肥胖型哮喘发病机制的研究进展
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摘要
肥胖和支气管哮喘是全球性公共健康问题。近年来,肥胖和支气管哮喘的发病率不断升高,且两者存在相关性,肥胖是支气管哮喘的主要危险因素之一,影响支气管哮喘病情的严重程度。肥胖型哮喘作为一种哮喘的新表型,在临床治疗中存在对激素不敏感、控制困难等问题。支气管哮喘的发病与机体免疫失衡相关,由Th2细胞及其细胞因子驱动嗜酸粒细胞浸润引起气道炎症是支气管哮喘的主要发病机制,不同于该经典途径,肥胖型哮喘在发病中主要涉及非Th2型炎症,但具体机制尚不明确。
Obesity and asthma are global public health problems. In recent years,the incidences of obesity and asthma have been increasing,and there is a correlation between them. Obesity is one of the main risk factors of asthma,affecting the severity of asthma. As a new phenotype of asthma,obesity asthma is insensitive to hormones and difficult to control in the clinical treatment. The pathogenesis of asthma is related to immune imbalance. Airway inflammation caused by eosinophil infiltration driven by Th2 cells and their cytokines is the main pathogenesis of asthma. Unlike the classical pathway,obesity asthma mainly involves non-Th2 inflammation,while the specific mechanism is still unclear.
Obesity and asthma are global public health problems. In recent years,the incidences of obesity and asthma have been increasing,and there is a correlation between them. Obesity is one of the main risk factors of asthma,affecting the severity of asthma. As a new phenotype of asthma,obesity asthma is insensitive to hormones and difficult to control in the clinical treatment. The pathogenesis of asthma is related to immune imbalance. Airway inflammation caused by eosinophil infiltration driven by Th2 cells and their cytokines is the main pathogenesis of asthma. Unlike the classical pathway,obesity asthma mainly involves non-Th2 inflammation,while the specific mechanism is still unclear.
引文
[1] Barros R,Moreiras P,Padrao P,et al. Obesity increases the prevalence and the incidence of asthma and worsens asthma severity[J].Clin Nutr,2017,36(4):10684074.
[2] Beuther DA,Sutherland ER. Overweight,obesity,and incident asthma:A meta-analysis of prospective epidemiologic studies[J].Am J Respir Crit Care Med,2007,175(7):661-666.
[3] Boulet LP,FitzGerald JM,Reddel HK. The revised 2014 GINA strategy report:Opportunities for change[J]. Curr Opin Pulm Med,2015,21(1):1-7.
[4] Sugerman H,Windsor A,Bessos M,et al. Intra-abdominal pressure,sagittal abdominal diameter and obesity comorbidity[J].J Intern Med, 1997,241(1):71-79.
[5] Jones RL,Nzekwu MM. The effects of body mass index on lung volumes[J]. Chest,2006,130(3):827-833.
[6] Biring, MS, Lewis MI, Liu JT,et al. Pulmonary physiologic changes of morbid obesity[J]. Am J Med Sci, 1999. 318(5):293-297.
[7] Jat KR,Kabra SK. Obesity and pulmonary function tests[J].Indian J Pediatr,2015,82(12):1089-1090.
[8] Zerah F,Harf A,Perlemuter L,et al. Effects of obesity on respiratory resistance[J]. Chest, 1993,103(5):1470-4476.
[9] Sin DD, Jones RL, Man SF. Obesity is a risk factor for dyspnea but not for airflow obstruction[J]. Arch Intern Med,2002,162(13):1477-1481.
[10] Fredberg JJ,Inouye DS,Mijailovich SM,et al. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm[J]. Am J Respir Crit Care Med,1999,159(3):959-967.
[11] King GG, Brown NJ, Diba C, et al. The effects of body weight on airway calibre[J]. Eur Respir J,2005,25(5):896-901.
[12] Wens veen FM,Valenti S,estan M,et al. The'Big Bang'in obese fat:Events initiating obesity-induced adipose tissue inflammation[J].Eur J Immunol,2015,45(9):2446-2456.
[13] Jesus JPV, Lima-Matos AS, Almeida PC A, et al. Obesity and asthma:Clinical and laboratory characterization of a common combination[J].J Bras Pneumol,2018,44(3):207-212.
