum RAPO attenuates dermal and pulmonary fibrosis in a mouse model of systemic sclerosis through macrophage modulation and growth of short-chain fatty acid producers. Immune Netw, 2024, 24(6): e41.
20. Xing Y, Liu Y, Sha S, et al. Multikingdom characterization of gut microbiota in patients with rheumatoid arthritis and rheumatoid arthritis-associated interstitial lung disease. J Med Virol, 2024, 96(7): e29781.
21. Bae SS, Dong TS, Wang J, et al. Altered gut microbiome in patients with dermatomyositis. ACR Open Rheumatol, 2022, 4(8): 658-670.
22. Jia XM, Wu BX, Chen BD, et al. Compositional and functional aberrance of the gut microbiota in treatment-na?ve patients with primary Sj?gren's syndrome. J Autoimmun, 2023, 141: 103050.
23. Chen B, You WJ, Liu XQ, et al. Chronic microaspiration of bile acids induces lung fibrosis through multiple mechanisms in rats. Clin Sci (Lond), 2017, 131(10): 951-963.
24. Bai L, Bernard K, Tang X, et al. Glutaminolysis epigenetically regulates antiapoptotic gene expression in idiopathic pulmonary fibrosis fibroblasts. Am J Respir Cell Mol Biol, 2019, 60(1): 49-57.
25. Fang L, Chen H, Kong R, et al. Endogenous tryptophan metabolite 5-methoxytryptophan inhibits pulmonary fibrosis by downregulating the TGF-β/SMAD3 and PI3K/AKT signaling pathway. Life Sci, 2020, 260: 118399.
26. Li JM, Yang DC, Oldham J, et al. Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis. Mol Ther, 2021, 29(4): 1487-1500.
27. Gaugg MT, Engler A, Bregy L, et al. Molecular breath analysis supports altered amino acid metabolism in idiopathic pulmonary fibrosis. Respirology, 2019, 24(5): 437-444.
28. Gorres KL, Raines RT. Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol, 2010, 45(2): 106-124.
29. Ren Y, Zhao J, Shi Y, et al. Simple determination of L-hydroxyproline in idiopathic pulmonary fibrosis lung tissues of rats using non-extractive high-performance liquid chromatography coupled with fluorescence detection after pre-column derivatization with novel synthetic 9-acetylimidazol-carbazole. J Pharm Biomed Anal, 2017, 142: 1-6.
30. Gao HG, Fisher PW, Lambi AG, et al. Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse. PLoS One, 2013, 8(8): e71875.
31. Ji Y, Dai Z, Sun S, et al. Hydroxyproline attenuates dextran sulfate sodium-induced colitis in mice: involvment of the NF-κB signaling and oxidative stress. Mol Nutr Food Res, 2018, 62(21): e1800494.
32. Bernard K, Logsdon NJ, Benavides GA, et al. Glutaminolysis is required for transforming growth factor-β1-induced myofibroblast differentiation and activation. J Biol Chem, 2018, 293(4): 1218-1228.
33. Hamanaka RB, O'Leary EM, Witt LJ, et al. Glutamine metabolism is required for collagen protein synthesis in lung fibroblasts. Am J Respir Cell Mol Biol, 2019, 61(5): 597-606.
34. Fu A, Alvarez-Perez JC, Avizonis D, et al. Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation. Nat Metab, 2020, 2(5): 432-446.
35. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol, 2004, 4(8): 583-594.
36. Kang YP, Lee SB, Lee JM, et al. Metabolic profiling regarding pathogenesis of idiopathic pulmonary fibrosis. J Proteome Res, 2016, 15(5): 1717-1724.
37. Kitowska K, Zakrzewicz D, K?nigshoff M, et al. Functional role and species-specific contribution of arginases in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2008, 294(1): L34-L45.
38. Li JM, Yang DC, Oldham J, et al. Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis. Mol Ther, 2021, 29(4): 1487-1500.
39. B?cker U, Nebe T, Herweck F, et al. Butyrate modulates intestinal epithelial cell-mediated neutrophil migration. Clin Exp Immunol, 2003, 131(1): 53-60.
40. Thorburn AN, McKenzie CI, Shen S, et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun, 2015, 23;6: 7320.
41. Trompette A, Gollwitzer ES, Pattaroni C, et al. Dietary fiber confers protection against flu by shaping ly6c- patrolling monocyte hematopoiesis and CD8⁺ T cell metabolism. immunity, 2018, 48(5): 992-1005,e8.
42. Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and "western-lifestyle" inflammatory diseases. Immunity, 2014, 40(6): 833-842.
43. Mirkovi? B, Murray MA, Lavelle GM, et al. The role of short-chain fatty acids, produced by anaerobic bacteria, in the cystic fibrosis airway. Am J Respir Crit Care Med, 2015, 192(11): 1314-1324.
44. Richards LB, Li M, Folkerts G, et al. Butyrate and propionate restore the cytokine and house dust mite compromised barrier function of human bronchial airway epithelial cells. Int J Mol Sci, 2020, 22(1): 65.
45. Schulz-Kuhnt A, Greif V, Hildner K, et al. ILC2 Lung-homing in cystic fibrosis patients: functional involvement of CCR6 and impact on respiratory failure. Front Immunol, 2020, 11: 691.
46. Sepahi A, Liu Q, Friesen L, et al. Dietary fiber metabolites regulate innate lymphoid cell responses. Mucosal Immunol, 2021, 14(2): 317-330.
47. Noguchi S, Eitoku M, Moriya S, et al. Regulation of gene expression by sodium valproate in epithelial-to-mesenchymal transition. Lung, 2015, 193(5): 691-700.
48. 朱平, 邢順鵬, 徐僑翌, 等. 正丁酸抑制脂多糖誘導肺纖維化的作用及機制. 中華危重病急救醫學, 2016, 28(1): 8-14.
49. Park HJ, Jeong OY, Chun SH, et al. Butyrate improves skin/lung fibrosis and intestinal dysbiosis in bleomycin-induced mouse models. Int J Mol Sci, 2021, 22(5): 2765.
50. Lee HY, Nam S, Kim MJ, et al. Butyrate prevents TGF-β1-induced alveolar myofibroblast differentiation and modulates energy metabolism. Metabolites, 2021, 11(5): 258.
51. Chen B, Cai HR, Xue S, et al. Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways. Respirology, 2016, 21(6): 1075-1080.
52. Chiang JY. Bile acid metabolism and signaling. Compr Physiol, 2013, 3(3): 1191-212.
53. Zhang L, Li T, Yu D, et al. FXR protects lung from lipopolysaccharide-induced acute injury. Mol Endocrinol, 2012, 26(1): 27-36.
54. Savarino E, Carbone R, Marabotto E, et al. Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J, 2013, 42(5): 1322-1331.

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