[14] Bedoret D,Wallemacq H,Marichal T,et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice[J].J Clin Invest,2009,119(12):3723-3738.
[15] Varol C,Mildner A,Jung S. Macrophages:Development and tissuespecialization[J]. Annu Rev Immunol,2015,33:643-675.
[16] Oliveira AG,Araujo TG,Carvalho BM,et al. Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet-induced obese rats[J]. Obesity(Silver Spring),2013,21(12):2545-2556.
[17] Hussell T, Bell TJ. Alveolar macrophages:Plasticity in a tissuespecific context[J]. Nat rev Immunol, 2014,14(2):81-93.
[18] Periyalil HA, Wood LG, Wright TA,et al. Obese asthmatics are characterized by altered adipose tissue macrophage activation[J].Clin Exp Allergy,2018,48(6):641-649.
[19] Tashiro H,Takahashi K,Sadamatsu H,et al. Saturated fatty acid increases lung macrophages and augments house dust miteinduced airway inflammation in mice fed with high fat diet[J].Inflammation,2017,40(3):1072-1086.
[20] Lumeng CN, Deyoung SM,Bodzin JL,et al. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity[J]. Diabetes,2007,56(1):16-23.
[21] Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction:Inflammation, fibrosis, and impaired angiogenesis[J].J Clin Invest,2017,127(1):74-82.
[22] Chehimi M, Vidal H, Eljaafari A. Pathogenic Role of IL-17-Producing Immune Cells in Obesity,and Related Inflammatory Diseases[J]. J Clin Med,2017,6(7). pii:E68.
[23] Nguyen DV, Linderholm A,Haczku A, et al. Glucagon-like peptide 1:A potential anti-inflammatory pathway in obesity-related asthma[J]. Pharmacol Ther,2017,180:139-143.
[24] Apostolopoulos V,de Courten MP, Stojanovska L,et al. The complex immunological and inflammatory network of adipose tissue in obesity[J]. Mol Nutr Food Res,2016,60(1):43-57.
[25] Umetsu DT. Mechanisms by which obesity impacts upon asthma[J]. Thorax,2017,72(2):174-177.
[26] Kim HY,Lee HJ,Chang YJ,et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity[J]. Nat Med,2014,20(1):54-61.
[27] Halim TY,Steer CA,Math L,et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation[J]. Immunity,2014,40(3):425-435.
[28] Zhou Y, Yu X,Chen H,et al. Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages[J]. Cell Metab,2015,22(6):1045-4058.
[29] Hubler MJ, Kennedy AJ. Role of lipids in the metabolism and activation of immune cells[J]. J Nutr Biochem,2016, 34:1-7.
[30] McGown C,Birerdinc A, Younossi ZM. Adipose tissue as an endocrine organ[J]. Clin Liver Dis,2014,18(1):41-58.
[31] Huang F, Del-Rio-Navarro BE,Torres-Alcantara S,et al. Adipokines, asymmetrical dimethylarginine,and pulmonary function in adolescents with asthma and obesity[J]. J Asthma,2017,54(2):153-161.
[32] Eising JB, Uiterwaal CS,Evelein AM,et al. Relationship betweenleptin and lung function in young healthy children[J]. Eur Respir J,2014,43(4):1189-4192.
[33] Sideleva O, Suratt BT, Black KE, et al. Obesity and asthma:An inflammatory disease of adipose tissue not the airway[J]. Am J Respir Crit Care Med,2012,186(7):598-605.
[34] Mai XM,Chen Y,Krewski D. Does leptin play a role in obesityasthma relationship[J]. Pediatr Allergy Immunol,2009,20(3):207-212.
[35] Kubo M. Innate and adaptive type 2 immunity in lung allergic inflammation[J]. Immunol Rev,2017,278(1):162-172.
[36] Scherer PE, Williams S,Fogliano M,et al. A novel serum protein similar to C1q, produced exclusively in adipocytes[J]. J Biol Chem,1995,270(45):26746-26749.
[37] Sood A, Shore SA. Adiponectin, Leptin, and Resistin in Asthma:Basic Mechanisms through Population Studies[J]. J Allergy(Cairo),2013,2013:785835.
[38] Williams AS, Kasahara DI, Verbout NG, el al. Role of the adiponectin binding protein, T-eadherin(Cdh13), in allergic airways responses in mice[J]. PLoS One, 2012,7(7):e41088.
[39] Calixto MC, Lintomen L, Schenka A, et al. Obesity enhances eosinophilic inflammation in a murine model of allergic asthma[J]. Br J Pharmacol,2010,159(3):617-625.
[40] Medoff BD, Okamoto Y, Leyton P,et al. Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling[J]. Am J Respir Cell Mol Biol, 2009, 41(4):397-406.
[41] Holguin F, Rojas M, Brown LA,et al. Airway and plasma leptin and adiponectin in lean and obese asthmatics and controls[J].J Asthma,2011,48(3):217-223.
[42] Aydin M,Koca C,Ozol D,et al. Interaction of metabolic syndrome with asthma in postmenopausal women:Role of adipokines[J].Inflammation,2013,36(6):1232-1238.
[43] Sood A, Qualls C, Schuyler M, et al. Low serum adiponectin predicts future risk for asthma in women[J]. Am J Respir Crit Care Med,2012,186(1):41-47.
[44] Rojas-Dotor S, Segura-Mendez NH, Miyagui-Namikawa K,et al.Expression of resistin, CXCR3, IP-10, CCR5 and MIP-1alpha in obese patients with different severity of asthma[J]. Biol Res,2013,46(1):13-20.
[45] Steppan CM, Bailey ST,Bhat S,et al. The hormone resistin links obesity to diabetes[J]. Nature,2001,409(6818):307-312.
[46] Ballantyne D, Scott H, MacDonald-Wicks L, et al. Resislin is a predictor of asthma risk and resistin:Adiponectin ratio is a negative predictor of lung function in asthma[J]. Clin Exp Allergy,2016,46(8):1056 4 065.
[47] Al Mutairi SS, Mojiminiyi OA, Shihab-Eldeen A, et al. Putative roles of circulating resistin in patients with asthma, COPD and cigarette smokers[J]. Dis Markers,2011,31(1):1-7.
[48] Muc M, Todo-Bom A, Mota-Pinto A,et al. Leptin and resistin in overweight patients with and without asthma[J]. Allergol Immunopathol(Madr),2014,42(5):415-421.
[49] Murphy A,Tantisira KG, Soto-Quiros ME,et al. PRKCA:A positional candidate gene for body mass index and asthma[J]. Am J Hum Genet,2009,85(1):87-96.
[50] Melen E, Himes BE, Brehm JM, et al. Analyses of shared genetic factors between asthma and obesity in children[J]. J Allergy Clin Immunol, 2010,126(3):631-637.
[51] Kuo NW,Tung KY,Tsai CH,et al.β3-Adrenergic receptor gene modifies the association between childhood obesity and asthma[J].J Allergy Clin Immunol,2014,134(3):731-733.
[52] Weiss ST. Obesity:Insight into the origins of asthma[J]. Nat Immunol,2005,6(6):537-539.
[53] Ahangari F,Sood A,Ma B,el al. Chitinase 3-like-1 regulates both visceral fat accumulation and asthma-like Th2 inflammation[J].Am J Respir Crit Care Med,2015,191(7):746-757.
[54] Waldecker M, Kautenburger T, Daumann H, et al. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon[J]. J Nutr Biochem,2008,19(9):587-593.
[55] Chatterjee TK, Basford JE, Knoll E,et al. HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding[J]. Diabetes,2014,63(1):176-187.
[56] Bhavsar P, Ahmad T, Adcock IM. The role of histone deacetylases in asthma and allergic diseases[J]. J Allergy Clin Immunol,2008,121(3):580-584.
[57] Thorburn AN, McKenzie CI,Shen S,et al. Evidence that asthma is a developmental origin disease influenced by maternal diet andbacterial metabolites[J]. Nat Commun,2015,6:7320.
[58] Tuomi K,Logomarsino JV. Bacterial Lipopolysaccharide,Lipopolysaccharide-Binding Protein, and Other Inflammatory Markers in Obesity and After Bariatric Surgery[J]. Metab Syndr Relat Disord,2016,14(6):279-288.
[59] Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis[J]. Nat Med,2014,20(2):159466.
[60] Holguin F,Comhair SA,Hazen SL,et al. An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype[J]. Am J Respir Crit Care Med,2013,187(2):153459.
[61] Scott HA, Gibson PG, Garg ML, et al. Dietary restriction and exercise improve airway inflammation and clinical outcomes in overweight and obese asthma:A randomized trial[J]. Clin Exp Allergy,2013,43(1):36-49.
[62] Mehari A,Afreen S,Ngwa J,et al. Obesity and Pulmonary Function in African Americans[J].PLoS One,2015,10(10):e0140610.
[63] Litonjua AA,Carey VJ,Laranjo N,et al. Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years:The VDAART Randomized Clinical Trial[J].JAMA,2016,315(4):362-370.
[64] Zhang JH,Chen YP,Yang X,et al. Vitamin D3 levels and NLRP3expression inmurine models of obese asthma:Association with asthma outcomes[J]. Braz J Med Biol Res,2017,51(1):e6841.
[2] Beuther DA,Sutherland ER. Overweight,obesity,and incident asthma:A meta-analysis of prospective epidemiologic studies[J].Am J Respir Crit Care Med,2007,175(7):661-666.
[3] Boulet LP,FitzGerald JM,Reddel HK. The revised 2014 GINA strategy report:Opportunities for change[J]. Curr Opin Pulm Med,2015,21(1):1-7.
[4] Sugerman H,Windsor A,Bessos M,et al. Intra-abdominal pressure,sagittal abdominal diameter and obesity comorbidity[J].J Intern Med, 1997,241(1):71-79.
[5] Jones RL,Nzekwu MM. The effects of body mass index on lung volumes[J]. Chest,2006,130(3):827-833.
[6] Biring, MS, Lewis MI, Liu JT,et al. Pulmonary physiologic changes of morbid obesity[J]. Am J Med Sci, 1999. 318(5):293-297.
[7] Jat KR,Kabra SK. Obesity and pulmonary function tests[J].Indian J Pediatr,2015,82(12):1089-1090.
[8] Zerah F,Harf A,Perlemuter L,et al. Effects of obesity on respiratory resistance[J]. Chest, 1993,103(5):1470-4476.
[9] Sin DD, Jones RL, Man SF. Obesity is a risk factor for dyspnea but not for airflow obstruction[J]. Arch Intern Med,2002,162(13):1477-1481.
[10] Fredberg JJ,Inouye DS,Mijailovich SM,et al. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm[J]. Am J Respir Crit Care Med,1999,159(3):959-967.
[11] King GG, Brown NJ, Diba C, et al. The effects of body weight on airway calibre[J]. Eur Respir J,2005,25(5):896-901.
[12] Wens veen FM,Valenti S,estan M,et al. The'Big Bang'in obese fat:Events initiating obesity-induced adipose tissue inflammation[J].Eur J Immunol,2015,45(9):2446-2456.
[13] Jesus JPV, Lima-Matos AS, Almeida PC A, et al. Obesity and asthma:Clinical and laboratory characterization of a common combination[J].J Bras Pneumol,2018,44(3):207-212.
[14] Bedoret D,Wallemacq H,Marichal T,et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice[J].J Clin Invest,2009,119(12):3723-3738.
[15] Varol C,Mildner A,Jung S. Macrophages:Development and tissuespecialization[J]. Annu Rev Immunol,2015,33:643-675.
[16] Oliveira AG,Araujo TG,Carvalho BM,et al. Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet-induced obese rats[J]. Obesity(Silver Spring),2013,21(12):2545-2556.
[17] Hussell T, Bell TJ. Alveolar macrophages:Plasticity in a tissuespecific context[J]. Nat rev Immunol, 2014,14(2):81-93.
[18] Periyalil HA, Wood LG, Wright TA,et al. Obese asthmatics are characterized by altered adipose tissue macrophage activation[J].Clin Exp Allergy,2018,48(6):641-649.
[19] Tashiro H,Takahashi K,Sadamatsu H,et al. Saturated fatty acid increases lung macrophages and augments house dust miteinduced airway inflammation in mice fed with high fat diet[J].Inflammation,2017,40(3):1072-1086.
[20] Lumeng CN, Deyoung SM,Bodzin JL,et al. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity[J]. Diabetes,2007,56(1):16-23.
[21] Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction:Inflammation, fibrosis, and impaired angiogenesis[J].J Clin Invest,2017,127(1):74-82.
[22] Chehimi M, Vidal H, Eljaafari A. Pathogenic Role of IL-17-Producing Immune Cells in Obesity,and Related Inflammatory Diseases[J]. J Clin Med,2017,6(7). pii:E68.
[23] Nguyen DV, Linderholm A,Haczku A, et al. Glucagon-like peptide 1:A potential anti-inflammatory pathway in obesity-related asthma[J]. Pharmacol Ther,2017,180:139-143.
[24] Apostolopoulos V,de Courten MP, Stojanovska L,et al. The complex immunological and inflammatory network of adipose tissue in obesity[J]. Mol Nutr Food Res,2016,60(1):43-57.
[25] Umetsu DT. Mechanisms by which obesity impacts upon asthma[J]. Thorax,2017,72(2):174-177.
[26] Kim HY,Lee HJ,Chang YJ,et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity[J]. Nat Med,2014,20(1):54-61.
[27] Halim TY,Steer CA,Math L,et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation[J]. Immunity,2014,40(3):425-435.
[28] Zhou Y, Yu X,Chen H,et al. Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages[J]. Cell Metab,2015,22(6):1045-4058.
[29] Hubler MJ, Kennedy AJ. Role of lipids in the metabolism and activation of immune cells[J]. J Nutr Biochem,2016, 34:1-7.
[30] McGown C,Birerdinc A, Younossi ZM. Adipose tissue as an endocrine organ[J]. Clin Liver Dis,2014,18(1):41-58.
[31] Huang F, Del-Rio-Navarro BE,Torres-Alcantara S,et al. Adipokines, asymmetrical dimethylarginine,and pulmonary function in adolescents with asthma and obesity[J]. J Asthma,2017,54(2):153-161.
[32] Eising JB, Uiterwaal CS,Evelein AM,et al. Relationship betweenleptin and lung function in young healthy children[J]. Eur Respir J,2014,43(4):1189-4192.
[33] Sideleva O, Suratt BT, Black KE, et al. Obesity and asthma:An inflammatory disease of adipose tissue not the airway[J]. Am J Respir Crit Care Med,2012,186(7):598-605.
[34] Mai XM,Chen Y,Krewski D. Does leptin play a role in obesityasthma relationship[J]. Pediatr Allergy Immunol,2009,20(3):207-212.
[35] Kubo M. Innate and adaptive type 2 immunity in lung allergic inflammation[J]. Immunol Rev,2017,278(1):162-172.
[36] Scherer PE, Williams S,Fogliano M,et al. A novel serum protein similar to C1q, produced exclusively in adipocytes[J]. J Biol Chem,1995,270(45):26746-26749.
[37] Sood A, Shore SA. Adiponectin, Leptin, and Resistin in Asthma:Basic Mechanisms through Population Studies[J]. J Allergy(Cairo),2013,2013:785835.
[38] Williams AS, Kasahara DI, Verbout NG, el al. Role of the adiponectin binding protein, T-eadherin(Cdh13), in allergic airways responses in mice[J]. PLoS One, 2012,7(7):e41088.
[39] Calixto MC, Lintomen L, Schenka A, et al. Obesity enhances eosinophilic inflammation in a murine model of allergic asthma[J]. Br J Pharmacol,2010,159(3):617-625.
[40] Medoff BD, Okamoto Y, Leyton P,et al. Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling[J]. Am J Respir Cell Mol Biol, 2009, 41(4):397-406.
[41] Holguin F, Rojas M, Brown LA,et al. Airway and plasma leptin and adiponectin in lean and obese asthmatics and controls[J].J Asthma,2011,48(3):217-223.
[42] Aydin M,Koca C,Ozol D,et al. Interaction of metabolic syndrome with asthma in postmenopausal women:Role of adipokines[J].Inflammation,2013,36(6):1232-1238.
[43] Sood A, Qualls C, Schuyler M, et al. Low serum adiponectin predicts future risk for asthma in women[J]. Am J Respir Crit Care Med,2012,186(1):41-47.
[44] Rojas-Dotor S, Segura-Mendez NH, Miyagui-Namikawa K,et al.Expression of resistin, CXCR3, IP-10, CCR5 and MIP-1alpha in obese patients with different severity of asthma[J]. Biol Res,2013,46(1):13-20.
[45] Steppan CM, Bailey ST,Bhat S,et al. The hormone resistin links obesity to diabetes[J]. Nature,2001,409(6818):307-312.
[46] Ballantyne D, Scott H, MacDonald-Wicks L, et al. Resislin is a predictor of asthma risk and resistin:Adiponectin ratio is a negative predictor of lung function in asthma[J]. Clin Exp Allergy,2016,46(8):1056 4 065.
[47] Al Mutairi SS, Mojiminiyi OA, Shihab-Eldeen A, et al. Putative roles of circulating resistin in patients with asthma, COPD and cigarette smokers[J]. Dis Markers,2011,31(1):1-7.
[48] Muc M, Todo-Bom A, Mota-Pinto A,et al. Leptin and resistin in overweight patients with and without asthma[J]. Allergol Immunopathol(Madr),2014,42(5):415-421.
[49] Murphy A,Tantisira KG, Soto-Quiros ME,et al. PRKCA:A positional candidate gene for body mass index and asthma[J]. Am J Hum Genet,2009,85(1):87-96.
[50] Melen E, Himes BE, Brehm JM, et al. Analyses of shared genetic factors between asthma and obesity in children[J]. J Allergy Clin Immunol, 2010,126(3):631-637.
[51] Kuo NW,Tung KY,Tsai CH,et al.β3-Adrenergic receptor gene modifies the association between childhood obesity and asthma[J].J Allergy Clin Immunol,2014,134(3):731-733.
[52] Weiss ST. Obesity:Insight into the origins of asthma[J]. Nat Immunol,2005,6(6):537-539.
[53] Ahangari F,Sood A,Ma B,el al. Chitinase 3-like-1 regulates both visceral fat accumulation and asthma-like Th2 inflammation[J].Am J Respir Crit Care Med,2015,191(7):746-757.
[54] Waldecker M, Kautenburger T, Daumann H, et al. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon[J]. J Nutr Biochem,2008,19(9):587-593.
[55] Chatterjee TK, Basford JE, Knoll E,et al. HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding[J]. Diabetes,2014,63(1):176-187.
[56] Bhavsar P, Ahmad T, Adcock IM. The role of histone deacetylases in asthma and allergic diseases[J]. J Allergy Clin Immunol,2008,121(3):580-584.
[57] Thorburn AN, McKenzie CI,Shen S,et al. Evidence that asthma is a developmental origin disease influenced by maternal diet andbacterial metabolites[J]. Nat Commun,2015,6:7320.
[58] Tuomi K,Logomarsino JV. Bacterial Lipopolysaccharide,Lipopolysaccharide-Binding Protein, and Other Inflammatory Markers in Obesity and After Bariatric Surgery[J]. Metab Syndr Relat Disord,2016,14(6):279-288.
[59] Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis[J]. Nat Med,2014,20(2):159466.
[60] Holguin F,Comhair SA,Hazen SL,et al. An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype[J]. Am J Respir Crit Care Med,2013,187(2):153459.
[61] Scott HA, Gibson PG, Garg ML, et al. Dietary restriction and exercise improve airway inflammation and clinical outcomes in overweight and obese asthma:A randomized trial[J]. Clin Exp Allergy,2013,43(1):36-49.
[62] Mehari A,Afreen S,Ngwa J,et al. Obesity and Pulmonary Function in African Americans[J].PLoS One,2015,10(10):e0140610.
[63] Litonjua AA,Carey VJ,Laranjo N,et al. Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years:The VDAART Randomized Clinical Trial[J].JAMA,2016,315(4):362-370.
[64] Zhang JH,Chen YP,Yang X,et al. Vitamin D3 levels and NLRP3expression inmurine models of obese asthma:Association with asthma outcomes[J]. Braz J Med Biol Res,2017,51(1):e6841.